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Lupin Peptides Lower Low-Density Lipoprotein (LDL) Cholesterol through an Up-regulation of the LDL Receptor/Sterol Regulatory Element Binding Protein 2 (SREBP2) Pathway at HepG2 Cell Line

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† Department of Pharmaceutical Sciences, University of Milan, Milan, Italy
§ HPF-Nutraceutics SRL, Milan, Italy
# Department of Chemistry, Materials and Chemical Engineering “Giulio Natta”, Polytechnic of Milan, Milan, Italy
*(A.A.) Phone: +39 02 503 19372. Fax: +39 02 503 19343. E-mail: [email protected].
Cite this: J. Agric. Food Chem. 2014, 62, 29, 7151-7159
Publication Date (Web):June 27, 2014
https://doi.org/10.1021/jf500795b
Copyright © 2014 American Chemical Society
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Abstract

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Previous experiments in suitable animal models and in mild hypercholesterolemic individuals have shown that the consumption of lupin proteins may be useful for controlling total and low-density lipoprotein (LDL) cholesterol levels. With the objective of providing evidence that peptides deriving from the hydrolysis of lupin proteins may be responsible of the observed activities and for investigating the mechanism of action, HepG2 cells were treated with lupin peptides obtained by either pepsin (P) or trypsin (T) hydrolysis, and molecular and functional investigations were performed on the LDL receptor/SREBP2 pathway. For the first time, this paper provides experimental evidence that lupin peptides are able to interfere with the HMGCoAR activity, up-regulating the LDL receptor (136 and 84% vs the control for P and T peptides, respectively, at 1 mg/mL) and SREBP2 proteins (148 and 73% vs the control for P and T peptides, respectively, at 1 mg/mL) via the activation of PI3K/Akt/GSK3β pathways and increasing the LDL uptake at HepG2 cell line (40 and 50% vs the control for P and T peptides, respectively, at 1 mg/mL). These results may be useful in explaining the activities observed in vivo in animals and humans treated with lupin protein.

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Introduction

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Lupin is a protein-rich grain legume, which has been domesticated for a long time and cultivated on different continents, for either animal or human nutrition. This generic term indicates four species: Lupinus albus (white lupin), Lupinus angustifolius (narrow-leaf lupin), Lupinus luteus (yellow lupin), and Lupinus mutabilis (Andean lupin). The seeds of these plants have some favorable features; in particular, the protein percentage is comparable to that of soybean,(1) and the content of indispensable amino acids is only slightly inferior. Lupin is also a good source of minerals,(1) unsaturated fatty acids,(2) vitamins,(1) and tocopherols,(3) whereas the concentrations of isoflavones(4) and other antinutrients are low.(5) Experiments in rats have shown that the nutritional quality of L. albus protein is satisfactory.(6) Old species contained undesirable quinolizidine alkaloids that in modern cultivars were decreased to very low amounts,(7) permitting the direct use of these seeds for different applications.(8, 9)
Besides these important nutritional features, lupin seed may also provide some health benefits, particularly in the area of hypertension(10) and dyslipidemia prevention. Some investigations in a rat model of hypercholesterolemia have demonstrated that diets containing either L. albus protein(11, 12) or L. angustifolius protein(13, 14) may significantly reduce both total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels versus control diets containing casein. The cholesterol-lowering activity of L. albus has also been confirmed in a hamster model of dyslipidemia.(15) Moreover, in a rabbit model of atheromatous plaque, L. albus protein has slowed plaque formation induced by a hyperlipidemic diet.(16) Finally, an uncontrolled clinical trial on L. albus(17) and two controlled on L. angustifolius(18, 19) have confirmed the hypocholesterolemic activity in humans. Despite these positive results, however, only very scarce data are available either on the mechanism of action or on the actual bioactive component(s) in lupin.
The favorable effects of plant proteins in cardiovascular prevention is well established; the first study on the hypocholesterolemic activity of soybean dates back to the 1970s.(20) Some relevant reviews and meta-analyses(21-23) summarize the numerous trials performed in the following years. In 1999 the U.S. Food and Drug Administration approved the health claim on the role of soybean protein in reducing the risk of cardiovascular disease.(24) The literature on soy may thus provide mechanistic information that may be also relevant in the case of other plant proteins, such as lupin. Studies in animal models and humans have demonstrated that the hypocholesterolemic effects of soy are due to the activation of LDL receptors (LDLR) that are relevant in the metabolic degradation of LDL-C. Soy protein was able to reverse the dramatic down-regulation of liver LDLR observed in rats on cholesterol/cholic acid dietary regimens versus casein,(25) and the expression of LDLR was increased in patients affected by familial hypercholesterolemia(26) and in moderately hypercholesterolemic individuals.(27) In parallel, in vitro and in vivo experiments have demonstrated that some specific soy peptides are responsible for the LDLR modulation.(28-32) Nevertheless, the mechanism at the molecular level has not been investigated in detail yet. These bioactive peptides, initially encrypted in the soy protein sequences, are probably enzymatically released during digestion and absorbed.(33)
The majority of plasma cholesterol is transported by the LDL fraction, and the cellular uptake of LDL is mediated by the LDLR. The circulating level of LDL is determined in large part by its rate of uptake through the hepatic LDLR pathway.(34, 35) Moreover, the LDLR plays a crucial role in Apo B turnover, being involved in determining the post-translation fate of apoB by increasing presecretory apoB degradation and mediating re-uptake of nascent lipoprotein particles.(36) In general, LDLR expression is finely tuned by changes in intracellular cholesterol.(37) A transcription factor known as the sterol-responsive element binding protein 2 (SREBP2) plays a critical role in LDLR mRNA expression.(38, 39) Among SREBP2 gene targets, the 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase (HMGCoAR) is particularly important. This enzyme plays a key role in the intracellular cholesterol biosynthesis, because it is the rate-controlling enzyme in the mevalonate pathway. After synthesis, SREBP2 forms a complex with the SREBP cleavage-activating protein (SCAP) and is localized in the endoplasmic reticulum (ER) as an inactive precursor (pro-SREBP2). Sterol deficiency results in the release of SREBP2/SCAP complex from ER and transport to the Golgi, where pro-SREBP2 is processed further, allowing the N-terminal fragment (mature SREBP2) to enter the nucleus and up-regulate transcription of LDLR and HMGCoAR.(40) In addition to SREBP2, other transcription factors may be involved in a context-dependent fashion in regulating the LDLR expression.
Recent studies(41, 42) identify a crucial signaling pathway, via phosphatidylinositol-3-kinase (PI3K)/Akt, as an important player in the regulation of cellular lipid metabolism. This pathway is the best known for its role in promoting cell growth, proliferation, and survival through increased glucose utilization and prevention of apoptosis.(43, 44) In particular, Akt has recently been implicated in a novel form of lipid metabolism regulation, through the SREBPs.(45) The physiological coordination between Akt and SREBPs pathways is needed to produce the lipids for new membrane synthesis, which in turn is required for growing and proliferating cells.(41, 42) Even though many studies have been focused on the SREBP-1c isoform,(45) new efforts are directed to explore and to investigate the link between Akt and SREBP2.(41, 46)
The objective of the present study was to characterize in detail the molecular mechanism at the basis of the cholesterol-lowering properties of L. albus protein observed in experimental and clinical investigations. On the basis of the hypothesis that the activity may depend on specific peptides encrypted in the protein sequences, a total protein extract from lupin seed was hydrolyzed either with pepsin (P peptides) or with trypsin (T peptides). The HepG2 cell line was treated with both kinds of peptides, and molecular and functional investigations were performed on the LDLR-SREBP2 and PI3K/Akt pathways, using a combination of techniques.

Materials and Methods

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Chemicals

Dulbecco’s modified Eagle’s medium (DMEM), l-glutamine, fetal bovine serum (FBS), phosphate-buffered saline (PBS), penicillin/streptomycin, chemiluminescent reagent, and 96-well plates were purchased from Euroclone (Milan, Italy). Bovine serum albumin (BSA), RIPA buffer, HMGCoAR Assay Kit, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and wortmannin were from Sigma-Aldrich (St. Louis, MO, USA). Antibodies against HMGCoAR were bought from Abcam (Cambridge, UK). Antibodies against β-actin, SREBP-2, rabbit Ig-HRP, and mouse Ig-HRP, PMSF, sodium orthovanadate inhibitors, and goat anti-rabbit Ig-HRP were purchased from Santa Cruz Biotechnology Inc. (Santa Cruz, CA, USA). Antibodies against the LDL receptor were from Pierce (Rockford, IL, USA). The inhibitor cocktail Complete Midi was from Roche (Basel, Switzerland). Mini protean TGX precast gel 7.5% and Mini nitrocellulose Transfer Packs were purchased from Bio-Rad (Hercules, CA, USA). LDL-DyLight 549 was from Cayman Chemical (Ann Arbor, MI, USA).

Preparation and Analysis of the Pepsin and Trypsin Peptide Mixtures

Lupin seeds of the species L. albus (cultivar Ares) were provided by Terrena (Matrignè-Ferchaud, France). The total protein extracts were obtained as previously reported.(47) Briefly, proteins were extracted from defatted flour with 100 mM Tris-HCl/0.5 M NaCl buffer, pH 8.2, for 2 h at 4 °C. The solid residue was eliminated by centrifugation at 6500g, for 20 min at 4 °C, and the supernatant was dialyzed against 100 mM Tris-HCl buffer, pH 8.2, for 24 h at 4 °C. The protein content was assessed according to the method of Bradford, using BSA as standard.
For the hydrolysis, the total protein extract was initially dissolved in Tris-HCl buffer 100 mM at pH 8, and then the pH was adjusted to the optimal hydrolysis conditions for each enzyme (pH 2 for pepsin and pH 8 for trypsin) by adding 1 M NaOH or 1 M HCl. The mixtures were incubated for 18 h, then the enzymes were inactivated, and the mixtures were purified by ultrafiltration through 3000 Da cutoff centrifuge filters (Amicon Ultra-0.5, Millipore, Billerica, MA, USA) at 12000g for 30 min at 4 °C. The peptide concentration in the permeates was measured according to a literature method,(48) based on chelating the peptide bonds by Cu(II) in alkaline media and monitoring the change of absorbance at 330 nm. Details are reported in a previous paper.(47)
The hydrolyzed mixtures were acidified with formic acid to a final 10% concentration. Eight microliters of tryptic digest for each band was injected in a nanochromatographic system, UltiMate 3000 RSLC nano-System (Thermo Scientific). The peptide mixtures were loaded on a reversed-phase trap column (Acclaim PepMap100, C18, 100 Å, 100 μm i.d. × 2 cm, Thermo Scientific) for the cleanup and preconcentration. After cleanup, the valve was switched to place the trap column in series with a fused silica reverse-phase column (picoFrit column, C18, 2.7 μm, New Objective). The peptides were eluted with a 30 min gradient from 4% buffer A (2% acetonitrile and 0.1% formic acid in water) to 60% buffer B (2% water and 0.1% formic acid in acetonitrile) at a constant flow rate of 300 nL/min. The chromatographic column was directly connected to an LTQ-XL mass spectrometer (Thermo Scientific) equipped with a nano spray ion source. Full scan mass spectra were acquired in the mass range from m/z 350 to 2000 Da, and the five most intense ions were automatically selected and fragmented in the ion trap. Target ions already selected for mass spectrometry (MS/MS) were dynamically excluded for 30 s. The MS data were analyzed separately by Mascot search engine (version 2.3.01) using Proteome Discover software (v. 1.2.0 Thermo) and consulting Uniprot_viridiplantae (30,264 sequences, 184,678,199 residues). Oxidation of methionine residues was set as variable modifications; two missed cleavages were allowed to trypsin; peptide mass tolerance was set to 1 Da and fragment mass tolerance to 0.8 Da; and an ion source cutoff of 20 was chosen. The false discovery rate obtained by Proteome Discoverer, consulting the Mascot decoy database, was <0.01. Tables 1S and 2S in the Supporting Information list the proteins and the unmatched peptides, with all relevant peptide signals, peptide sequences, ion score, variable modifications and mass errors.

Cell Culture Conditions

HepG2 cell line was bought from ATCC (HB-8065, ATCC from LGC Standards, Milan, Italy). The HepG2 cell line was cultured in DMEM high-glucose with stable l-glutamine supplemented with 10% FBS, 100 U/mL penicillin, and 100 μg/mL streptomycin (complete growth medium) and incubated at 37 °C under 5% CO2 atmosphere. HepG2 cells were used for no more than 20 passages after thawing because the increase of the number of passages may change the cell characteristics and impair assay results.

MTT

HepG2 cells (3 ×104/well) were seeded in 96-well plates and treated with 0.3, 0.5, 1.0, 2.5, 5.0, and 10.0 mg/mL of P and T peptides, respectively, or vehicle (100 mM Tris) in complete growth media for 48 h. Subsequently, the treatment solvent was aspirated and 100 μL/well of MTT filtered solution added for 48 h. After the incubation time, 0.5 mg/mL MTT solution was aspirated and 100 μL/well of MTT lysis buffer (8 mM HCl + 0.5% NP-40 in DMSO) added. After 5 min of slow shaking, the absorbance at 575 nm was read on an LT 4000 spectrophotometer.

HMGCoAR Activity Assay

The assay buffer, the NADPH, the substrate solution, and the HMG-CoA reductase were provided in the HMGCoAR Assay Kit (Sigma). The experiments were carried out following the manufacturer’s instructions at 37 °C. In particular, each reaction (200 μL) was prepared by adding the reagents in the following order: 1× assay buffer; 0.1, 0.25, 0.5, 1.0, and 2.5 mg/mL of T peptides or 0.5, 1.0, and 2.5 mg/mL of P peptides or vehicle (C); NADPH (4 μL); substrate solution (12 μL); and finally HMG-CoA reductase (catalytic domain) (2 μL). Subsequently, the samples were mixed and the absorbance at 340 nm read by a Synergy H1 microplate reader from Biotek at times 0 and 10 min. The HMGC-CoA-dependent oxidation of NADPH and the inhibition properties of lupin peptides were measured by the absorbance reduction, which is directly proportional to the enzyme activity.

Western Blot Analysis

HepG2 cells (1.5 × 105/well, 24-well plate) were treated with 0.5, 1, and 2.5 mg/mL of P and T peptides for 24 h. For the experiments in the presence of wortmannin, cells were treated with 1 mg/mL P and 0.5 mg/mL T peptides in the presence or absence of 1 μM inhibitor for 24 h. After each treatment, cells were scraped in 40 μL of ice-cold lysis buffer (RIPA buffer + inhibitor cocktail + 1:100 PMSF + 1:100 sodium orthovanadate) and transferred in an ice-cold microcentrifuge tube. After centrifugation at 13300 rpm for 15 min at 4 °C, the supernatant was recovered and transferred into a new ice-cold tube. Total proteins were quantified according to the Bradford method, and 50 μg of total proteins was loaded on a precast 7.5% sodium dodecyl sulfate–polyacrylamide (SDS-PAGE) gel at 130 V for 45 min. Subsequently, the gel was pre-equilibrated with 0.04% SDS in H2O for 15 min at room temperature and transferred to a nitrocellulose membrane (Mini nitrocellulose Transfer Packs,) using a Trans-blot Turbo at 1.3 A and 25 V for 7 min. Target proteins, on milk-blocked membrane, were detected by primary antibodies as follows: rabbit anti-SREBP2, rabbit anti-LDLR, anti-HMGCoAR, antipospho-Akt (ser473), antipospho-GSK3α/β (ser21/ser9), and anti-β-actin. Secondary antibodies conjugated with HRP and a chemiluminescent reagent were used to visualize target proteins, and their signal was quantified using ImageJ software. The internal control, β-actin, was used to normalize loading variations. In the case of SREBP2, the band at 70 kDa, corresponding to the N-terminal fragment (mature SREBP2 protein), was detected and quantified.

Fluorescent LDL Uptake Cell-Based Assay

HepG2 cells (3 ×104/well) were seeded in 96-well plates and kept in complete growth medium for 2 days before treatment. The third day, cells were treated with 1.0 mg/mL P peptides and 0.25 mg/mL T peptides, respectively, or vehicle (100 mM Tris) for 24 h. For the experiments in the presence of the PI3K inhibitor, HepG2 cells were treated with 1.0 mg/mL P peptides and 0.5 mg/mL T peptides in the presence or absence of 100 nM wortmannin and in the presence of the only inhibitor, as control, in DMEM without FBS for 24 h. At the end of the treatment periods, the culture medium was replaced with 75 μL/well LDL-DyLight 549 working solution. The cells were additionally incubated for 2 h at 37 °C, and then the culture medium was aspirated and replaced with PBS 100 μL/well. The degree of LDL uptake was measured using the Synergy H1 fluorescent plate reader from Biotek (excitation and emission wavelengths 540 and 570 nm, respectively).

Statistical Analysis

Statistical analyses were carried out by one-way ANOVA (Graphpad Prism 6) followed by Dunnett’s test. Values were expressed as means ± SEM; P values <0.05 were considered to be significant.

Results

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Preparation and Analysis of the Peptide Mixtures

A total protein extract from lupin seed was hydrolyzed with pepsin and trypsin to produce P peptides and T peptides, respectively. The two samples were analyzed by nano-LC-MS/MS. The chromatograms (Figure 1) showed two diverse profiles due to the different peptide compositions of the digested samples. The number of potentially bioactive peptides is very high in both samples, because more than 2000 peptides were detected in the pepsin-digested mixture and about 3000 in the trypsin-digested one (Tables 1S and 2S in the Supporting Information).

Figure 1

Figure 1. Nano-LC MS/MS of lupin peptide mixtures: (A, B) chromatogram and full scan mass spectrum of T peptides; (C, D) chromatogram and full scan mass spectrum of P peptides.

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It was possible to assign only a small number of peptides to known lupin proteins by Mascot software consulting the Uniprot_viridiplantae database. The other peptides were sequenced, but not assigned to protein hits, possibly due to the very incomplete sequencing of lupin proteins. The recognized peptides in the P sample belong to the main storage proteins in lupin seed: 21 peptides to the vicilins [L. albus vicilin-like protein (Q53HY0) and L. albus β-conglutin (Q6EBC1)]; 7 peptides to the legumins [L. angustifolius conglutin-α 3 (F5B8V8)], and 8 peptides to γ-conglutin [L. albus conglutin-γ (Q9FSH9)], a sulfur-rich basic protein typical of lupin (4–5%).
The identified peptides in the T sample are the following: 16 peptides belong to the vicilins [L. albus vicilin-like protein (Q53HY0), L. albus β-conglutin precursor (Q6EBC1), and L. angustifolius conglutin β (B0YJF8)]; 4 to the legumins [L. angustifolius legumin-like protein (Q53I55)], and 2 to δ-conglutin, a 2S protein [L. albus conglutin δ seed storage protein precursor (Q99235)]. Two peptides were assigned to other plant proteins, probably because the lupin sequences are not present in the database: Zea mays actin partial (ADF3).

HepG2 Cell Viability

MTT experiments were performed to exclude the peptide doses with potential toxic effects on the HepG2 cell line. No significant cell mortality was observed up to 2.5 mg/mL after a 48 h treatment versus vehicle (C, 100 mM Tris), suggesting that neither P nor T peptides induce cell mortality in this dose range, whereas about 20 and 80% cell mortalities were observed at 5.0 and 10 mg/mL, respectively (Figure 2). For this reason, all of the following experiments, aimed at investigating the molecular and functional effects of P and T peptides, were conducted using doses of ≤2.5 mg/mL.

Figure 2

Figure 2. HepG2 cell viability after P and T peptide treatment. Bar graphs indicate the results of MTT cell viability assay of HepG2 cells after P and T peptide treatment for 48 h. Data points represent averages ± SEM of three independent experiments in triplicate. (∗∗) P < 0.001 and (∗∗∗) P < 0.0001 versus C. P, pepsin peptides; T, trypsin peptides; C, control.

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Effects of P and T Peptides on the Catalytic Domain of HMGCoAR

To check the direct ability of P and T peptides to inhibit HMGCoAR, an in vitro assay was performed using the purified catalytic domain of this enzyme. Both P and T peptides were capable of inhibiting HMGCoAR, but with very different activities and potencies (Figure 3). In fact, P peptides inhibited the enzyme with a statistical significance (−17%) only at the maximum tested dose (2.5 mg/mL), whereas they are ineffective at 0.5 and 1.0 mg/mL. On the contrary, T peptides showed a statistically significant reduction of the HMGCoAR activity at all tested doses: in fact, the enzyme activity was reduced by 37% at 0.25 mg/mL, by 57% at 0.5 mg/mL, and by 61% at 1.0 and 2.5 mg/mL.

Figure 3

Figure 3. Lupin peptide effect on the catalytic domain of HMGCoAR. Bars indicate the effects of P peptides (0.5, 1.0, and 2.5 mg/mL) (A) and T peptides (0.25, 0.5, 1.0, and 2.5 mg/mL) (B) on HMGCoAR activity. HMGCoAR, physiologically, catalyzes the four-electron reduction of HMG-CoA to coenzyme A (CoA) and mevalonate (HMG-CoA + 2NADPH + 2H+ > mevalonate + 2NADP+ + CoA-SH). In this assay, the decrease in absorbance at 340 nm, which represents the oxidation of NADPH by the catalytic subunit of HMGCoAR in the presence of the substrate HMG-CoA, was measured spectrophotometrically. Data points represent averages ± SEM of three independent experiments in triplicate. (∗∗) P < 0.001 and (∗∗∗) P < 0.0001 versus C. P, pepsin peptides; T, trypsin peptides; C, control.

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Lupin Peptides Mediate the Up-regulation of LDLR-SREBP2 at HepG2 Cells

HepG2 cells were treated for 24 h with P and T peptides at concentrations of 0.5, 1.0, and 2.5 mg/mL. Immunoblotting experiments showed that the treatments with lupin peptides induce an up-regulation of the SREBP2 protein level. In particular, P peptides up-regulate the SREBP2 protein level by 100, 148, and 162% versus the control, whereas T peptides increase the SREBP2 protein level by 80, 73, and 44% versus the control, after 0.5, 1.0, and 2.5 mg/mL treatments, respectively (Figure 4B).

Figure 4

Figure 4. Effect of P and T peptides on the SREBP2, LDLR, and HMGCoAR protein levels. HepG2 cells (1.5 × 105) were treated with 0.5, 1.0, and 2.5 mg/mL of P and T peptides for 24 h, respectively. SREBP2, LDLR, HMGCoAR, and β-actin immunoblotting signals were detected using specific anti-SREBP2, anti-LDLR, anti-HMGCoAR, and anti-β-actin primary antibodies, respectively (A). SREBP2 (B), LDLR (C), and HMGCoAR (D) signals were quantified by ImageJ software and normalized with β-actin signals. Bars represent averages of duplicate samples ± SEM of three independent experiments. (∗) P < 0.05 and (∗∗) P < 0.001 versus C. P, pepsin peptides; T, trypsin peptides; C, control.

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In the same experiments, also the LDLR and HMGCoAR protein levels were measured by immunoblotting. Figure 4C shows that both P and T peptides are able to induce a statistically significant up-regulation of LDLR protein in HepG2 cells versus the control, but with different behaviors. In particular, at 0.5, 1.0, and 2.5 mg/mL P peptides mediate 147, 136, and 120% inductions of the LDLR protein, whereas T peptides mediate a ∼85% up-regulation at 0.5 and 1.0 mg/mL and a 61% up-regulation at 2.5 mg/mL versus the control (Figure 4C). These results are in agreement with the up-regulation of SREBP2 protein level.
Both P and T peptides affect the HMGCoAR levels (Figure 4D), but with very different behaviors and activities. Precisely, P peptides increase the synthesis of HMGCoAR by 82% at 0.5 mg/mL, by 212% at 1.0 mg/mL, and by 340% at 2.5 mg/mL versus the control, that is, in a dose-dependent manner. On the contrary, treatment with T peptides enhances the production of HMGCoAR by 233% at 0.5 mg/mL and by only 97% at 1.0 mg/mL, whereas it is practically inactive at 2.5 mg/mL.

Lupin Peptides Increase LDL Uptake at the HepG2 Cell Line

Fluorescent LDL uptake experiments were performed for evaluating the cholesterol-lowering properties of lupin peptides from a functional point of view. Precisely, the fluorescent LDL uptake was examined in HepG2 cells following a 24 h incubation with P and T peptides. Figure 5 shows that both P and T peptides are able to increase the LDL uptake versus the control in a statistically significant way. In particular, treatment with P peptides at concentrations of 1.0 and 2.5 mg/mL increases the LDL uptake by 42 and 45%, respectively, versus the control, whereas the LDL uptake increase was not statistically significant at 0.5 mg/mL. On the other hand, at concentrations of 0.25, 0.5, and 1.0 mg/mL T peptides significantly raise the LDL uptake by 52, 50, and 70%, respectively, versus the control.

Figure 5

Figure 5. LDL uptake after P and T peptide treatments. HepG2 cells (3 × 104) were treated with P (0.5, 1.0, and 2.5 mg/mL) and T (0.25, 05, and 1.0 mg/mL) peptides for 24 h. LDL-Dylight 549 (10.0 μg/mL) was incubated for an additional 2 h. Excess LDL-Dylight 549 was removed, cells were washed two times with PBS, and specific fluorescent LDL uptake was analyzed by Synergy H1 (Biotek). Data points represent averages ± SEM of three independent experiments in triplicate. (∗) P < 0.05 and (∗∗) P < 0.001 versus C. P, pepsin peptides; T, trypsin peptides; C, control.

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Lupin Peptides Mediate LDLR-SREBP2 Up-regulation through the Activation of PI3K/Akt/GSK3β Kinases

To examine the effect of lupin peptides on the activation of Akt and GSK3β (its direct substrate), immunoblot analyses were performed on lysates from treated HepG2 cells using antibodies, which are specific for Akt phosphorylated at serine residue 473 and for GSK3β phosphorylated at serine residue 9. In accordance with the preceding immunoblot experiments, HepG2 cells were treated with P and T peptides at concentrations of 1.0 and 0.5 mg/mL, and the variation of phosphorylated Akt and GSK3β levels was investigated. Figure 6B shows that the treatments with lupin peptides increased the Akt phosphorylation in a dose-dependent manner: by 92 and 125%, respectively, after treatment with P peptides at 0.5 and 1.0 mg/mL and by 144 and 196%, respectively, after treatment with T peptides at 0.5 and 1.0 mg/mL.

Figure 6

Figure 6. Effect of P and T peptides on the activation of Akt (Ser473) and GSK3 (Ser9). HepG2 cells (1.5 × 105) were treated with 0.5 and 1 mg/mL of P and T peptides for 24 h, respectively. The phosphorylation levels of Akt (Ser473) (A) and GSK3 (Ser9) (C) and β-actin immunoblotting signals were detected using specific anti-posphoAkt (Ser473), anti-posphoGSK3β (Ser9), and anti-β-actin primary antibodies, respectively. PosphoAkt signals (B) and posphoGSK3β (D) were quantified by ImageJ software and normalized with β-actin signals. Bars represent averages of duplicate samples ± SEM of three independent experiments. (∗) P < 0.05, (∗∗) P < 0.001, and (∗∗∗) P < 0.0001 versus C. P, pepsin peptides; T, trypsin peptides; C, control; pAkt, posphoAkt; pGSK3β, posphoGSK3β.

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Additionally, P peptides mediate a 60% increase of the phosphorylation level of GSK3β at 0.5 mg/mL and a 74% increase at 1.0 mg/mL versus the control. After T peptide treatments, instead, the GSK3β phosphorylation level was increased by 133% at 0.5 mg/mL and by only 75% at 1.0 mg/mL (Figure 6D).
Treatment with 1 μM wortmannin, a PI3K inhibitor, inhibited the Akt phosphorylation either in the presence or in the absence of both lupin peptide mixtures. Figure 7A shows a representative immunoblot and the relative intensity of the phospho-Akt bands. The quantification and normalization against actin bands from three different experiments, each performed in duplicate, is shown in Figure 7B. This figure clearly demonstrates that the wortmannin co-incubation with P and T peptides is able to reduce by about 40 and 50% the Akt phosphorylation level, abolishing the Akt phosphorylation induced by lupin peptides.

Figure 7

Figure 7. Involvement of PI3K/Akt pathway activation in the regulation of the LDLR–SREBP2 pathway through which lupin peptides mediate the cholesterol-lowering effects. HepG2 cells (1.5 × 105) were treated with 1.0 and 0.5 mg/mL of P and T peptides in the presence or absence of wortmannin for 24 h, respectively. The phosphorylation level of Akt (Ser473) (A) and β-actin immunoblotting signals were detected using specific anti-posphoAkt (Ser473) and anti-β-actin primary antibodies, respectively. Relative intensity of posphoAkt signals (B) was quantified by ImageJ software and normalized with β-actin signals. Panel C shows the LDL uptake after treatment with the PI3K inhibitor. HepG2 cells (3 × 104) were treated with P (1.0 mg/mL) and T (0.5 mg/mL) peptides in the presence or absence of wortmannin and inhibitor alone for 24 h. LDL-Dylight 549 (10.0 μg/mL) was incubated for additional 2 h. Excess LDL-Dylight 549 was removed, and cells were washed two times with PBS. Specific fluorescent LDL uptake was analyzed by Synergy H1 (Biotek). Bars represent averages of duplicate samples ± SEM of three independent experiments. pAkt, posphoAkt; P, pepsin peptides; T, trypsin peptides; C, control.

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To confirm the involvement of the PI3K/Akt pathway activation in the regulation of the LDLR-SREBP2 pathway, functional LDL uptake experiments were performed in the presence of wortmannin. As Figure 7C shows, P peptides and T peptides are able to increase the LDL uptake with respect to the basal level, but these uptakes are blocked in the presence of wortmannin. Precisely, the LDL uptake is blocked at the basal level either in the presence of the inhibitor alone or in the co-incubation with P and T peptides, demonstrating that the LDL uptake induced by lupin peptides is abolished by treatment with this well-known PI3K inhibitor.

Discussion

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As already indicated in the Introduction, some experimental studies(11-14) and a few clinical trials(17-19) gave clear indications that lupin proteins are able to induce hypocholesterolemic effects in vivo. The present investigation at HepG2 cells was aimed at providing some further information on the mechanism through which the lupin peptides may be responsible of the observed activities.
The main findings of this study are the following: (i) T peptides are able to directly interfere with the HMGCoAR activity, whereas P peptides are much less effective. (ii) Both P and T peptides modulate the cholesterol metabolism at HepG2 cell line, through the up-regulation of the pathway involving the LDLR. (iii) Both P and T peptide treatments increase the LDL-uptake. (iv) Activation of the Akt/GSK3β pathway is involved in the up-regulation of the LDLR-SREBP2 pathway.
HMGCoAR is the rate-controlling enzyme of cellular cholesterol biosynthesis pathway, and therefore it constitutes the target of numerous investigations aimed at lowering the rate of cholesterol biosynthesis.(49) Therefore, initially in vitro experiments were performed using the purified catalytic domain of the enzyme with the objective of clarifying whether lupin peptides were able to directly inhibit the activity of HMGCoAR. As shown in Figure 3, T peptides but not P peptides act as enzyme inhibitors.
The LDLR expression and the receptor protein localization at cellular membranes are strictly correlated to the intracellular cholesterol biosynthesis pathway. In fact, the transcription of the LDLR and the genes required for cholesterol and fatty acid synthesis are controlled by membrane-bound transcription factors called SREBPs,(50) and the intracellular cholesterol acts with a negative feedback inhibition mechanism.(51) The SREBP2 isoform is responsible for the LDLR and HMGCoAR transcription, and the SREBP2 maturation is regulated by the intracellular cholesterol homeostasis. Thus, the up-regulation of LDLR represents a useful strategy to control plasma LDL cholesterol levels. Our findings demonstrate that both lupin peptide mixtures are able to up-regulate the LDLR protein levels through an increase of SREBP2 protein. However, a detailed investigation of the LDLR pathway revealed that lupin peptides produce different effects on the HMGCoAR level. In particular, whereas P peptides are able to increase the enzyme protein level in a dose-dependent manner, T peptides up-regulate the enzyme protein levels in a significant way versus the control at 0.5 mg/mL; the increase remains statistically significant, but it is smaller at 1.0 mg/mL, and it is finally completely abolished at 2.5 mg/mL (Figure 4D).
These pieces of evidence suggest that both peptide mixtures modulate the cholesterol metabolism pathway through the induction of LDLR protein levels due to an increase of SREBP2 protein, although their potencies of induction are different.
In agreement with immunoblotting results, the increase of LDLR protein levels leads to an increase of LDL uptake (Figure 5). Our findings suggest that both P and T peptides are able to significantly induce the LDL clearance, and this result is strictly correlated to an increase of LDLR protein level.
Recently, studies have indicated that there are links between the Akt and the SREBP pathways: in fact, emerging evidence shows that Akt is implicated in the regulation of lipid metabolism through the activation of SREBPs.(45, 52-55) Luu and co-workers(41) showed that insulin-like growth factor-1, an inducer of Akt signaling, acutely increases SREBP2 activation. This study provided evidence that Akt contributes to the regulation of cholesterol metabolism through activating SREBP2.
Even if the precise target or targets of Akt remain elusive and not clarified, part of our investigation was dedicated to evaluating the effects of lupin peptides on the PI3K/Akt pathway. Our study provides experimental evidence that either P or T peptides from lupin protein are able to induce increases of Akt and GSK3β phosphorylation levels, which are completely abolished by treatment with a well-known PI3K inhibitor, such as wortmannin. A constitutively active form of Akt activated the LDLR.(53) Our findings clearly support this study, because both P and T peptides increase the LDLR protein levels and induce an increased fluorescent LDL uptake at HepG2 cells. Moreover, after treatment with both lupin peptides in the presence of wortmannin, LDL uptake is blocked versus the P and T treatments alone, demonstrating that the inhibition of PI3K/Akt has general effects on cellular lipid homeostasis, although the precise Akt target or targets are not definitely assigned yet.
In conclusion, this is the first study providing evidence that peptide mixtures obtained by the hydrolysis of lupin proteins are able to modulate the LDLR/SREBP2 pathway with the final effect of an increased LDL uptake. Because, as indicated above, both P peptides and T peptides are complex mixtures, it appears very difficult to sort out which may be the peptides responsible for the observed activities. It is, however, possible to affirm that the diversity in the behaviors of the two peptide mixtures derives from their different compositions. Further work will be necessary to investigate these aspects in detail. This is also the first study to investigate in detail the mechanism of the hypocholesterolemic activity of peptides deriving from a plant protein, because, even in the case of soy, only partial information is available.(26-32)

Supporting Information

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Tables 1S and 2S. This material is available free of charge via the Internet at http://pubs.acs.org.

Author Contributions

Ideation and design of experiments: C.L. Experiments: biotechnology, C.L. and C.Z.; mass spectrometry analysis, A.D.; peptide preparation, G.M.S.; analysis of data, C.L., C.Z., and A.D.; figure preparation, C.Z; retrieval of grants, A.A; manuscript writing, C.L. and A.A.

Funding Information

Research was funded by the European Union Seventh Framework Programme (FP7/2007–2013), under Grant Agreement 285819. We are indebted to Regione Lombardia and HPF-Nutraceutics SRL (Milan, Italy) for the partial funding of a postdoctoral fellowship to C.Z. and to the Carlo Sirtori Foundation (Milan, Italy) for having provided most of the equipment used in this experimentation.

The authors declare no competing financial interest.

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Abbreviations Used

HMGCoAR

3-hydroxy-3-methylglutaryl CoA reductase

LDL

low-density lipoprotein

LDLR

LDL receptor

L. albus

Lupinus albus

MTT

3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide

SREBP2

sterol regulatory element binding protein 2

SCAP

SREBP cleavage-activating protein

ER

endoplasmic reticulum

P peptides

pepsin peptides

T peptides

trypsin peptides

PI3K

phosphoinositide 3-kinase

Akt

protein kinase B

GSK3β

glycogen synthase kinase-3β

References

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This article references 55 other publications.

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    Six cultivars of Lupinus albus L. (white lupin) were grown in 2 subcontinental-climate environments and one Mediterranean-climate environment in Italy, to assess the influence of genotypic (G) and genotype × environment (GE) interaction effects on grain yield and grain content of oil, total satd. fatty acids (FAs), polyunsatd. FAs, monounsatd. FAs, and ω-3/ω-6 FA ratio. The variance of genotypic effects was much larger than the GE interaction variance for all variables, except for grain yield, indicating that oil content and FA compn. of different varieties can be assessed reliably in just a few test environments. Gas-chromatog. analyses highlighted that linoleic acid and α-linolenic acid were in the range 1.76-4.76 mg/g flour (7.79-15.81% of total FAs) and 1.17-3.14 mg/g flour (5.40-10.36% of total FAs), resp. As a consequence, the analyzed lupin seeds exhibited a very favorable ω-3/ω-6 FA ratio, ranging from 0.49 to 0.79.
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    Grain legumes contain numerous phytochems. useful for their nutritional or nutraceutical properties, such as tocopherols, involved in the prevention of cardiovascular disease and eye pathologies. In this work, tocopherols were quantified in soybean, chickpea, lentil, pea, common bean, broad bean, and three lupin species. In all samples, the gamma congener was the most abundant tocopherol, followed by minor quantities of alpha-tocopherol (with the exception of common bean lacking in this congener) and delta-tocopherol (with the exception of Lupinus angustifolius and Lupinus mutabilis). Beta-tocopherol and tocotrienols were never detected. Some samples of soybean, pea, white lupin and chickpea contained over 10 mg/100 g seeds of total tocopherols. In order to est. the nutritional value, the vitamin E activity was calcd. Chickpea, soybean and, to a lesser extent, lupin, broad bean and pea may contribute in a relevant way to the daily intake of this vitamin.
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    A protein isolate from white lupin (Lupinus albus; L-ISO) has potential as a novel human food ingredient, but its nutritional effects are unknown. The authors evaluated protein quality and effects on body compn. in rats of isoenergic diets of L-ISO, lactalbumin, or casein with both restricted (10-day) and ad libitum (28-day)intake. The diets were equiv. in protein per se, but supplementation was used to balance essential amino acid levels. In both studies, the rats consumed similar amts. of each diet, and no effect of diet on the gain:feed ratio was obsd., though gain:N ratio and net protein utilization were slightly lower for the L-ISO diet. Lower large intestinal wts. after the L-ISO than after the lactalbumin diet were obsd. in both studies. The L-ISO diet resulted in lowered body fat percentage in the 10-day study but in an elevated level in the 28-day study. Liver compn. (DNA, RNA, glycogen, and fat) and plasma levels of some amino acids (His, Thr, Ala, Pro, Tyr, Val, and Met) were affected by diet, but no effects on plasma lipid, glucose, or uric acid were obsd. The L-ISO diet did not affect feed intake and has adequate nutritional quality in rats while modifying large intestinal wt. in a potentially beneficial manner, suggesting potential for this protein in human nutrition.
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    The intake of lupin-based foods could imply the exposure of consumers to quinolizidine alkaloids. The objectives of this study were to assess the genetic variation among and within 11 geog. regions of Lupinus albus ecotypes, verify the quinolizidine alkaloids amt. of alkaloid-poor L. Albus and Lupinus angustifolius varieties, and assess the effect of two climatically contrasting Italian environments on the alkaloid content. The quantitation was performed by GC-MS, and in all samples lupanine was the most abundant quinolizidine alkaloid, followed by albine and 13α-hydroxylupanine for L. Albus and by 13α-hydroxylupanine and angustifoline for L. angustifolius. Some regions tended to have a high (Azores) or low (Egypt, Near East, Maghreb) total alkaloids content, but the variation among ecotypes within regions was larger than that among regions following the estn. of variance components. Alkaloid-poor varieties tended to have higher total alkaloid contents when grown in the subcontinental climate site, exceeding in some cases the limit of 0.200 mg/g.
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    This paper describes a pilot process for obtaining protein isolates from white lupin seed with improved water soly. and technofunctional properties as well as reduced thermal damage. After a careful optimization of the process parameters, two valuable food ingredients were prepd.: lupin protein isolate type E, with a useful emulsifying capacity, and lupin protein isolate type F, with a high capability of foam formation and stabilization. The spray-drying process was particularly crit. for inducing some thermal damage, but a careful selection of the conditions permitted ingredients having only marginally impaired lysine bioavailability to be obtained. The reproducibility of the protein extn. process was tested on two different lupin varieties.
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    Journal of Agricultural and Food Chemistry (2014), 62 (8), 1846-1851CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)
    Recently, the enzymic hydrolysis of Lupinus albus and Lupinus angustifolius proteins with pepsin was showed to produce peptides able to inhibit the angiotensin-converting enzyme (ACE). The objective of the present work was to test different hydrolytic enzymes and to investigate three lupin species (L. albus, L. angustifolius, Lupinus luteus) with the final goal of selecting the best enzyme/species combination for an efficient prodn. of ACE-inhibitory peptide mixts. Pepsin gave peptides with the best IC50 values (mean value on three species 186 ± 10 μg/mL), followed by pepsin + trypsin (198 ± 16 μg/mL), chymotrypsin (213 ± 83 μg/mL), trypsin (405 ± 54 μg/mL), corolase PP (497 ± 32 μg/mL), umamizyme (865 ± 230 μg/mL), and flavourzyme (922 ± 91 μg/mL). The three species showed similar activity scales, but after pepsin + trypsin and chymotrypsin treatments, L. luteus peptide mixts. resulted to be significantly the most active. This investigation indicates that lupin proteins may be a valuable source of ACE-inhibitory peptides, which may explain the activity obsd. in exptl. and clin. studies and foresee the application of lupin proteins into functional foods or dietary supplements.
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    Sirtori, C. R.; Lovati, M. R.; Manzoni, C.; Castiglioni, S.; Duranti, M.; Magni, C.; Morandi, S.; D’Agostina, A.; Arnoldi, A. Proteins of white lupin seed, a naturally isoflavone-poor legume, reduce cholesterolemia in rats and increase LDL receptor activity in HepG2 cells J. Nutr. 2004, 134, 18– 23
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    White lupin (Lupinus albus) is a widely cultivated crop that has been consumed for many years in Western Europe. It may be a useful alternative for individuals wishing to substitute animal with plant proteins for cardiovascular disease prevention. Lupin seeds have very low contents of isoflavones and lupin protein isolates are essentially isoflavone free. In rats fed casein-based diet with cholesterol and cholic acid, relatively low intakes (50 mg by gavage daily for 2 wk) of total lupin protein ext. decreased blood plasma total and VLDL+LDL cholesterol concns. by 21 and 30%, resp. To elucidate the lipid-lowering mechanism, LDL receptor activity was evaluated in human hepatoma cell line HepG2 in vitro. In this cell model, the lupin total protein ext. was essentially inactive, whereas one purified minor protein component, conglutin γ, had remarkable upregulatory effects, with maximal increases of 53 and 21% for LDL uptake and degrdn., resp. This indicated that lupin, although isoflavone free, has hypocholesterolemic activity similar to that of other leguminous proteins in an established animal model. The cholesterol decrease appears to be assocd. with stimulation of LDL receptors by a well-defined protein component of the lupin seeds as demonstrated in vitro.
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    Bettzieche, A.; Brandsch, C.; Weisse, K.; Hirche, F.; Eder, K.; Stangl, G. Lupin protein influences the expression of hepatic genes involved in fatty acid synthesis and triacylglycerol hydrolysis of adult rats Br. J. Nutr. 2008, 99, 952– 962
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    British Journal of Nutrition (2008), 99 (5), 952-962CODEN: BJNUAV; ISSN:0007-1145. (Cambridge University Press)
    To assess the effect of lupin protein on concns. of lipids in plasma lipoproteins and liver and hepatic mRNA concns. of genes involved in lipid metab., adult rats were fed egg albumin-based diets contg. either lupin protein from Lupinus albus or casein (50 g/kg) supplemented (hypercholesterolemic) or not (normolipemic) with a cholesterol-cholate mixt. for 20 d. Lupin protein compared with casein lowered the concns. of TAG in liver (P<0·01) and circulating VLDL + chylomicrons (P<0·05) of hypercholesterolemic rats, but not of normolipemic rats. Hepatic mRNA concns. of genes involved in fatty acid synthesis such as sterol regulatory element-binding protein-1c, glucose-6-phosphate dehydrogenase, fatty acid synthase, stearoyl-CoA desaturase-1 and acyl-CoA:glycerol-3-phosphate acyltransferase were lower and mRNA concns. of lipoprotein lipase, hepatic lipase and apoA5 involved in TAG hydrolysis were higher in rats fed lupin protein than in rats fed casein. These effects were stronger in hypercholesterolemic rats than in normolipemic rats. Hypercholesterolemic rats fed the lupin protein had higher liver cholesterol concns. (P<0·01) and lower levels of LDL-cholesterol (P<0·05) than rats fed casein. No effect of lupin protein was obsd. on cholesterol concn. in VLDL + chylomicrons and HDL and hepatic mRNA concns. of genes involved in cholesterol and bile acid metab. In conclusion, the present study shows that lupin protein has hypotriacylglycerolemic action possibly via down regulation of fatty acid synthesis genes and up regulation of genes involved in TAG hydrolysis. Alterations in cholesterol metab. could not be explained on the basis of mRNA data.
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    Bettzieche, A.; Brandsch, C.; Schmidt, M.; Weisse, K.; Eder, K.; Stangl, G. Differing effect of protein isolates from different cultivars of blue lupin on plasma lipoproteins of hypercholesterolemic rats Biosci., Biotechnol., Biochem. 2008, 72, 3114– 3121
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    Bettzieche, Anja; Brandsch, Corinna; Schmidt, Manja; Weisse, Kristin; Eder, Klaus; Stangl, Gabriele I.
    Bioscience, Biotechnology, and Biochemistry (2008), 72 (12), 3114-3121CODEN: BBBIEJ; ISSN:0916-8451. (Japan Society for Bioscience, Biotechnology, and Agrochemistry)
    Protein from white lupin is capable of lowering plasma lipids. We investigated in this study the effect of total protein exts. (TPEs) from different cultivars of blue lupin (Probor, Vitabor and Boregine) and α-/β-conglutin from Boregine on the plasma lipids of rats. Rats were fed on a hypercholesterolemic diet contg. either lupin protein (50 g/kg) or casein (50 g/kg) for 17 d. The rats fed with TPE from Vitabor and α-/β-conglutin had lower triglyceride concns. in the plasma (-24% and -21%, resp.) and very-low-d. lipoprotein (VLDL; -40% and -29%, resp.) than the rats fed with casein. TPE from Vitabor was also capable of lowering low-d. lipoprotein (LDL) cholesterol (-37%). In the liver of the rats fed with TPE from Vitabor, the expression of the genes involved in triglyceride and cholesterol synthesis was down-regulated. This study shows that the Vitabor cultivar of blue lupin had the most beneficial effect on plasma lipids which was presumed to have been caused by the down-regulation of genes involved in lipid synthesis.
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  14. 14
    Parolini, C.; Rigamonti, E.; Marchesi, M.; Busnelli, M.; Cinquanta, P.; Manzini, S.; Sirtori, C.; Chiesa, G. Cholesterol-lowering effect of dietary Lupinus angustifolius proteins in adult rats through regulation of genes involved in cholesterol homeostasis Food Chem. 2012, 132, 1475– 1479
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    14
    Cholesterol-lowering effect of dietary Lupinus angustifolius proteins in adult rats through regulation of genes involved in cholesterol homeostasis
    Parolini, Cinzia; Rigamonti, Elena; Marchesi, Marta; Busnelli, Marco; Cinquanta, Paola; Manzini, Stefano; Sirtori, Cesare R.; Chiesa, Giulia
    Food Chemistry (2012), 132 (3), 1475-1479CODEN: FOCHDJ; ISSN:0308-8146. (Elsevier Ltd.)
    In the absence of a clear indication from previous studies, a rat study was designed to evaluate a possible hypolipidemic effect of Lupinus angustifolius (blue lupin) proteins. Rats were fed for 28 days Nath's hypercholesterolemic diets contg. 20% casein or blue lupin proteins. After 14 and 28 days of dietary treatment, blue-lupin-fed rats had markedly lower plasma total cholesterol levels than rats fed casein (-53.0% and -55.3%, resp., p < 0.0005). No significant differences were instead obsd. for triglyceride and HDL-cholesterol levels between the two groups. Lupin-protein-fed rats displayed higher hepatic mRNA levels of SREBP-2, a major transcriptional regulator of intracellular cholesterol levels, and CYP7A1, the rate-limiting enzyme in bile acid biosynthesis (p < 0.05). In conclusion, the present study demonstrates a marked cholesterol-lowering activity of proteins from L. angustifolius in rats. Moreover, blue lupin proteins appear to affect cellular lipid homeostasis by up-regulating SREBP-2 and CYP7A1 genes.
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  15. 15
    Fontanari, G.; Batistuti, J.; da Cruz, R.; Saldiva, P.; Areas, J. Cholesterol-lowering effect of whole lupin (Lupinus albus) seed and its protein isolate Food Chem. 2012, 132, 1521– 1526
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    15
    Cholesterol-lowering effect of whole lupin (Lupinus albus) seed and its protein isolate
    Fontanari, Gustavo Guadagnucci; Batistuti, Jose Paschoal; Jose da Cruz, Robison; Saldiva, Paulo Hilario Nascimento; Areas, Jose Alfredo Gomes
    Food Chemistry (2012), 132 (3), 1521-1526CODEN: FOCHDJ; ISSN:0308-8146. (Elsevier Ltd.)
    This study describes the hypocholesterolemic effect of whole lupin and its protein in hamsters. The diets were: casein (control group HC), lupin protein isolate (group HPI) and whole lupin seed (group HWS). Diets from HPI and HWS promoted a significant redn. of total cholesterol and non-HDL cholesterol in the hamsters' plasma as compared with HC. The true digestibility of HPI and HC groups were similar and differed significantly from the HWS one, which in turn showed a significant difference in total sterol excretion as compared to the former groups. Histol. anal. of the liver revealed that animals fed on HPI and HWS diets presented a low level of steatosis (level 1) as compared to the ones fed on HC diet (level 4). Our findings demonstrate that protein isolate from Lupinus albus from Brazil has a metabolic effect on endogenous cholesterol metab. and a protector effect on development of hepatic steatosis.
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  16. 16
    Marchesi, M.; Parolini, C.; Diani, E.; Rigamonti, E.; Cornelli, L.; Arnoldi, A.; Sirtori, C. R.; Chiesa, G. Hypolipidaemic and anti-atherosclerotic effects of lupin proteins in a rabbit model Br. J. Nutr. 2008, 100, 707– 710
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    Hypolipidaemic and anti-atherosclerotic effects of lupin proteins in a rabbit model
    Marchesi, Marta; Parolini, Cinzia; Diani, Erika; Rigamonti, Elena; Cornelli, Lorena; Arnoldi, Anna; Sirtori, Cesare R.; Chiesa, Giulia
    British Journal of Nutrition (2008), 100 (4), 707-710CODEN: BJNUAV; ISSN:0007-1145. (Cambridge University Press)
    The biol. activities of a protein isolate from lupin (Lupinus albus) were studied in a rabbit model of atherosclerosis. Focal plaque development was induced at both common carotid arteries by perivascular injury. After surgery, animals were fed three different diets for 90 d, all with 1% cholesterol, 15% SFA and 20% protein; the protein source was casein (CAS), lupin proteins (LUP) or 50% CAS + 50% LUP (CAS + LUP). Lower cholesterolemia was detected in the LUP v. the CAS group at 60 and 90 d of treatment (-40.3% and -33.5%, resp.; P < 0.05). Cryosection analyses of the carotids indicated a significant redn. in focal lesion progression in the LUP vs. the CAS group (-37.4%; P < 0.05). In summary, in a rabbit model of atherosclerosis, a protein isolate from L. albus reduced cholesterolemia and exerted a remarkable protective activity against atherosclerosis progression.
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  17. 17
    Naruszewicz, M.; Nowicka, G.; Klosiewicz-Latoszek, L.; Arnoldi, A.; Sirtori, C. Effect of lupin protein (Lupinus albus) on cardiovascular risk factors in smokers with mild hypercholesterolemia Circulation 2006, 114, 874– 874
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  18. 18
    Sirtori, C. R.; Triolo, M.; Bosisio, R.; Bondioli, A.; Calabresi, L.; De Vergori, V.; Gomaraschi, M.; Mombelli, G.; Pazzucconi, F.; Zacherl, C.; Arnoldi, A. Hypocholesterolaemic effects of lupin protein and pea protein/fibre combinations in moderately hypercholesterolaemic individuals Br. J. Nutr. 2012, 107, 1176– 1183
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    18
    Hypocholesterolaemic effects of lupin protein and pea protein/fibre combinations in moderately hypercholesterolaemic individuals
    Sirtori, Cesare R.; Triolo, Michela; Bosisio, Raffaella; Bondioli, Alighiero; Calabresi, Laura; De Vergori, Viviana; Gomaraschi, Monica; Mombelli, Giuliana; Pazzucconi, Franco; Zacherl, Christian; Arnoldi, Anna
    British Journal of Nutrition (2012), 107 (8), 1176-1183CODEN: BJNUAV; ISSN:0007-1145. (Cambridge University Press)
    The present study was aimed to evaluate the effect of plant proteins (lupin protein or pea protein) and their combinations with sol. fibers (oat fiber or apple pectin) on plasma total and LDL-cholesterol levels. A randomised, double-blind, parallel group design was followed: after a 4-wk run-in period, participants were randomised into seven treatment groups, each consisting of twenty-five participants. Each group consumed two bars contg. specific protein/fiber combinations: the ref. group consumed casein+cellulose; the second and third groups consumed bars contg. lupin or pea proteins+cellulose; the fourth and fifth groups consumed bars contg. casein and oat fiber or apple pectin; the sixth group and seventh group received bars contg. combinations of pea protein and oat fiber or apple pectin, resp. Bars contg. lupin protein+cellulose ( - 116 mg/l, - 4·2 %), casein+apple pectin ( - 152 mg/l, - 5·3 %), pea protein+oat fiber ( - 135 mg/l, - 4·7 %) or pea protein+apple pectin ( - 168 mg/l, - 6·4 %) resulted in significant redns. of total cholesterol levels (P < 0·05), whereas no cholesterol changes were obsd. in the subjects consuming the bars contg. casein+cellulose, casein+oat fiber or pea protein+cellulose. The present study shows the hypocholesterolemic activity and potential clin. benefits of consuming lupin protein or combinations of pea protein and a sol. fiber, such as oat fiber or apple pectin.
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  19. 19
    Bähr, M.; Fechner, A.; Kiehntopf, M.; Jahreis, G. Consuming a mixed diet enriched with lupin protein beneficially affects plasma lipids in hypercholesterolemic subjects: a randomized controlled trial Clin. Nutr. 2014, DOI: 10.1016/j.clnu.2014.03.008
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    Sirtori, C. R.; Agradi, E.; Conti, F.; Mantero, O.; Gatti, E. Soybean-protein diet in the treatment of type-II hyperlipoproteinaemia Lancet 1977, 1, 275– 277
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    Soybean-protein diet in the treatment of type-II hyperlipoproteinaemia
    Sirtori C R; Agradi E; Conti F; Mantero O; Gatti E
    Lancet (1977), 1 (8006), 275-7 ISSN:0140-6736.
    A soybean textured protein induced a 14% decrease of plasma-cholesterol levels after two weeks and 21% after three when substituted for animal proteins in a group of 20 patients with type-II hyperlipoproteinaemia. Comparison of soybean diet with a standard low-lipid diet in the same patients, according to a cross-over protocol, indicated that this hypocholesterolaemic effect was not due to differences in the lipid composition of the two diets. The hypothesis that a soy protein has a hypocholesterolaemic action per se is supported by the results of a subsequent experiment in 8 type-II patients in whom the addition of cholesterol (500 mg/day) to soy protein did not modify the hypocholesterolaemic response.
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  21. 21
    Sirtori, C. R.; Eberini, I.; Arnoldi, A. Hypocholesterolaemic effects of soya proteins: results of recent studies are predictable from the Anderson meta-analysis data Br. J. Nutr. 2007, 97, 816– 822
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    Hypocholesterolaemic effects of soya proteins: results of recent studies are predictable from the Anderson meta-analysis data
    Sirtori, Cesare R.; Eberini, Ivano; Arnoldi, Anna
    British Journal of Nutrition (2007), 97 (5), 816-822CODEN: BJNUAV; ISSN:0007-1145. (Cambridge University Press)
    A review. In 1995, Anderson et al. published a meta-anal., derived from most of the clin. studies on soya proteins given to individuals with varying levels of cholesterolemia that had been reported up to that time. The meta-anal. clearly indicated that cholesterolemias were generally reduced by diets with soya given as a partial or total substitution of animal proteins, with final mean total and LDL-cholesterol redns. of 23·2 mg/dL and 21·7 mg/dL, resp. These findings were recently strongly criticized, based on the evaluation of later studies, frequently involving individuals with normal or moderately elevated cholesterolemias. In the present paper, these more recent studies were re-evaluated using a 'nomogram' prepd. on the basis of the quartiles of initial cholesterol concns. in the Anderson meta-anal. and their corresponding CI for net cholesterol change. The five studies belonging to the first quartile and thirteen out of the fourteen belonging to the second quartile gave results perfectly in line with the nomogram. Out of the fourteen studies belonging to the third quartile, ten agreed with the nomogram and two gave lower cholesterol redns., whereas two gave higher redns. Unfortunately, none of the recent studies belonged to the fourth quartile as treatment with statins or other lipid-lowering drugs is now mandatory in the presence of very high cholesterol levels. The re-evaluation thus shows that the thirty-three studies published in the past 10 years are in agreement with the Anderson meta-anal. and confirm its validity.
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  22. 22
    Anderson, J. W.; Johnstone, B. M.; Cook-Newell, M. E. Meta-analysis of the effects of soy protein intake on serum lipids N. Engl. J. Med. 1995, 333, 276– 282
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    Meta-analysis of the effects of soy protein intake on serum lipids
    Anderson, James W.; Johnstone, Bryan M.; Cook-Newell, Margaret
    New England Journal of Medicine (1995), 333 (5), 276-82CODEN: NEJMAG; ISSN:0028-4793. (Massachusetts Medical Society)
    In lab. animals, the consumption of soy protein, rather than animal protein, decreases serum cholesterol concns., but studies in humans have been inconclusive. In this meta-anal. of 38 controlled clin. trials, the authors examd. the relation between soy protein consumption and serum lipid concns. in humans. The authors used a random-effects model to quantify the av. effects of soy protein intake on serum lipids in the studies the authors examd. and used hierarchical mixed-effects regression models to predict variation as a function of the characteristics of the studies. In most of the studies, the intake of energy, fat, satd. fat, and cholesterol was similar when the subjects ingested control and soy-contg. diets; soy protein intake averaged 47 g per day. Ingestion of soy protein was assocd. with the following net changes in serum lipid concns. from the concns. reached with the control diet: total cholesterol, a decrease of 23.2 mg per dL (0.60 mmol per L; 95% confidence interval, 13.5 to 32.9 mg per dL [0.35 to 0.85 mmol per L]), or 9.3%; low-d. lipoprotein (LDL) cholesterol, a decrease of 21.7 mg per dL (0.56 mmol per L; 95% confidence interval, 11.2 to 3.17 mg per dL [0.30 to 0.82 mmol per L]), or 12.9%; and triglycerides, a decrease of 13.3 mg per dL (0.15 mmol per L; 95% confidence interval 0.3 to 25.7 mg per dL [0.003 to 0.29 mmol per L]), or 10.5%. The changes in serum cholesterol and LDL cholesterol concns. were directly related to the initial serum cholesterol concn. The ingestion of soy protein was assocd. with a nonsignificant 2.4% increase in serum concns. of high-d. lipoprotein (HDL) cholesterol. The authors found that the consumption of soy protein rather than animal protein significantly decreased serum concns. of total cholesterol, LDL cholesterol, and triglycerides.
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    Harland, J.; Haffner, T. Systematic review, meta-analysis and regression of randomised controlled trials reporting an association between an intake of circa 25 g soya protein per day and blood cholesterol Atherosclerosis 2008, 200, 13– 27
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    23
    Systematic review, meta-analysis and regression of randomised controlled trials reporting an association between an intake of circa 25g soya protein per day and blood cholesterol
    Harland, Janice I.; Haffner, Tanya A.
    Atherosclerosis (Amsterdam, Netherlands) (2008), 200 (1), 13-27CODEN: ATHSBL; ISSN:0021-9150. (Elsevier B.V.)
    Aims: To det. the effect of a daily intake of circa 25 g soya protein on blood lipids in adults with normal or mildly elevated cholesterolemia. Methods: Medline and other scientific databases were searched to identify randomized controlled trials (RCTs); these were systematically reviewed against pre-detd. criteria. Eligible RCTs evaluated the effect of 25 g (range 15-40 g) soya protein on measures of blood lipids. Results from RCTs were pooled using std. meta-anal. methods. Results: Thirty studies contg. 42 treatment arms (n = 2913), with an av. soya protein intake of 26.9 g met the inclusion criteria. Soya protein inclusion led to redns. in std. difference in mean low d. lipoprotein (LDL), total cholesterol and blood triglycerides of 0.23 mmol/L (95% confidence interval (CI) -0.160 to -0.306, p < 0.0001), 0.22 mmol/L (95% CI -0.142 to -0.291, p < 0.0001) and 0.08 mmol/L (95% CI -0.004 to -0.158, p = 0.04), resp. There was no effect on mean difference in apolipoprotein A (ApoA), but ApoB was reduced by 0.021 g/L (p = 0.01) in the soya group. Meta-regression anal. indicated no dose response relationship between soya protein intake in the range of 15-40 g and std. difference in LDL or HDL. All data were tested for heterogeneity and none identified. Conclusions: The inclusion of modest amts. soya protein (ca. 25 g) into the diet of adults with normal or mild hypercholesterolemia resulted in small, highly significant redns. in total and LDL cholesterol, equiv. to ca. 6% LDL redn. This practically achievable intake, particularly when combined with other dietary measures, can make a useful contribution to blood cholesterol management.
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    FDA. Food labeling health claims: soybean protein and coronary heart disease. Final rule. Fed. Regist. 1999, 64, 57699– 57733.
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    Sirtori, C. R.; Galli, G.; Lovati, M. R.; Carrara, P.; Bosisio, E.; Kienle, M. G. Effects of dietary proteins on the regulation of liver lipoprotein receptors in rats J. Nutr. 1984, 114, 1493– 1500
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    Effects of dietary proteins on the regulation of liver lipoprotein receptors in rats
    Sirtori, Cesare R.; Galli, Giovanni; Lovati, Maria Rosa; Carrara, Patrizia; Bosisio, Enrica; Kienle, Marzia Galli
    Journal of Nutrition (1984), 114 (8), 1493-500CODEN: JONUAI; ISSN:0022-3166.
    Female rats fed a 1.2% cholesterol [57-88-5] diet with animal proteins (casein) develop a significant hypercholesterolemia, with a marked increase of very-low-d. lipoprotein (VLDL)-assocd. cholesterol. Substitution of soybean proteins for casein in the diet counteracts the increase of both total and VLDL cholesterol. Studies of liver receptor activity were carried out with both casein and soybean-cholesterol diets, to define the site of action of soybean proteins. Binding of a cholesterol-rich lipoprotein fraction (β-VLDL) to hepatic membranes is normal when a soybean-cholesterol diet is administered, and markedly reduced with casein-cholesterol. The activities of receptor-linked enzymes, hydroxymethylglutaryl-CoA reductase [9028-35-7], cholesterol 7α-hydroxylase [9037-53-0], and acyl-CoA:cholesterol O-acyltransferase (ACATase) [9027-63-8], were differently affected by the 2 diets. The reductase activity is reduced by both diets with, however, significantly higher enzyme activities in the soybean-cholesterol-fed group. Both 7α-hydroxylase and ACATase activity levels are significantly raised by casein-cholesterol but are in a normal range with soybean-cholesterol. Thus, the hepatic receptor regulation of cholesterol metab. is differently affected by animal and vegetable proteins in the diet.
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  26. 26
    Lovati, M. R.; Manzoni, C.; Canavesi, A.; Sirtori, M.; Vaccarino, V.; Marchi, M.; Gaddi, G.; Sirtori, C. R. Soybean protein diet increases low density lipoprotein receptor activity in mononuclear cells from hypercholesterolemic patients J. Clin. Invest. 1987, 80, 1498– 1502
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    Soybean protein diet increases low density lipoprotein receptor activity in mononuclear cells from hypercholesterolemic patients
    Lovati M R; Manzoni C; Canavesi A; Sirtori M; Vaccarino V; Marchi M; Gaddi G; Sirtori C R
    The Journal of clinical investigation (1987), 80 (5), 1498-502 ISSN:0021-9738.
    The effect of two diets containing different protein sources (animal vs. soybean) on the low density lipoprotein (LDL) receptor activity was tested in freshly isolated mononuclear cells from 12 individuals with severe type II hyperlipoproteinemia. The two diets, both taken for 4 wk in a crossover design were of otherwise identical composition. During the soybean protein diet period, total cholesterol was reduced by 15.9% and LDL-cholesterol by 16.4%. The diet containing animal proteins exerted no significant change in plasma lipid levels vs. the baseline findings. The soybean diet regimen dramatically affected the degradation of LDL by mononuclear cells. Degradation was increased 16-fold vs. the basal activity and 8-fold compared with the standard low lipid diet with animal proteins. There was, however, no clear relationship between the reduction of total and LDL-cholesterolemia and the increased LDL degradation. These findings confirm similar data previously obtained in cholesterol-fed rats and suggest that some factor/s, most likely of a protein nature, may regulate the expression of lipoprotein receptors in peripheral cells, particularly when receptor activity is suppressed by experimental diets and/or spontaneous hypercholesterolemia.
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  27. 27
    Baum, J. A.; Teng, H.; Erdman, J. W. J.; Weigel, R. M.; Klein, B. P.; Persky, V. W.; Freels, S.; Surya, P.; Bakhit, R. M.; Ramos, E.; Shay, N. F.; Potter, S. M. Long-term intake of soy protein improves blood lipid profiles and increases mononuclear cell low-density-lipoprotein receptor messenger RNA in hypercholesterolemic, postmenopausal women Am. J. Clin. Nutr. 1998, 68, 545– 551
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    Long-term intake of soy protein improves blood lipid profiles and increases mononuclear cell low-density-lipoprotein receptor messenger RNA in hypercholesterolemic, postmenopausal women
    Baum, Jo Ann; Teng, Hongyu; Erdman, John W., Jr.; Weigel, Ronald M.; Klein, Barbara P.; Persky, Victoria W.; Freels, Sally; Surya, Paul; Bakhit, Raga M.; Ramos, Elizabeth; Shay, Neil F.; Potter, Susan M.
    American Journal of Clinical Nutrition (1998), 68 (3), 545-551CODEN: AJCNAC; ISSN:0002-9165. (American Society for Clinical Nutrition)
    The long-term clin. effects of soy protein contg. various amts. of isoflavones on lipoproteins, mononuclear cell LDL receptor mRNA concns., and other selected cardiovascular risk factors are not well known. Sixty-six hypercholesterolemic, free-living, postmenopausal women were investigated during a 6-mo parallel-group, double-blind trial with 3 interventions. After a control period of 14 d, all subjects were randomly assigned to 1 of 3 dietary groups (all with 40 g protein): a National Cholesterol Education Program (NCEP) Step 1 diet with protein from casein and nonfat dry milk (control), an NCEP Step 1 diet with protein from isolated soy protein contg. moderate amts. of isoflavones (ISP56), or an NCEP Step 1 diet with protein from isolated soy protein contg. high amts. of isoflavones (ISP90). Non-HDL cholesterol in both the ISP56 and ISP90 groups was reduced compared with the control group (P < 0.05), whereas total cholesterol was not changed. HDL cholesterol increased in both the ISP56 and ISP90 groups (P < 0.05), whereas the ratio of total to HDL cholesterol decreased significantly in both groups compared with the control (P < 0.05). Mononuclear cell LDL receptor mRNA concns. increased in subjects consuming ISP56 or ISP90 compared with the control (P < 0.05). These results indicate that soy protein, with different amts. of isoflavones, may decrease the risk of cardiovascular disease via improved blood lipid profiles, and that the mechanism by which apolipoprotein B-contg. lipoproteins were depressed may be via alterations in LDL receptor quantity or activity.
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    Manzoni, C.; Duranti, M.; Eberini, I.; Scharnag, H.; März, W.; Castiglioni, S.; Lovati, M. Subcellular localization of soybean 7S globulin in HepG2 cells and LDL receptor up-regulation by its alpha′ constituent subunit J. Nutr. 2003, 133, 2149– 2155
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    Subcellular localization of soybean 7S globulin in HepG2 cells and LDL receptor Up-regulation by its α' constituent subunit
    Manzoni, Cristina; Duranti, Marcello; Eberini, Ivano; Scharnag, Hubert; Maerz, Winfried; Castiglioni, Silvia; Lovati, Maria R.
    Journal of Nutrition (2003), 133 (7), 2149-2155CODEN: JONUAI; ISSN:0022-3166. (American Society for Nutritional Sciences)
    The aims of this work were to monitor the subcellular localization of soybean 7S globulin in HepG2 cells and det. its interaction with cell protein components, by using laser-induced fluorescence capillary electrophoresis (LIF-CE). Furthermore, we evaluated in the same cell line the involvement of the α' constituent subunit from 7S globulin in the modulation of LDL catabolism. The results indicated a main fluorescein isothiocyanate-tagged 7S globulin (FITC-7S) component in the cytosolic fraction, that was not present in the nuclear compartment. The electrophoretic mobility of this tagged component suggested either a dissocn. of the 7S oligomer or its partial intracellular degrdn. Interactions of soybean 7S globulin with FITC-thioredoxin 1 and FITC-cyclophilin B, HepG2 cell membrane proteins, were demonstrated in in vitro assays. In a sep. expt. with HepG2 cells, the ability of the α' subunit purified from soybean 7S globulin to modulate the activity of the LDL receptors was evaluated by tracking the uptake and degrdn. of labeled LDL. The up-regulation of LDL receptors by the α' subunit, as further confirmed by a LDL receptor promoter assay, was significantly greater than that found in the control cells. In conclusion, this study, while confirming our previous indirect evidence of the key role of α' subunit on the cell cholesterol homeostasis, reveals a potentially interesting assocn. of soybean 7S globulin with proteins, such as thioredoxin 1 and cyclophilin B, that are involved in cell protection against oxidative stress.
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  29. 29
    Duranti, M.; Lovati, M. R.; Dani, V.; Barbiroli, A.; Scarafoni, A.; Castiglioni, S.; Ponzone, C.; Morazzoni, P. The alpha′ subunit from soybean 7S globulin lowers plasma lipids and upregulates liver beta-VLDL receptors in rats fed a hypercholesterolemic diet J. Nutr. 2004, 134, 1334– 1339
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    29
    The α' subunit from soybean 7S globulin lowers plasma lipids and upregulates liver β-VLDL receptors in rats fed a hypercholesterolemic diet
    Duranti, Marcello; Lovati, Maria Rosa; Dani, Valeria; Barbiroli, Alberto; Scarafoni, Alessio; Castiglioni, Silvia; Ponzone, Cesare; Morazzoni, Paolo
    Journal of Nutrition (2004), 134 (6), 1334-1339CODEN: JONUAI; ISSN:0022-3166. (American Society for Nutritional Sciences)
    Recent studies on the effects of soybean 7S globulin (β-conglycinin) subunits on the upregulation of low-d. lipoprotein (LDL) receptors in Hep G2 cells identified the α' subunit as the candidate responsible for this biol. effect. In vivo evaluation of this subunit on cholesterol homeostasis was hampered by the lack of suitable amts. of α' chain. A novel sepn. procedure allowed us to investigate the effects of the α' subunit on blood plasma cholesterol and triglyceride levels and on the activity of liver β-VLDL receptors in male Sprague-Dawley rats fed hypercholesterolemic (HC) diet. The rats in 9 groups were fed for 28 days std. diet, HC diet, HC diet + 5, 10 or 20 mg α' subunit/kg body wt./day, HC diet + 50, 100 or 200 mg soybean 7S globulin/kg body wt./day, and HC diet + 200 mg clofibrate/kg body wt./day. The highest dose of the α' subunit decreased blood plasma cholesterol and triglyceride levels by 36 and 34%, resp., in rats fed the HC diet. Clofibrate decreased blood plasma cholesterol and triglyceride levels by 38 and 41%, resp. The activity of liver β-VLDL receptors in rats fed the HC diet with the highest dose of the α' subunit had 96% increase in binding compared with the HC diet group, thus restoring the receptor activity to that of rats fed the std. diet. The data provide in vivo evidence of both blood plasma lipid-lowering properties and upregulation of liver β-VLDL receptors induced by dietary soybean 7S globulin α' subunit.
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    Consonni, A.; Lovati, M. R.; Parolari, A.; Manzoni, C.; Morazzoni, P.; Magni, C.; Duranti, M. Heterologous expression and purification of the soybean 7S globulin α′ subunit extension region: in vitro evidence of its involvement in cell cholesterol homeostasis Protein Express. Purif. 2011, 80, 125– 129
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    Cho, S.; Juillerat, M.; Lee, C. Identification of LDL-receptor transcription stimulating peptides from soybean hydrolysate in human hepatocytes J. Agric. Food Chem. 2008, 56, 4372– 4376
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    Identification of LDL-receptor transcription stimulating peptides from soybean hydrolysate in human hepatocytes
    Cho, Seong-Jun; Juillerat, Marcel A.; Lee, Cherl-Ho
    Journal of Agricultural and Food Chemistry (2008), 56 (12), 4372-4376CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)
    Soybean protein and its hydrolyzate have been reported to have cholesterol-lowering property, but the responsible components are still largely unknown. In previous study, we found that soybean protein hydrolyzate (SPH) prepd. with the protease from Bacillus amyloliquefaciens FSE-68, strongly stimulates transcription of low d. lipoprotein receptor (LDL-R). To identify LDL-R transcription stimulating peptides in human hepatocytes, the SPH was fractionated with gel permeation chromatog. and the active fraction was further sepd. by using reverse-phase chromatog. Several peptides in the most active fraction were identified by LC/MS and MS/MS anal. LDL-R transcription stimulating peptides were synthesized on the basis of identified sequences, and their effect on LDL-R transcription was tested in vitro. Among the synthesized peptides, Phe-Val-Val-Asn-Ala-Thr-Ser-Asn (FVVNATSN) showed the strongest activity, and LDL-R transcription of hepatic cells was increased to 248.8% (compared to 100% of untreated control) by FVVNATSN at a concn. of 100 μM. This study provides direct evidence that peptides derived from soybean protein can influence LDL-R transcription in hepatocytes.
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    Mochizuki, Y.; Maebuchi, M.; Kohno, M.; Hirotsuka, M.; Wadahama, H.; Moriyama, T.; Kawada, T.; Urade, R. Changes in lipid metabolism by soy β-conglycinin-derived peptides in HepG2 cells J. Agric. Food Chem. 2009, 57, 1473– 1480
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    Changes in Lipid Metabolism by Soy β-Conglycinin-Derived Peptides in HepG2 Cells
    Mochizuki, Yuko; Maebuchi, Motohiro; Kohno, Mitsutaka; Hirotsuka, Motohiko; Wadahama, Hiroyuki; Moriyama, Tatsuya; Kawada, Teruo; Urade, Reiko
    Journal of Agricultural and Food Chemistry (2009), 57 (4), 1473-1480CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)
    In this study, HepG2 cells were treated with short peptides (7S-peptides) derived from highly purified soybean β-conglycinin (7S), which was free from lipophilic protein, and the effect of the peptide treatment on lipid metab. was detd. 7S-peptide treatment suppressed the secretion of apolipoprotein B-100 from HepG2 cells into the medium. The 7S-peptides also suppressed the incorporation of 3H-glycerol and 14C-acetate into triacylglyceride but not into major phospholipids, such as phosphatidylcholine and phosphatidylethanolamine. Addnl., the synthesis of cholesterol esters was dramatically decreased for 2 h after the addn. of the 7S-peptides, whereas the synthesis of cholesterol remained unchanged by 4 h and increased by 8 h after the addn. of the 7S-peptides. The cleaved nuclear form of SREBP-2 increased 8 h after the addn. of the 7S peptides, suggesting a decrease in intracellular cholesterol levels. Anal. of changes in mRNA expression after 7S-peptide treatment suggested that the 7S-peptides lower the level of cholesterol in the endoplasmic reticulum, increase the mRNA of genes related to β-oxidn. of fatty acids, and increase the synthesis of cholesterol. From these results, it may be concluded that the peptides derived from 7S altered the lipid metab. to decrease secretion of apolipoprotein B-100-contg. lipoprotein from HepG2 cells.
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    Vermeirssen, V.; van Camp, J.; Verstraete, W. Bioavailability of angiotensin I converting enzyme inhibitory peptides Br. J. Nutr. 2004, 92, 357– 366
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    Bioavailability of angiotensin I converting enzyme inhibitory peptides
    Vermeirssen, Vanessa; van Camp, John; Verstraete, Willy
    British Journal of Nutrition (2004), 92 (3), 357-366CODEN: BJNUAV; ISSN:0007-1145. (CABI Publishing)
    A review. Hypertension or high blood pressure is a significant health problem worldwide. Bioactive peptides that inhibit angiotensin I converting enzyme (ACE) in the cardiovascular system can contribute to the prevention and treatment of hypertension. These ACE inhibitory peptides are derived from many food proteins, esp. milk proteins. An ACE inhibitory activity in vitro does not always imply an antihypertensive effect in vivo. Even if it does, it is very difficult to establish a direct relationship between in vitro and in vivo activity. This is mainly due to the bioavailability of the ACE inhibitory peptides after oral administration and the fact that peptides may influence blood pressure by mechanisms other than ACE inhibition. To exert an antihypertensive effect after oral ingestion, ACE inhibitory peptides have to reach the cardiovascular system in an active form. Therefore, they need to remain active during digestion by human proteases and be transported through the intestinal wall into the blood. The bioavailability of some ACE inhibitory peptides has been studied. It is also known that (hydroxy)proline-contg. peptides are generally resistant to degrdn. by digestive enzymes. Peptides can be absorbed intact through the intestine by paracellular and transcellular routes, but the potency of the bioactivity after absorption is inversely correlated to chain length. In addn., some strategies are proposed to increase the bioavailability of ACE inhibitory peptides. Further research into the bioavailability of ACE inhibitory peptides will lead to the development of more effective ACE inhibitory peptides and foods.
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    Brugger, D.; Schuster, H.; Zöllner, N. Familial hypercholesterolemia and familial defective apolipoprotein B-100: comparison of the phenotypic expression In 116 cases Eur. J. Med. Res. 1996, 1, 383– 386
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    Familial hypercholesterolemia and familial defective apolipoprotein B-100: comparison of the phenotypic expression In 116 cases
    Brugger D; Schuster H; Zollner N
    European journal of medical research (1996), 1 (8), 383-6 ISSN:0949-2321.
    Familial hypercholesterolemia (FH) is characterized by an increased level of LDL cholesterol, tendon xanthomas and an elevated risk of premature coronary artery disease (CAD). FH is caused by different mutations in the low density lipoprotein receptor (LDLR) gene or by a G to A mutation in exon 26 of the apolipoprotein B gene causing familial defective apolipoprotein B-100 (FDB). To compare the phenotypic expression of either defect, we studied 83 patients (76 heterozygous and 7 homozygous persons) with LDLR defects and 33 heterozygous FDB patients from Germany. We took into account other risk factors for CAD. In contrast to earlier studies, our patients where prospectively ascertained from the lipid clinic and tested for the G-A mutation. The average total cholesterol level in plasma was 413.7 mg/dl in LDLR patients and 321.8 mg/dl in FDB patients. Patients with LDLR defects had a significantly higher risk of myocardial infarction, coronary artery bypass graft, positive coronary angiography, atherosclerotic plaques in the carotid arteries and CAD (p<0.01) than patients with FDB. CAD was present in 33% and plaques in the carotid arteries in 82% of the patients with LDLR defects. No patient with FDB had severe CAD, while only 52% had plaques in the carotid arteries (p<0.05). Thus in our study, hypercholesterolemia and premature atherosclerosis were more common in LDLR patients than in FDB patients. We believe that the striking difference in CHD incidence is not sufficiently explained by the higher LDL levels in LDLR patients. A possible explanation may be that in LDLR patients, the metabolism of low density lipoproteins, intermediate density lipoproteins and very low density lipoproteins is disrupted, whereas in FDB patients there is only disruption in apo B-containing LDL.
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    Ishibashi, S.; Brown, M. S.; Goldstein, J. L.; Gerard, R. D.; Hammer, R. E.; Herz, J. Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery J. Clin. Invest. 1993, 92, 883– 893
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    Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery
    Ishibashi, Shun; Brown, Michael S.; Goldstein, Joseph L.; Gerard, Robert D.; Hammer, Robert E.; Herz, Joachim
    Journal of Clinical Investigation (1993), 92 (2), 883-93CODEN: JCINAO; ISSN:0021-9738.
    The authors employed homologous recombination in embryonic stem cells to produce mice lacking functional LDL receptor genes. Homozygous male and female mice lacking LDL receptors (LDLR-/- mice) were viable and fertile. Total plasma cholesterol levels were twofold higher than those of wild-type littermates, owing to a seven- to ninefold increase in intermediate d. lipoproteins (IDL) and LDL without a significant change in HDL. Plasma triglyceride levels were normal. The half-lives for i.v. administered 125I-VLDL and 125I-LDL were prolonged by 30-fold and 2.5-fold, resp., but the clearance of 125I-HDL was normal in the LDLR-/1 mice. Unlike wild-type mice, LDLR-/- mice responded to moderate amts. of dietary cholesterol (0.2% cholesterol/10% coconut oil) with a major increase in the cholesterol content of IDL and LDL particles. The elevated IDL/LDL level of LDLR-/- mice was reduced to normal 4 d after the i.v. injection of a recombinant replication-defective adenovirus encoding the human LDL receptor driven by the cytomegalovirus promoter. The virus restored expression of LDL receptor protein in the liver and increased the clearance of 125I-VLDL. The authors conclude that the LDL receptor is responsible in part for the low levels of VLDL, IDL, and LDL in wild-type mice and that adenovirus-encoded LDL receptors can acutely reverse the hypercholesterolemic effects of LDL receptor deficiency.
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    Twisk, J.; Gillian-Daniel, D. L.; Tebon, A.; Wang, L.; Barrett, P. H.; Attie, A. D. The role of the LDL receptor in apolipoprotein B secretion J. Clin. Invest. 2000, 105, 521– 532
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    The role of the LDL receptor in apolipoprotein B secretion
    Twisk, Jaap; Gillian-Daniel, Donald L.; Tebon, Angie; Wang, Lin; Barrett, P. Hugh R.; Attie, Alan D.
    Journal of Clinical Investigation (2000), 105 (4), 521-532CODEN: JCINAO; ISSN:0021-9738. (American Society for Clinical Investigation)
    Familial hypercholesterolemia is caused by mutations in the LDL receptor gene (Ldlr). Elevated plasma LDL levels result from slower LDL catabolism and a paradoxical lipoprotein overprodn. We explored the relationship between the presence of the LDL receptor and lipoprotein secretion in hepatocytes from both wild-type and LDL receptor-deficient mice. Ldlr-/- hepatocytes secreted apoB100 at a 3.5-fold higher rate than did wild-type hepatocytes. ApoB mRNA abundance, initial apoB synthetic rate, and abundance of the microsomal triglyceride transfer protein 97-kDa subunit did not differ between wild-type and Ldlr-/- cells. Pulse-chase anal. and multicompartmental modeling revealed that in wild-type hepatocytes, approx. 55% of newly synthesized apoB100 was degraded. However, in Ldlr-/- cells, less than 20% of apoB was degraded. In wild-type hepatocytes, approx. equal amts. of LDL receptor-dependent apoB100 degrdn. occurred via reuptake and presecretory mechanisms. Adenovirus-mediated overexpression of the LDL receptor in Ldlr-/- cells resulted in degrdn. of approx. 90% of newly synthesized apoB100. These studies show that the LDL receptor alters the proportion of apoB that escapes co- or post-translational presecretory degrdn. and mediates the reuptake of newly secreted apoB-contg. lipoprotein particles.
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    Hussain, M. M. Structural, biochemical and signaling properties of the low-density lipoprotein receptor gene family Front. Biosci. 2001, 6, D417– D428
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    Structural, biochemical and signaling properties of the low-density lipoprotein receptor gene family
    Hussain, M. Mahmood
    Frontiers in Bioscience [online computer file] (2001), 6 (), D417-D428CODEN: FRBIF6; ISSN:1093-4715. (Frontiers in Bioscience)
    A review, with refs. The low-d. lipoprotein (LDL) receptor (LDL-R) family members (LDL-R, LRP, megalin, VLDL-R, apoER2) bind several extra-cellular structurally dissimilar ligands and internalize them for degrdn. by lysosomes by a process called receptor-mediated endocytosis. The receptor-mediated endocytosis involves immobilization of circulating ligands onto the cell-surface followed by their internalization and degrdn. All the receptors can perform both of these functions. However, in the majority of the cases, other proteins immobilize ligands on to the cell-surface and subsequent internalization is mediated by these receptors. The LDL-R and LRP play important roles in plasma cholesterol homeostasis and fetal development. Megalin is an antigenic determinant for Heymann nephritis in rats and may be important for re-absorption of various mols. by the kidney. VLDL-R homolog in chicken is essential for female fertility. This receptor and apoER2 are crit. for the proper development of the brain in mice. The members of the LDL-R gene family contain several complement-type and EGF precursor-like repeats, and single transmembrane and cytoplasmic domain. Cysteine-rich complement-type repeats contg. DxSDE sequences at the C-termini constitute ligand-binding domains. In contrast to the ligand binding domains, receptor-binding domains in different ligands do not share sequence homol. It has been proposed that pos. electrostatic surface potentials, not the primary sequences, in different ligands constitute receptor-binding domains. The EGF precursor homol. repeats in receptors are important for the dissocn. of ligands from receptors in endocytic vesicles. The transmembrane domain is necessary for anchoring to membranes and the cytoplasmic domain is required for their targeting to coated pits and subsequent internalization. The receptor-mediated endocytosis involves recognition of the NPXY motif by clathrin. Recently, this motif has also been implicated in signaling pathways that are crucial in brain development. The signaling process involves the recognition of the NPXY motif by Disabled-1 protein and possibly other proteins involved in intracellular signaling cascade. The LDL-R gene family has provided important insights into the mechanisms of ligand catabolism and may serve as new targets for the treatment of different cardiovascular and neuronal disorders. In the future, their role in signaling may provide novel insights into brain development and neuronal layering.
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    Castoreno, A. B.; Wang, Y.; Stockinger, W.; Jarzylo, L. A.; Du, H.; Pagnon, J. C.; Shieh, E. C.; Nohturfft, A. Transcriptional regulation of phagocytosis-induced membrane biogenesis by sterol regulatory element binding proteins Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 13129– 13134
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    Transcriptional regulation of phagocytosis-induced membrane biogenesis by sterol regulatory element binding proteins
    Castoreno, Adam B.; Wang, Yan; Stockinger, Walter; Jarzylo, Larissa A.; Du, Hong; Pagnon, Joanne C.; Shieh, Eugenie C.; Nohturfft, Axel
    Proceedings of the National Academy of Sciences of the United States of America (2005), 102 (37), 13129-13134CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    In the process of membrane biogenesis several dozen proteins must operate in precise concert to generate ≈100 lipids at appropriate concns. To study the regulation of bilayer assembly in a cell cycle-independent manner, we have exploited the fact that phagocytes replenish membranes expended during particle engulfment in a rapid phase of lipid synthesis. In response to phagocytosis of latex beads, human embryonic kidney 293 cells synthesized cholesterol and phospholipids at amts. equiv. to the surface area of the internalized particles. Lipid synthesis was accompanied by increased transcription of several lipogenic proteins, including the low-d. lipoprotein receptor, enzymes required for cholesterol synthesis (3-hydroxy-3-methylglutaryl CoA synthase, 3-hydroxy-3-methylglutaryl CoA reductase), and fatty acid synthase. Phagocytosis triggered the proteolytic activation of two lipogenic transcription factors, sterol regulatory element binding protein-1a (SREBP-1a) and SREBP-2. Proteolysis of SREBPs coincided with the appearance of their transcriptionally active N termini in the nucleus and 3-fold activation of an SREBP-specific reporter gene. In previous studies with cultured cells, proteolytic activation of SREBP-1a and SREBP-2 has been obsd. in response to selective starvation of cells for cholesterol and unsatd. fatty acids. However, under the current conditions, SREBP-1a and SREBP-2 are induced without lipid deprivation. SREBP activation is inhibited by high levels of the SREBP-interacting proteins Insig1 or the cytosolic domain of SREBP cleavage-activating protein. Upon overexpression of these proteins, phagocytosis-induced transcription and lipid synthesis were blocked. These results identify SREBPs as essential regulators of membrane biogenesis and provide a useful system for further studies on membrane homeostasis.
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    Horton, J. D.; Shimomura, I.; Brown, M. S.; Hammer, R. E.; Goldstein, J. L.; Shimano, H. Activation of cholesterol synthesis in preference to fatty acid synthesis in liver and adipose tissue of transgenic mice overproducing sterol regulatory element-binding protein-2 J. Clin. Invest. 1998, 101, 2331– 2339
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    Activation of cholesterol synthesis in preference to fatty acid synthesis in liver and adipose tissue of transgenic mice overproducing sterol regulatory element-binding protein-2
    Horton, Jay D.; Shimomura, Iichiro; Brown, Michael S.; Hammer, Robert E.; Goldstein, Joseph L.; Shimano, Hitoshi
    Journal of Clinical Investigation (1998), 101 (11), 2331-2339CODEN: JCINAO; ISSN:0021-9738. (Rockefeller University Press)
    We produced transgenic mice that express a dominant-pos. truncated form of sterol regulatory element-binding protein-2 (SREBP-2) in liver and adipose tissue. The encoded protein lacks the membrane-binding and COOH-terminal regulatory domains, and it is therefore not susceptible to neg. regulation by cholesterol. Livers from the transgenic mice showed increases in mRNAs encoding multiple enzymes of cholesterol biosynthesis, the LDL receptor, and fatty acid biosynthesis. The elevations in mRNA for 3-hydroxy-3-methylglutaryl CoA (HMG CoA) synthase and HMG CoA reductase were esp. marked (13-fold and 75-fold, resp.). As a result, the transgenic livers showed a 28-fold increase in the rate of cholesterol synthesis and a lesser fourfold increase in fatty acid synthesis, as measured by i.p. injection of [3H]water. These results contrast with previously reported effects of dominant-pos. SREBP-1a, which activated fatty acid synthesis more than cholesterol synthesis. In adipose tissue of the SREBP-2 transgenics, the mRNAs for cholesterol biosynthetic enzymes were elevated, but the mRNAs for fatty acid biosynthetic enzymes were not. We conclude that SREBP-2 is a relatively selective activator of cholesterol synthesis, as opposed to fatty acid synthesis, in liver and adipose tissue of mice.
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    Brown, M. S.; Goldstein, J. L. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor Cell 1997, 89, 331– 340
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    The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor
    Brown, Michael S.; Goldstein, Joseph L.
    Cell (Cambridge, Massachusetts) (1997), 89 (3), 331-340CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
    A review with 62 refs. End-product regulation of cholesterol metab. is achieved predominantly through repression of transcription of genes that govern the synthesis of cholesterol and its receptor-mediated uptake from plasma lipoproteins. As an end-product repressor, cholesterol presents a special problem because it is an insol. lipid that resides almost exclusively in cell membranes. How does the cell sense the level of a membrane-embedded lipid, and how is that information transmitted to the nucleus to regulate transcription. Answers are emerging from studies of a novel family of membrane-bound transcription factors called sterol regulatory element-binding proteins (SREBPs) that regulate multiple genes involved in cholesterol biosynthesis and uptake. Here, the SREBPs are reviewed, focusing on the novel way in which sterols regulate their proteolytic release from membranes. For SREBP-2, release from the membrane is accomplished by a two-step proteolytic cascade that is regulated by sterols. Insight into this processing pathway may shed light on Alzheimer's disease and coronary artery disease.
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    Luu, W.; Sharpe, L. J.; Stevenson, J.; Brown, A. J. Akt acutely activates the cholesterogenic transcription factor SREBP-2 Biochim. Biophys. Acta 2012, 1823, 458– 464
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    Akt acutely activates the cholesterogenic transcription factor SREBP-2
    Luu, Winnie; Sharpe, Laura J.; Stevenson, Julian; Brown, Andrew J.
    Biochimica et Biophysica Acta, Molecular Cell Research (2012), 1823 (2), 458-464CODEN: BBAMCO; ISSN:0167-4889. (Elsevier B.V.)
    Akt is an essential protein kinase for cell growth, proliferation, and survival. Perturbed Akt regulation is assocd. with a no. of human diseases, such as cancer and diabetes. Recently, evidence has emerged that Akt is involved in the regulation of the sterol-regulatory element binding proteins, which are master transcriptional regulators of lipid metab. This offers a means by which synthesis of new membrane can be coordinated with cell growth and proliferation. However, the link between Akt and sterol-regulatory element binding protein-2, the major isoform participating in cholesterol regulation, is relatively unexplored. In the present study, we employed insulin-like growth factor-1 as an inducer of Akt signalling, and showed that it increased sterol-regulatory element binding protein-2 activation acutely (within 1 h). This insulin-like growth factor-1-induced sterol-regulatory element binding protein-2 activation was blunted when Akt was inhibited pharmacol. or molecularly with small interfering RNA. Furthermore, we employed a rapalog heterodimerization system to specifically and rapidly activate Akt, and found that sterol-regulatory element binding protein-2 activation was increased in response to Akt activation. Together, this study provides compelling evidence that Akt contributes to the acute regulation of cholesterol metab. through activating sterol-regulatory element binding protein-2.
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    Coordination of lipid metabolism in membrane biogenesis
    Nohturfft, Axel; Zhang, Shao Chong
    Annual Review of Cell and Developmental Biology (2009), 25 (), 539-566CODEN: ARDBF8; ISSN:1081-0706. (Annual Reviews Inc.)
    A review. Bilayer synthesis during membrane biogenesis involves the concerted assembly of multiple lipid species, requiring coordination of the level of lipid synthesis, uptake, turnover, and subcellular distribution. Here, the authors discuss some of the salient conclusions regarding the coordination of lipid synthesis that have emerged from work in mammalian and yeast cells. The principal instruments of global control are a small no. of transcription factors that target a wide range of genes encoding enzymes that operate in a given metabolic pathway. Crit. in mammalian cells are sterol regulatory element-binding proteins (SREBPs) that stimulate the expression of genes for the uptake and synthesis of cholesterol and fatty acids. From work with Saccharomyces cerevisiae, much has been learned about glycerophospholipid and ergosterol regulation through Ino2p/Ino4p and Upc2p transcription factors, resp. Lipid supply is fine-tuned through a multitude of neg. feedback circuits initiated by both end products and intermediates of lipid synthesis pathways. Moreover, there is evidence that the diversity of membrane lipids is maintained through cross-regulatory effects, whereby classes of lipids activate the activity of enzymes operating in another metabolic branch.
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    Whiteman, Eileen L.; Cho, Han; Birnbaum, Morris J.
    Trends in Endocrinology and Metabolism (2002), 13 (10), 444-451CODEN: TENME4; ISSN:1043-2760. (Elsevier Science Ltd.)
    A review. Since its discovery more than a decade ago, the Ser/Thr kinase Akt/PKB (protein kinase B) has been recognized as being remarkably well conserved across a broad range of species and involved in a diverse array of cellular processes. Among its many roles, Akt appears to be common to signaling pathways that mediate the metabolic effects of insulin in several physiol. important target tissues. Refining our understanding of those pivotal mol. components that normally coordinate insulin action throughout the body is essential for a full understanding of insulin resistance in diabetes mellitus and ultimately the successful treatment of this disease.
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    Biochimie (2004), 86 (11), 839-848CODEN: BICMBE; ISSN:0300-9084. (Elsevier B.V.)
    Sterol regulatory element binding proteins (SREBPs) are a family of transcription factors that regulate lipid homeostasis by controlling the expression of a range of enzymes required for endogenous cholesterol, fatty acid (FA), triacylglycerol and phospholipid synthesis. The three SREBP isoforms, SREBP-1a, SREBP-1c and SREBP-2, have different roles in lipid synthesis. In vivo studies using transgenic and knockout mice suggest that SREBP-1c is involved in FA synthesis and insulin-induced glucose metab. (particularly in lipogenesis), whereas SREBP-2 is relatively specific to cholesterol synthesis. The SREBP-1a isoform seems to be implicated in both pathways. SREBP transcription factors are synthesized as inactive precursors bound to the endoplasmic reticulum (ER) membranes. Upon activation, the precursor undergoes a sequential two-step cleavage process to release the NH2-terminal active domain in the nucleus (designated nSREBPs). SREBP processing is mainly controlled by cellular sterol content. When sterol levels decrease, the precursor is cleaved to activate cholesterogenic genes and maintain cholesterol homeostasis. This sterol-sensitive process appears to be a major point of regulation for the SREBP-1a and SREBP-2 isoforms but not for SREBP-1c. Moreover, the SREBP-1c isoform seems to be mainly regulated at the transcriptional level by insulin. The unique regulation and activation properties of each SREBP isoform facilitate the coordinate regulation of lipid metab.; however, further studies are needed to understand the detailed regulation pathways that specifically regulate each SREBP isoform.
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  21. Ruth Boachie, Shixiang Yao, Chibuike C Udenigwe. Molecular mechanisms of cholesterol-lowering peptides derived from food proteins. Current Opinion in Food Science 2018, 20, 58-63. DOI: 10.1016/j.cofs.2018.03.006.
  22. Maria Hayes, Stephen Bleakley. Peptides from plants and their applications. 2018,,, 603-622. DOI: 10.1016/B978-0-08-100736-5.00025-9.
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  25. Chiara Pavanello, Carmen Lammi, Massimiliano Ruscica, Raffaella Bosisio, Giuliana Mombelli, Chiara Zanoni, Laura Calabresi, Cesare R. Sirtori, Paolo Magni, Anna Arnoldi. Effects of a lupin protein concentrate on lipids, blood pressure and insulin resistance in moderately dyslipidaemic patients: A randomised controlled trial. Journal of Functional Foods 2017, 37, 8-15. DOI: 10.1016/j.jff.2017.07.039.
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  • Abstract

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    Figure 1

    Figure 1. Nano-LC MS/MS of lupin peptide mixtures: (A, B) chromatogram and full scan mass spectrum of T peptides; (C, D) chromatogram and full scan mass spectrum of P peptides.

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    Figure 2

    Figure 2. HepG2 cell viability after P and T peptide treatment. Bar graphs indicate the results of MTT cell viability assay of HepG2 cells after P and T peptide treatment for 48 h. Data points represent averages ± SEM of three independent experiments in triplicate. (∗∗) P < 0.001 and (∗∗∗) P < 0.0001 versus C. P, pepsin peptides; T, trypsin peptides; C, control.

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    Figure 3

    Figure 3. Lupin peptide effect on the catalytic domain of HMGCoAR. Bars indicate the effects of P peptides (0.5, 1.0, and 2.5 mg/mL) (A) and T peptides (0.25, 0.5, 1.0, and 2.5 mg/mL) (B) on HMGCoAR activity. HMGCoAR, physiologically, catalyzes the four-electron reduction of HMG-CoA to coenzyme A (CoA) and mevalonate (HMG-CoA + 2NADPH + 2H+ > mevalonate + 2NADP+ + CoA-SH). In this assay, the decrease in absorbance at 340 nm, which represents the oxidation of NADPH by the catalytic subunit of HMGCoAR in the presence of the substrate HMG-CoA, was measured spectrophotometrically. Data points represent averages ± SEM of three independent experiments in triplicate. (∗∗) P < 0.001 and (∗∗∗) P < 0.0001 versus C. P, pepsin peptides; T, trypsin peptides; C, control.

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    Figure 4

    Figure 4. Effect of P and T peptides on the SREBP2, LDLR, and HMGCoAR protein levels. HepG2 cells (1.5 × 105) were treated with 0.5, 1.0, and 2.5 mg/mL of P and T peptides for 24 h, respectively. SREBP2, LDLR, HMGCoAR, and β-actin immunoblotting signals were detected using specific anti-SREBP2, anti-LDLR, anti-HMGCoAR, and anti-β-actin primary antibodies, respectively (A). SREBP2 (B), LDLR (C), and HMGCoAR (D) signals were quantified by ImageJ software and normalized with β-actin signals. Bars represent averages of duplicate samples ± SEM of three independent experiments. (∗) P < 0.05 and (∗∗) P < 0.001 versus C. P, pepsin peptides; T, trypsin peptides; C, control.

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    Figure 5

    Figure 5. LDL uptake after P and T peptide treatments. HepG2 cells (3 × 104) were treated with P (0.5, 1.0, and 2.5 mg/mL) and T (0.25, 05, and 1.0 mg/mL) peptides for 24 h. LDL-Dylight 549 (10.0 μg/mL) was incubated for an additional 2 h. Excess LDL-Dylight 549 was removed, cells were washed two times with PBS, and specific fluorescent LDL uptake was analyzed by Synergy H1 (Biotek). Data points represent averages ± SEM of three independent experiments in triplicate. (∗) P < 0.05 and (∗∗) P < 0.001 versus C. P, pepsin peptides; T, trypsin peptides; C, control.

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    Figure 6

    Figure 6. Effect of P and T peptides on the activation of Akt (Ser473) and GSK3 (Ser9). HepG2 cells (1.5 × 105) were treated with 0.5 and 1 mg/mL of P and T peptides for 24 h, respectively. The phosphorylation levels of Akt (Ser473) (A) and GSK3 (Ser9) (C) and β-actin immunoblotting signals were detected using specific anti-posphoAkt (Ser473), anti-posphoGSK3β (Ser9), and anti-β-actin primary antibodies, respectively. PosphoAkt signals (B) and posphoGSK3β (D) were quantified by ImageJ software and normalized with β-actin signals. Bars represent averages of duplicate samples ± SEM of three independent experiments. (∗) P < 0.05, (∗∗) P < 0.001, and (∗∗∗) P < 0.0001 versus C. P, pepsin peptides; T, trypsin peptides; C, control; pAkt, posphoAkt; pGSK3β, posphoGSK3β.

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    Figure 7

    Figure 7. Involvement of PI3K/Akt pathway activation in the regulation of the LDLR–SREBP2 pathway through which lupin peptides mediate the cholesterol-lowering effects. HepG2 cells (1.5 × 105) were treated with 1.0 and 0.5 mg/mL of P and T peptides in the presence or absence of wortmannin for 24 h, respectively. The phosphorylation level of Akt (Ser473) (A) and β-actin immunoblotting signals were detected using specific anti-posphoAkt (Ser473) and anti-β-actin primary antibodies, respectively. Relative intensity of posphoAkt signals (B) was quantified by ImageJ software and normalized with β-actin signals. Panel C shows the LDL uptake after treatment with the PI3K inhibitor. HepG2 cells (3 × 104) were treated with P (1.0 mg/mL) and T (0.5 mg/mL) peptides in the presence or absence of wortmannin and inhibitor alone for 24 h. LDL-Dylight 549 (10.0 μg/mL) was incubated for additional 2 h. Excess LDL-Dylight 549 was removed, and cells were washed two times with PBS. Specific fluorescent LDL uptake was analyzed by Synergy H1 (Biotek). Bars represent averages of duplicate samples ± SEM of three independent experiments. pAkt, posphoAkt; P, pepsin peptides; T, trypsin peptides; C, control.

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  • References

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    This article references 55 other publications.

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      Grain legumes contain numerous phytochems. useful for their nutritional or nutraceutical properties, such as tocopherols, involved in the prevention of cardiovascular disease and eye pathologies. In this work, tocopherols were quantified in soybean, chickpea, lentil, pea, common bean, broad bean, and three lupin species. In all samples, the gamma congener was the most abundant tocopherol, followed by minor quantities of alpha-tocopherol (with the exception of common bean lacking in this congener) and delta-tocopherol (with the exception of Lupinus angustifolius and Lupinus mutabilis). Beta-tocopherol and tocotrienols were never detected. Some samples of soybean, pea, white lupin and chickpea contained over 10 mg/100 g seeds of total tocopherols. In order to est. the nutritional value, the vitamin E activity was calcd. Chickpea, soybean and, to a lesser extent, lupin, broad bean and pea may contribute in a relevant way to the daily intake of this vitamin.
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      A protein isolate from white lupin (Lupinus albus; L-ISO) has potential as a novel human food ingredient, but its nutritional effects are unknown. The authors evaluated protein quality and effects on body compn. in rats of isoenergic diets of L-ISO, lactalbumin, or casein with both restricted (10-day) and ad libitum (28-day)intake. The diets were equiv. in protein per se, but supplementation was used to balance essential amino acid levels. In both studies, the rats consumed similar amts. of each diet, and no effect of diet on the gain:feed ratio was obsd., though gain:N ratio and net protein utilization were slightly lower for the L-ISO diet. Lower large intestinal wts. after the L-ISO than after the lactalbumin diet were obsd. in both studies. The L-ISO diet resulted in lowered body fat percentage in the 10-day study but in an elevated level in the 28-day study. Liver compn. (DNA, RNA, glycogen, and fat) and plasma levels of some amino acids (His, Thr, Ala, Pro, Tyr, Val, and Met) were affected by diet, but no effects on plasma lipid, glucose, or uric acid were obsd. The L-ISO diet did not affect feed intake and has adequate nutritional quality in rats while modifying large intestinal wt. in a potentially beneficial manner, suggesting potential for this protein in human nutrition.
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      The intake of lupin-based foods could imply the exposure of consumers to quinolizidine alkaloids. The objectives of this study were to assess the genetic variation among and within 11 geog. regions of Lupinus albus ecotypes, verify the quinolizidine alkaloids amt. of alkaloid-poor L. Albus and Lupinus angustifolius varieties, and assess the effect of two climatically contrasting Italian environments on the alkaloid content. The quantitation was performed by GC-MS, and in all samples lupanine was the most abundant quinolizidine alkaloid, followed by albine and 13α-hydroxylupanine for L. Albus and by 13α-hydroxylupanine and angustifoline for L. angustifolius. Some regions tended to have a high (Azores) or low (Egypt, Near East, Maghreb) total alkaloids content, but the variation among ecotypes within regions was larger than that among regions following the estn. of variance components. Alkaloid-poor varieties tended to have higher total alkaloid contents when grown in the subcontinental climate site, exceeding in some cases the limit of 0.200 mg/g.
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      Journal of Agricultural and Food Chemistry (2006), 54 (1), 92-98CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)
      This paper describes a pilot process for obtaining protein isolates from white lupin seed with improved water soly. and technofunctional properties as well as reduced thermal damage. After a careful optimization of the process parameters, two valuable food ingredients were prepd.: lupin protein isolate type E, with a useful emulsifying capacity, and lupin protein isolate type F, with a high capability of foam formation and stabilization. The spray-drying process was particularly crit. for inducing some thermal damage, but a careful selection of the conditions permitted ingredients having only marginally impaired lysine bioavailability to be obtained. The reproducibility of the protein extn. process was tested on two different lupin varieties.
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      Doxastakis, G.; Papageorgiou, M.; Mandalou, D.; Irakli, M.; Papalamprou, E.; D’Agostina, A.; Resta, D.; Boschin, G.; Arnoldi, A. Technological properties and non-enzymatic browning of white lupin protein enriched spaghetti Food Chem. 2007, 101, 57– 64
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      Journal of Agricultural and Food Chemistry (2014), 62 (8), 1846-1851CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)
      Recently, the enzymic hydrolysis of Lupinus albus and Lupinus angustifolius proteins with pepsin was showed to produce peptides able to inhibit the angiotensin-converting enzyme (ACE). The objective of the present work was to test different hydrolytic enzymes and to investigate three lupin species (L. albus, L. angustifolius, Lupinus luteus) with the final goal of selecting the best enzyme/species combination for an efficient prodn. of ACE-inhibitory peptide mixts. Pepsin gave peptides with the best IC50 values (mean value on three species 186 ± 10 μg/mL), followed by pepsin + trypsin (198 ± 16 μg/mL), chymotrypsin (213 ± 83 μg/mL), trypsin (405 ± 54 μg/mL), corolase PP (497 ± 32 μg/mL), umamizyme (865 ± 230 μg/mL), and flavourzyme (922 ± 91 μg/mL). The three species showed similar activity scales, but after pepsin + trypsin and chymotrypsin treatments, L. luteus peptide mixts. resulted to be significantly the most active. This investigation indicates that lupin proteins may be a valuable source of ACE-inhibitory peptides, which may explain the activity obsd. in exptl. and clin. studies and foresee the application of lupin proteins into functional foods or dietary supplements.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BC2cXhsFeqtb0%253D&md5=aa85637050c242bebbb38607ebaa835a
    11. 11
      Sirtori, C. R.; Lovati, M. R.; Manzoni, C.; Castiglioni, S.; Duranti, M.; Magni, C.; Morandi, S.; D’Agostina, A.; Arnoldi, A. Proteins of white lupin seed, a naturally isoflavone-poor legume, reduce cholesterolemia in rats and increase LDL receptor activity in HepG2 cells J. Nutr. 2004, 134, 18– 23
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      11
      Proteins of white lupin seed, a naturally isoflavone-poor legume, reduce cholesterolemia in rats and increase LDL receptor activity in HepG2 cells
      Sirtori, Cesare R.; Lovati, Maria Rosa; Manzoni, Cristina; Castiglioni, Silvia; Duranti, Marcello; Magni, Chiara; Morandi, Sheila; D'Agostina, Alessandra; Arnoldi, Anna
      Journal of Nutrition (2004), 134 (1), 18-23CODEN: JONUAI; ISSN:0022-3166. (American Society for Nutritional Sciences)
      White lupin (Lupinus albus) is a widely cultivated crop that has been consumed for many years in Western Europe. It may be a useful alternative for individuals wishing to substitute animal with plant proteins for cardiovascular disease prevention. Lupin seeds have very low contents of isoflavones and lupin protein isolates are essentially isoflavone free. In rats fed casein-based diet with cholesterol and cholic acid, relatively low intakes (50 mg by gavage daily for 2 wk) of total lupin protein ext. decreased blood plasma total and VLDL+LDL cholesterol concns. by 21 and 30%, resp. To elucidate the lipid-lowering mechanism, LDL receptor activity was evaluated in human hepatoma cell line HepG2 in vitro. In this cell model, the lupin total protein ext. was essentially inactive, whereas one purified minor protein component, conglutin γ, had remarkable upregulatory effects, with maximal increases of 53 and 21% for LDL uptake and degrdn., resp. This indicated that lupin, although isoflavone free, has hypocholesterolemic activity similar to that of other leguminous proteins in an established animal model. The cholesterol decrease appears to be assocd. with stimulation of LDL receptors by a well-defined protein component of the lupin seeds as demonstrated in vitro.
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    12. 12
      Bettzieche, A.; Brandsch, C.; Weisse, K.; Hirche, F.; Eder, K.; Stangl, G. Lupin protein influences the expression of hepatic genes involved in fatty acid synthesis and triacylglycerol hydrolysis of adult rats Br. J. Nutr. 2008, 99, 952– 962
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      Lupin protein influences the expression of hepatic genes involved in fatty acid synthesis and triacylglycerol hydrolysis of adult rats
      Bettzieche, Anja; Brandsch, Corinna; Weisse, Kristin; Hirche, Frank; Eder, Klaus; Stangl, Gabriele I.
      British Journal of Nutrition (2008), 99 (5), 952-962CODEN: BJNUAV; ISSN:0007-1145. (Cambridge University Press)
      To assess the effect of lupin protein on concns. of lipids in plasma lipoproteins and liver and hepatic mRNA concns. of genes involved in lipid metab., adult rats were fed egg albumin-based diets contg. either lupin protein from Lupinus albus or casein (50 g/kg) supplemented (hypercholesterolemic) or not (normolipemic) with a cholesterol-cholate mixt. for 20 d. Lupin protein compared with casein lowered the concns. of TAG in liver (P<0·01) and circulating VLDL + chylomicrons (P<0·05) of hypercholesterolemic rats, but not of normolipemic rats. Hepatic mRNA concns. of genes involved in fatty acid synthesis such as sterol regulatory element-binding protein-1c, glucose-6-phosphate dehydrogenase, fatty acid synthase, stearoyl-CoA desaturase-1 and acyl-CoA:glycerol-3-phosphate acyltransferase were lower and mRNA concns. of lipoprotein lipase, hepatic lipase and apoA5 involved in TAG hydrolysis were higher in rats fed lupin protein than in rats fed casein. These effects were stronger in hypercholesterolemic rats than in normolipemic rats. Hypercholesterolemic rats fed the lupin protein had higher liver cholesterol concns. (P<0·01) and lower levels of LDL-cholesterol (P<0·05) than rats fed casein. No effect of lupin protein was obsd. on cholesterol concn. in VLDL + chylomicrons and HDL and hepatic mRNA concns. of genes involved in cholesterol and bile acid metab. In conclusion, the present study shows that lupin protein has hypotriacylglycerolemic action possibly via down regulation of fatty acid synthesis genes and up regulation of genes involved in TAG hydrolysis. Alterations in cholesterol metab. could not be explained on the basis of mRNA data.
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    13. 13
      Bettzieche, A.; Brandsch, C.; Schmidt, M.; Weisse, K.; Eder, K.; Stangl, G. Differing effect of protein isolates from different cultivars of blue lupin on plasma lipoproteins of hypercholesterolemic rats Biosci., Biotechnol., Biochem. 2008, 72, 3114– 3121
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      13
      Differing effect of protein isolates from different cultivars of blue lupin on plasma lipoproteins of hypercholesterolemic rats
      Bettzieche, Anja; Brandsch, Corinna; Schmidt, Manja; Weisse, Kristin; Eder, Klaus; Stangl, Gabriele I.
      Bioscience, Biotechnology, and Biochemistry (2008), 72 (12), 3114-3121CODEN: BBBIEJ; ISSN:0916-8451. (Japan Society for Bioscience, Biotechnology, and Agrochemistry)
      Protein from white lupin is capable of lowering plasma lipids. We investigated in this study the effect of total protein exts. (TPEs) from different cultivars of blue lupin (Probor, Vitabor and Boregine) and α-/β-conglutin from Boregine on the plasma lipids of rats. Rats were fed on a hypercholesterolemic diet contg. either lupin protein (50 g/kg) or casein (50 g/kg) for 17 d. The rats fed with TPE from Vitabor and α-/β-conglutin had lower triglyceride concns. in the plasma (-24% and -21%, resp.) and very-low-d. lipoprotein (VLDL; -40% and -29%, resp.) than the rats fed with casein. TPE from Vitabor was also capable of lowering low-d. lipoprotein (LDL) cholesterol (-37%). In the liver of the rats fed with TPE from Vitabor, the expression of the genes involved in triglyceride and cholesterol synthesis was down-regulated. This study shows that the Vitabor cultivar of blue lupin had the most beneficial effect on plasma lipids which was presumed to have been caused by the down-regulation of genes involved in lipid synthesis.
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    14. 14
      Parolini, C.; Rigamonti, E.; Marchesi, M.; Busnelli, M.; Cinquanta, P.; Manzini, S.; Sirtori, C.; Chiesa, G. Cholesterol-lowering effect of dietary Lupinus angustifolius proteins in adult rats through regulation of genes involved in cholesterol homeostasis Food Chem. 2012, 132, 1475– 1479
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      14
      Cholesterol-lowering effect of dietary Lupinus angustifolius proteins in adult rats through regulation of genes involved in cholesterol homeostasis
      Parolini, Cinzia; Rigamonti, Elena; Marchesi, Marta; Busnelli, Marco; Cinquanta, Paola; Manzini, Stefano; Sirtori, Cesare R.; Chiesa, Giulia
      Food Chemistry (2012), 132 (3), 1475-1479CODEN: FOCHDJ; ISSN:0308-8146. (Elsevier Ltd.)
      In the absence of a clear indication from previous studies, a rat study was designed to evaluate a possible hypolipidemic effect of Lupinus angustifolius (blue lupin) proteins. Rats were fed for 28 days Nath's hypercholesterolemic diets contg. 20% casein or blue lupin proteins. After 14 and 28 days of dietary treatment, blue-lupin-fed rats had markedly lower plasma total cholesterol levels than rats fed casein (-53.0% and -55.3%, resp., p < 0.0005). No significant differences were instead obsd. for triglyceride and HDL-cholesterol levels between the two groups. Lupin-protein-fed rats displayed higher hepatic mRNA levels of SREBP-2, a major transcriptional regulator of intracellular cholesterol levels, and CYP7A1, the rate-limiting enzyme in bile acid biosynthesis (p < 0.05). In conclusion, the present study demonstrates a marked cholesterol-lowering activity of proteins from L. angustifolius in rats. Moreover, blue lupin proteins appear to affect cellular lipid homeostasis by up-regulating SREBP-2 and CYP7A1 genes.
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    15. 15
      Fontanari, G.; Batistuti, J.; da Cruz, R.; Saldiva, P.; Areas, J. Cholesterol-lowering effect of whole lupin (Lupinus albus) seed and its protein isolate Food Chem. 2012, 132, 1521– 1526
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      15
      Cholesterol-lowering effect of whole lupin (Lupinus albus) seed and its protein isolate
      Fontanari, Gustavo Guadagnucci; Batistuti, Jose Paschoal; Jose da Cruz, Robison; Saldiva, Paulo Hilario Nascimento; Areas, Jose Alfredo Gomes
      Food Chemistry (2012), 132 (3), 1521-1526CODEN: FOCHDJ; ISSN:0308-8146. (Elsevier Ltd.)
      This study describes the hypocholesterolemic effect of whole lupin and its protein in hamsters. The diets were: casein (control group HC), lupin protein isolate (group HPI) and whole lupin seed (group HWS). Diets from HPI and HWS promoted a significant redn. of total cholesterol and non-HDL cholesterol in the hamsters' plasma as compared with HC. The true digestibility of HPI and HC groups were similar and differed significantly from the HWS one, which in turn showed a significant difference in total sterol excretion as compared to the former groups. Histol. anal. of the liver revealed that animals fed on HPI and HWS diets presented a low level of steatosis (level 1) as compared to the ones fed on HC diet (level 4). Our findings demonstrate that protein isolate from Lupinus albus from Brazil has a metabolic effect on endogenous cholesterol metab. and a protector effect on development of hepatic steatosis.
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    16. 16
      Marchesi, M.; Parolini, C.; Diani, E.; Rigamonti, E.; Cornelli, L.; Arnoldi, A.; Sirtori, C. R.; Chiesa, G. Hypolipidaemic and anti-atherosclerotic effects of lupin proteins in a rabbit model Br. J. Nutr. 2008, 100, 707– 710
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      16
      Hypolipidaemic and anti-atherosclerotic effects of lupin proteins in a rabbit model
      Marchesi, Marta; Parolini, Cinzia; Diani, Erika; Rigamonti, Elena; Cornelli, Lorena; Arnoldi, Anna; Sirtori, Cesare R.; Chiesa, Giulia
      British Journal of Nutrition (2008), 100 (4), 707-710CODEN: BJNUAV; ISSN:0007-1145. (Cambridge University Press)
      The biol. activities of a protein isolate from lupin (Lupinus albus) were studied in a rabbit model of atherosclerosis. Focal plaque development was induced at both common carotid arteries by perivascular injury. After surgery, animals were fed three different diets for 90 d, all with 1% cholesterol, 15% SFA and 20% protein; the protein source was casein (CAS), lupin proteins (LUP) or 50% CAS + 50% LUP (CAS + LUP). Lower cholesterolemia was detected in the LUP v. the CAS group at 60 and 90 d of treatment (-40.3% and -33.5%, resp.; P < 0.05). Cryosection analyses of the carotids indicated a significant redn. in focal lesion progression in the LUP vs. the CAS group (-37.4%; P < 0.05). In summary, in a rabbit model of atherosclerosis, a protein isolate from L. albus reduced cholesterolemia and exerted a remarkable protective activity against atherosclerosis progression.
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    17. 17
      Naruszewicz, M.; Nowicka, G.; Klosiewicz-Latoszek, L.; Arnoldi, A.; Sirtori, C. Effect of lupin protein (Lupinus albus) on cardiovascular risk factors in smokers with mild hypercholesterolemia Circulation 2006, 114, 874– 874
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    18. 18
      Sirtori, C. R.; Triolo, M.; Bosisio, R.; Bondioli, A.; Calabresi, L.; De Vergori, V.; Gomaraschi, M.; Mombelli, G.; Pazzucconi, F.; Zacherl, C.; Arnoldi, A. Hypocholesterolaemic effects of lupin protein and pea protein/fibre combinations in moderately hypercholesterolaemic individuals Br. J. Nutr. 2012, 107, 1176– 1183
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      18
      Hypocholesterolaemic effects of lupin protein and pea protein/fibre combinations in moderately hypercholesterolaemic individuals
      Sirtori, Cesare R.; Triolo, Michela; Bosisio, Raffaella; Bondioli, Alighiero; Calabresi, Laura; De Vergori, Viviana; Gomaraschi, Monica; Mombelli, Giuliana; Pazzucconi, Franco; Zacherl, Christian; Arnoldi, Anna
      British Journal of Nutrition (2012), 107 (8), 1176-1183CODEN: BJNUAV; ISSN:0007-1145. (Cambridge University Press)
      The present study was aimed to evaluate the effect of plant proteins (lupin protein or pea protein) and their combinations with sol. fibers (oat fiber or apple pectin) on plasma total and LDL-cholesterol levels. A randomised, double-blind, parallel group design was followed: after a 4-wk run-in period, participants were randomised into seven treatment groups, each consisting of twenty-five participants. Each group consumed two bars contg. specific protein/fiber combinations: the ref. group consumed casein+cellulose; the second and third groups consumed bars contg. lupin or pea proteins+cellulose; the fourth and fifth groups consumed bars contg. casein and oat fiber or apple pectin; the sixth group and seventh group received bars contg. combinations of pea protein and oat fiber or apple pectin, resp. Bars contg. lupin protein+cellulose ( - 116 mg/l, - 4·2 %), casein+apple pectin ( - 152 mg/l, - 5·3 %), pea protein+oat fiber ( - 135 mg/l, - 4·7 %) or pea protein+apple pectin ( - 168 mg/l, - 6·4 %) resulted in significant redns. of total cholesterol levels (P < 0·05), whereas no cholesterol changes were obsd. in the subjects consuming the bars contg. casein+cellulose, casein+oat fiber or pea protein+cellulose. The present study shows the hypocholesterolemic activity and potential clin. benefits of consuming lupin protein or combinations of pea protein and a sol. fiber, such as oat fiber or apple pectin.
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    19. 19
      Bähr, M.; Fechner, A.; Kiehntopf, M.; Jahreis, G. Consuming a mixed diet enriched with lupin protein beneficially affects plasma lipids in hypercholesterolemic subjects: a randomized controlled trial Clin. Nutr. 2014, DOI: 10.1016/j.clnu.2014.03.008
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      Sirtori, C. R.; Agradi, E.; Conti, F.; Mantero, O.; Gatti, E. Soybean-protein diet in the treatment of type-II hyperlipoproteinaemia Lancet 1977, 1, 275– 277
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      Soybean-protein diet in the treatment of type-II hyperlipoproteinaemia
      Sirtori C R; Agradi E; Conti F; Mantero O; Gatti E
      Lancet (1977), 1 (8006), 275-7 ISSN:0140-6736.
      A soybean textured protein induced a 14% decrease of plasma-cholesterol levels after two weeks and 21% after three when substituted for animal proteins in a group of 20 patients with type-II hyperlipoproteinaemia. Comparison of soybean diet with a standard low-lipid diet in the same patients, according to a cross-over protocol, indicated that this hypocholesterolaemic effect was not due to differences in the lipid composition of the two diets. The hypothesis that a soy protein has a hypocholesterolaemic action per se is supported by the results of a subsequent experiment in 8 type-II patients in whom the addition of cholesterol (500 mg/day) to soy protein did not modify the hypocholesterolaemic response.
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    21. 21
      Sirtori, C. R.; Eberini, I.; Arnoldi, A. Hypocholesterolaemic effects of soya proteins: results of recent studies are predictable from the Anderson meta-analysis data Br. J. Nutr. 2007, 97, 816– 822
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      Hypocholesterolaemic effects of soya proteins: results of recent studies are predictable from the Anderson meta-analysis data
      Sirtori, Cesare R.; Eberini, Ivano; Arnoldi, Anna
      British Journal of Nutrition (2007), 97 (5), 816-822CODEN: BJNUAV; ISSN:0007-1145. (Cambridge University Press)
      A review. In 1995, Anderson et al. published a meta-anal., derived from most of the clin. studies on soya proteins given to individuals with varying levels of cholesterolemia that had been reported up to that time. The meta-anal. clearly indicated that cholesterolemias were generally reduced by diets with soya given as a partial or total substitution of animal proteins, with final mean total and LDL-cholesterol redns. of 23·2 mg/dL and 21·7 mg/dL, resp. These findings were recently strongly criticized, based on the evaluation of later studies, frequently involving individuals with normal or moderately elevated cholesterolemias. In the present paper, these more recent studies were re-evaluated using a 'nomogram' prepd. on the basis of the quartiles of initial cholesterol concns. in the Anderson meta-anal. and their corresponding CI for net cholesterol change. The five studies belonging to the first quartile and thirteen out of the fourteen belonging to the second quartile gave results perfectly in line with the nomogram. Out of the fourteen studies belonging to the third quartile, ten agreed with the nomogram and two gave lower cholesterol redns., whereas two gave higher redns. Unfortunately, none of the recent studies belonged to the fourth quartile as treatment with statins or other lipid-lowering drugs is now mandatory in the presence of very high cholesterol levels. The re-evaluation thus shows that the thirty-three studies published in the past 10 years are in agreement with the Anderson meta-anal. and confirm its validity.
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      Anderson, J. W.; Johnstone, B. M.; Cook-Newell, M. E. Meta-analysis of the effects of soy protein intake on serum lipids N. Engl. J. Med. 1995, 333, 276– 282
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      Meta-analysis of the effects of soy protein intake on serum lipids
      Anderson, James W.; Johnstone, Bryan M.; Cook-Newell, Margaret
      New England Journal of Medicine (1995), 333 (5), 276-82CODEN: NEJMAG; ISSN:0028-4793. (Massachusetts Medical Society)
      In lab. animals, the consumption of soy protein, rather than animal protein, decreases serum cholesterol concns., but studies in humans have been inconclusive. In this meta-anal. of 38 controlled clin. trials, the authors examd. the relation between soy protein consumption and serum lipid concns. in humans. The authors used a random-effects model to quantify the av. effects of soy protein intake on serum lipids in the studies the authors examd. and used hierarchical mixed-effects regression models to predict variation as a function of the characteristics of the studies. In most of the studies, the intake of energy, fat, satd. fat, and cholesterol was similar when the subjects ingested control and soy-contg. diets; soy protein intake averaged 47 g per day. Ingestion of soy protein was assocd. with the following net changes in serum lipid concns. from the concns. reached with the control diet: total cholesterol, a decrease of 23.2 mg per dL (0.60 mmol per L; 95% confidence interval, 13.5 to 32.9 mg per dL [0.35 to 0.85 mmol per L]), or 9.3%; low-d. lipoprotein (LDL) cholesterol, a decrease of 21.7 mg per dL (0.56 mmol per L; 95% confidence interval, 11.2 to 3.17 mg per dL [0.30 to 0.82 mmol per L]), or 12.9%; and triglycerides, a decrease of 13.3 mg per dL (0.15 mmol per L; 95% confidence interval 0.3 to 25.7 mg per dL [0.003 to 0.29 mmol per L]), or 10.5%. The changes in serum cholesterol and LDL cholesterol concns. were directly related to the initial serum cholesterol concn. The ingestion of soy protein was assocd. with a nonsignificant 2.4% increase in serum concns. of high-d. lipoprotein (HDL) cholesterol. The authors found that the consumption of soy protein rather than animal protein significantly decreased serum concns. of total cholesterol, LDL cholesterol, and triglycerides.
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      Harland, J.; Haffner, T. Systematic review, meta-analysis and regression of randomised controlled trials reporting an association between an intake of circa 25 g soya protein per day and blood cholesterol Atherosclerosis 2008, 200, 13– 27
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      23
      Systematic review, meta-analysis and regression of randomised controlled trials reporting an association between an intake of circa 25g soya protein per day and blood cholesterol
      Harland, Janice I.; Haffner, Tanya A.
      Atherosclerosis (Amsterdam, Netherlands) (2008), 200 (1), 13-27CODEN: ATHSBL; ISSN:0021-9150. (Elsevier B.V.)
      Aims: To det. the effect of a daily intake of circa 25 g soya protein on blood lipids in adults with normal or mildly elevated cholesterolemia. Methods: Medline and other scientific databases were searched to identify randomized controlled trials (RCTs); these were systematically reviewed against pre-detd. criteria. Eligible RCTs evaluated the effect of 25 g (range 15-40 g) soya protein on measures of blood lipids. Results from RCTs were pooled using std. meta-anal. methods. Results: Thirty studies contg. 42 treatment arms (n = 2913), with an av. soya protein intake of 26.9 g met the inclusion criteria. Soya protein inclusion led to redns. in std. difference in mean low d. lipoprotein (LDL), total cholesterol and blood triglycerides of 0.23 mmol/L (95% confidence interval (CI) -0.160 to -0.306, p < 0.0001), 0.22 mmol/L (95% CI -0.142 to -0.291, p < 0.0001) and 0.08 mmol/L (95% CI -0.004 to -0.158, p = 0.04), resp. There was no effect on mean difference in apolipoprotein A (ApoA), but ApoB was reduced by 0.021 g/L (p = 0.01) in the soya group. Meta-regression anal. indicated no dose response relationship between soya protein intake in the range of 15-40 g and std. difference in LDL or HDL. All data were tested for heterogeneity and none identified. Conclusions: The inclusion of modest amts. soya protein (ca. 25 g) into the diet of adults with normal or mild hypercholesterolemia resulted in small, highly significant redns. in total and LDL cholesterol, equiv. to ca. 6% LDL redn. This practically achievable intake, particularly when combined with other dietary measures, can make a useful contribution to blood cholesterol management.
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      FDA. Food labeling health claims: soybean protein and coronary heart disease. Final rule. Fed. Regist. 1999, 64, 57699– 57733.
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      Sirtori, C. R.; Galli, G.; Lovati, M. R.; Carrara, P.; Bosisio, E.; Kienle, M. G. Effects of dietary proteins on the regulation of liver lipoprotein receptors in rats J. Nutr. 1984, 114, 1493– 1500
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      Effects of dietary proteins on the regulation of liver lipoprotein receptors in rats
      Sirtori, Cesare R.; Galli, Giovanni; Lovati, Maria Rosa; Carrara, Patrizia; Bosisio, Enrica; Kienle, Marzia Galli
      Journal of Nutrition (1984), 114 (8), 1493-500CODEN: JONUAI; ISSN:0022-3166.
      Female rats fed a 1.2% cholesterol [57-88-5] diet with animal proteins (casein) develop a significant hypercholesterolemia, with a marked increase of very-low-d. lipoprotein (VLDL)-assocd. cholesterol. Substitution of soybean proteins for casein in the diet counteracts the increase of both total and VLDL cholesterol. Studies of liver receptor activity were carried out with both casein and soybean-cholesterol diets, to define the site of action of soybean proteins. Binding of a cholesterol-rich lipoprotein fraction (β-VLDL) to hepatic membranes is normal when a soybean-cholesterol diet is administered, and markedly reduced with casein-cholesterol. The activities of receptor-linked enzymes, hydroxymethylglutaryl-CoA reductase [9028-35-7], cholesterol 7α-hydroxylase [9037-53-0], and acyl-CoA:cholesterol O-acyltransferase (ACATase) [9027-63-8], were differently affected by the 2 diets. The reductase activity is reduced by both diets with, however, significantly higher enzyme activities in the soybean-cholesterol-fed group. Both 7α-hydroxylase and ACATase activity levels are significantly raised by casein-cholesterol but are in a normal range with soybean-cholesterol. Thus, the hepatic receptor regulation of cholesterol metab. is differently affected by animal and vegetable proteins in the diet.
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    26. 26
      Lovati, M. R.; Manzoni, C.; Canavesi, A.; Sirtori, M.; Vaccarino, V.; Marchi, M.; Gaddi, G.; Sirtori, C. R. Soybean protein diet increases low density lipoprotein receptor activity in mononuclear cells from hypercholesterolemic patients J. Clin. Invest. 1987, 80, 1498– 1502
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      Soybean protein diet increases low density lipoprotein receptor activity in mononuclear cells from hypercholesterolemic patients
      Lovati M R; Manzoni C; Canavesi A; Sirtori M; Vaccarino V; Marchi M; Gaddi G; Sirtori C R
      The Journal of clinical investigation (1987), 80 (5), 1498-502 ISSN:0021-9738.
      The effect of two diets containing different protein sources (animal vs. soybean) on the low density lipoprotein (LDL) receptor activity was tested in freshly isolated mononuclear cells from 12 individuals with severe type II hyperlipoproteinemia. The two diets, both taken for 4 wk in a crossover design were of otherwise identical composition. During the soybean protein diet period, total cholesterol was reduced by 15.9% and LDL-cholesterol by 16.4%. The diet containing animal proteins exerted no significant change in plasma lipid levels vs. the baseline findings. The soybean diet regimen dramatically affected the degradation of LDL by mononuclear cells. Degradation was increased 16-fold vs. the basal activity and 8-fold compared with the standard low lipid diet with animal proteins. There was, however, no clear relationship between the reduction of total and LDL-cholesterolemia and the increased LDL degradation. These findings confirm similar data previously obtained in cholesterol-fed rats and suggest that some factor/s, most likely of a protein nature, may regulate the expression of lipoprotein receptors in peripheral cells, particularly when receptor activity is suppressed by experimental diets and/or spontaneous hypercholesterolemia.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A280%3ADyaL1c%252FlvFGqtg%253D%253D&md5=832826e3bc68e9e478cf5c1c0c0febf1
    27. 27
      Baum, J. A.; Teng, H.; Erdman, J. W. J.; Weigel, R. M.; Klein, B. P.; Persky, V. W.; Freels, S.; Surya, P.; Bakhit, R. M.; Ramos, E.; Shay, N. F.; Potter, S. M. Long-term intake of soy protein improves blood lipid profiles and increases mononuclear cell low-density-lipoprotein receptor messenger RNA in hypercholesterolemic, postmenopausal women Am. J. Clin. Nutr. 1998, 68, 545– 551
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      Long-term intake of soy protein improves blood lipid profiles and increases mononuclear cell low-density-lipoprotein receptor messenger RNA in hypercholesterolemic, postmenopausal women
      Baum, Jo Ann; Teng, Hongyu; Erdman, John W., Jr.; Weigel, Ronald M.; Klein, Barbara P.; Persky, Victoria W.; Freels, Sally; Surya, Paul; Bakhit, Raga M.; Ramos, Elizabeth; Shay, Neil F.; Potter, Susan M.
      American Journal of Clinical Nutrition (1998), 68 (3), 545-551CODEN: AJCNAC; ISSN:0002-9165. (American Society for Clinical Nutrition)
      The long-term clin. effects of soy protein contg. various amts. of isoflavones on lipoproteins, mononuclear cell LDL receptor mRNA concns., and other selected cardiovascular risk factors are not well known. Sixty-six hypercholesterolemic, free-living, postmenopausal women were investigated during a 6-mo parallel-group, double-blind trial with 3 interventions. After a control period of 14 d, all subjects were randomly assigned to 1 of 3 dietary groups (all with 40 g protein): a National Cholesterol Education Program (NCEP) Step 1 diet with protein from casein and nonfat dry milk (control), an NCEP Step 1 diet with protein from isolated soy protein contg. moderate amts. of isoflavones (ISP56), or an NCEP Step 1 diet with protein from isolated soy protein contg. high amts. of isoflavones (ISP90). Non-HDL cholesterol in both the ISP56 and ISP90 groups was reduced compared with the control group (P < 0.05), whereas total cholesterol was not changed. HDL cholesterol increased in both the ISP56 and ISP90 groups (P < 0.05), whereas the ratio of total to HDL cholesterol decreased significantly in both groups compared with the control (P < 0.05). Mononuclear cell LDL receptor mRNA concns. increased in subjects consuming ISP56 or ISP90 compared with the control (P < 0.05). These results indicate that soy protein, with different amts. of isoflavones, may decrease the risk of cardiovascular disease via improved blood lipid profiles, and that the mechanism by which apolipoprotein B-contg. lipoproteins were depressed may be via alterations in LDL receptor quantity or activity.
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    28. 28
      Manzoni, C.; Duranti, M.; Eberini, I.; Scharnag, H.; März, W.; Castiglioni, S.; Lovati, M. Subcellular localization of soybean 7S globulin in HepG2 cells and LDL receptor up-regulation by its alpha′ constituent subunit J. Nutr. 2003, 133, 2149– 2155
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      Subcellular localization of soybean 7S globulin in HepG2 cells and LDL receptor Up-regulation by its α' constituent subunit
      Manzoni, Cristina; Duranti, Marcello; Eberini, Ivano; Scharnag, Hubert; Maerz, Winfried; Castiglioni, Silvia; Lovati, Maria R.
      Journal of Nutrition (2003), 133 (7), 2149-2155CODEN: JONUAI; ISSN:0022-3166. (American Society for Nutritional Sciences)
      The aims of this work were to monitor the subcellular localization of soybean 7S globulin in HepG2 cells and det. its interaction with cell protein components, by using laser-induced fluorescence capillary electrophoresis (LIF-CE). Furthermore, we evaluated in the same cell line the involvement of the α' constituent subunit from 7S globulin in the modulation of LDL catabolism. The results indicated a main fluorescein isothiocyanate-tagged 7S globulin (FITC-7S) component in the cytosolic fraction, that was not present in the nuclear compartment. The electrophoretic mobility of this tagged component suggested either a dissocn. of the 7S oligomer or its partial intracellular degrdn. Interactions of soybean 7S globulin with FITC-thioredoxin 1 and FITC-cyclophilin B, HepG2 cell membrane proteins, were demonstrated in in vitro assays. In a sep. expt. with HepG2 cells, the ability of the α' subunit purified from soybean 7S globulin to modulate the activity of the LDL receptors was evaluated by tracking the uptake and degrdn. of labeled LDL. The up-regulation of LDL receptors by the α' subunit, as further confirmed by a LDL receptor promoter assay, was significantly greater than that found in the control cells. In conclusion, this study, while confirming our previous indirect evidence of the key role of α' subunit on the cell cholesterol homeostasis, reveals a potentially interesting assocn. of soybean 7S globulin with proteins, such as thioredoxin 1 and cyclophilin B, that are involved in cell protection against oxidative stress.
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    29. 29
      Duranti, M.; Lovati, M. R.; Dani, V.; Barbiroli, A.; Scarafoni, A.; Castiglioni, S.; Ponzone, C.; Morazzoni, P. The alpha′ subunit from soybean 7S globulin lowers plasma lipids and upregulates liver beta-VLDL receptors in rats fed a hypercholesterolemic diet J. Nutr. 2004, 134, 1334– 1339
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      The α' subunit from soybean 7S globulin lowers plasma lipids and upregulates liver β-VLDL receptors in rats fed a hypercholesterolemic diet
      Duranti, Marcello; Lovati, Maria Rosa; Dani, Valeria; Barbiroli, Alberto; Scarafoni, Alessio; Castiglioni, Silvia; Ponzone, Cesare; Morazzoni, Paolo
      Journal of Nutrition (2004), 134 (6), 1334-1339CODEN: JONUAI; ISSN:0022-3166. (American Society for Nutritional Sciences)
      Recent studies on the effects of soybean 7S globulin (β-conglycinin) subunits on the upregulation of low-d. lipoprotein (LDL) receptors in Hep G2 cells identified the α' subunit as the candidate responsible for this biol. effect. In vivo evaluation of this subunit on cholesterol homeostasis was hampered by the lack of suitable amts. of α' chain. A novel sepn. procedure allowed us to investigate the effects of the α' subunit on blood plasma cholesterol and triglyceride levels and on the activity of liver β-VLDL receptors in male Sprague-Dawley rats fed hypercholesterolemic (HC) diet. The rats in 9 groups were fed for 28 days std. diet, HC diet, HC diet + 5, 10 or 20 mg α' subunit/kg body wt./day, HC diet + 50, 100 or 200 mg soybean 7S globulin/kg body wt./day, and HC diet + 200 mg clofibrate/kg body wt./day. The highest dose of the α' subunit decreased blood plasma cholesterol and triglyceride levels by 36 and 34%, resp., in rats fed the HC diet. Clofibrate decreased blood plasma cholesterol and triglyceride levels by 38 and 41%, resp. The activity of liver β-VLDL receptors in rats fed the HC diet with the highest dose of the α' subunit had 96% increase in binding compared with the HC diet group, thus restoring the receptor activity to that of rats fed the std. diet. The data provide in vivo evidence of both blood plasma lipid-lowering properties and upregulation of liver β-VLDL receptors induced by dietary soybean 7S globulin α' subunit.
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    30. 30
      Consonni, A.; Lovati, M. R.; Parolari, A.; Manzoni, C.; Morazzoni, P.; Magni, C.; Duranti, M. Heterologous expression and purification of the soybean 7S globulin α′ subunit extension region: in vitro evidence of its involvement in cell cholesterol homeostasis Protein Express. Purif. 2011, 80, 125– 129
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      Cho, S.; Juillerat, M.; Lee, C. Identification of LDL-receptor transcription stimulating peptides from soybean hydrolysate in human hepatocytes J. Agric. Food Chem. 2008, 56, 4372– 4376
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      Identification of LDL-receptor transcription stimulating peptides from soybean hydrolysate in human hepatocytes
      Cho, Seong-Jun; Juillerat, Marcel A.; Lee, Cherl-Ho
      Journal of Agricultural and Food Chemistry (2008), 56 (12), 4372-4376CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)
      Soybean protein and its hydrolyzate have been reported to have cholesterol-lowering property, but the responsible components are still largely unknown. In previous study, we found that soybean protein hydrolyzate (SPH) prepd. with the protease from Bacillus amyloliquefaciens FSE-68, strongly stimulates transcription of low d. lipoprotein receptor (LDL-R). To identify LDL-R transcription stimulating peptides in human hepatocytes, the SPH was fractionated with gel permeation chromatog. and the active fraction was further sepd. by using reverse-phase chromatog. Several peptides in the most active fraction were identified by LC/MS and MS/MS anal. LDL-R transcription stimulating peptides were synthesized on the basis of identified sequences, and their effect on LDL-R transcription was tested in vitro. Among the synthesized peptides, Phe-Val-Val-Asn-Ala-Thr-Ser-Asn (FVVNATSN) showed the strongest activity, and LDL-R transcription of hepatic cells was increased to 248.8% (compared to 100% of untreated control) by FVVNATSN at a concn. of 100 μM. This study provides direct evidence that peptides derived from soybean protein can influence LDL-R transcription in hepatocytes.
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      Mochizuki, Y.; Maebuchi, M.; Kohno, M.; Hirotsuka, M.; Wadahama, H.; Moriyama, T.; Kawada, T.; Urade, R. Changes in lipid metabolism by soy β-conglycinin-derived peptides in HepG2 cells J. Agric. Food Chem. 2009, 57, 1473– 1480
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      Changes in Lipid Metabolism by Soy β-Conglycinin-Derived Peptides in HepG2 Cells
      Mochizuki, Yuko; Maebuchi, Motohiro; Kohno, Mitsutaka; Hirotsuka, Motohiko; Wadahama, Hiroyuki; Moriyama, Tatsuya; Kawada, Teruo; Urade, Reiko
      Journal of Agricultural and Food Chemistry (2009), 57 (4), 1473-1480CODEN: JAFCAU; ISSN:0021-8561. (American Chemical Society)
      In this study, HepG2 cells were treated with short peptides (7S-peptides) derived from highly purified soybean β-conglycinin (7S), which was free from lipophilic protein, and the effect of the peptide treatment on lipid metab. was detd. 7S-peptide treatment suppressed the secretion of apolipoprotein B-100 from HepG2 cells into the medium. The 7S-peptides also suppressed the incorporation of 3H-glycerol and 14C-acetate into triacylglyceride but not into major phospholipids, such as phosphatidylcholine and phosphatidylethanolamine. Addnl., the synthesis of cholesterol esters was dramatically decreased for 2 h after the addn. of the 7S-peptides, whereas the synthesis of cholesterol remained unchanged by 4 h and increased by 8 h after the addn. of the 7S-peptides. The cleaved nuclear form of SREBP-2 increased 8 h after the addn. of the 7S peptides, suggesting a decrease in intracellular cholesterol levels. Anal. of changes in mRNA expression after 7S-peptide treatment suggested that the 7S-peptides lower the level of cholesterol in the endoplasmic reticulum, increase the mRNA of genes related to β-oxidn. of fatty acids, and increase the synthesis of cholesterol. From these results, it may be concluded that the peptides derived from 7S altered the lipid metab. to decrease secretion of apolipoprotein B-100-contg. lipoprotein from HepG2 cells.
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      Vermeirssen, V.; van Camp, J.; Verstraete, W. Bioavailability of angiotensin I converting enzyme inhibitory peptides Br. J. Nutr. 2004, 92, 357– 366
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      Bioavailability of angiotensin I converting enzyme inhibitory peptides
      Vermeirssen, Vanessa; van Camp, John; Verstraete, Willy
      British Journal of Nutrition (2004), 92 (3), 357-366CODEN: BJNUAV; ISSN:0007-1145. (CABI Publishing)
      A review. Hypertension or high blood pressure is a significant health problem worldwide. Bioactive peptides that inhibit angiotensin I converting enzyme (ACE) in the cardiovascular system can contribute to the prevention and treatment of hypertension. These ACE inhibitory peptides are derived from many food proteins, esp. milk proteins. An ACE inhibitory activity in vitro does not always imply an antihypertensive effect in vivo. Even if it does, it is very difficult to establish a direct relationship between in vitro and in vivo activity. This is mainly due to the bioavailability of the ACE inhibitory peptides after oral administration and the fact that peptides may influence blood pressure by mechanisms other than ACE inhibition. To exert an antihypertensive effect after oral ingestion, ACE inhibitory peptides have to reach the cardiovascular system in an active form. Therefore, they need to remain active during digestion by human proteases and be transported through the intestinal wall into the blood. The bioavailability of some ACE inhibitory peptides has been studied. It is also known that (hydroxy)proline-contg. peptides are generally resistant to degrdn. by digestive enzymes. Peptides can be absorbed intact through the intestine by paracellular and transcellular routes, but the potency of the bioactivity after absorption is inversely correlated to chain length. In addn., some strategies are proposed to increase the bioavailability of ACE inhibitory peptides. Further research into the bioavailability of ACE inhibitory peptides will lead to the development of more effective ACE inhibitory peptides and foods.
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      Brugger, D.; Schuster, H.; Zöllner, N. Familial hypercholesterolemia and familial defective apolipoprotein B-100: comparison of the phenotypic expression In 116 cases Eur. J. Med. Res. 1996, 1, 383– 386
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      Familial hypercholesterolemia and familial defective apolipoprotein B-100: comparison of the phenotypic expression In 116 cases
      Brugger D; Schuster H; Zollner N
      European journal of medical research (1996), 1 (8), 383-6 ISSN:0949-2321.
      Familial hypercholesterolemia (FH) is characterized by an increased level of LDL cholesterol, tendon xanthomas and an elevated risk of premature coronary artery disease (CAD). FH is caused by different mutations in the low density lipoprotein receptor (LDLR) gene or by a G to A mutation in exon 26 of the apolipoprotein B gene causing familial defective apolipoprotein B-100 (FDB). To compare the phenotypic expression of either defect, we studied 83 patients (76 heterozygous and 7 homozygous persons) with LDLR defects and 33 heterozygous FDB patients from Germany. We took into account other risk factors for CAD. In contrast to earlier studies, our patients where prospectively ascertained from the lipid clinic and tested for the G-A mutation. The average total cholesterol level in plasma was 413.7 mg/dl in LDLR patients and 321.8 mg/dl in FDB patients. Patients with LDLR defects had a significantly higher risk of myocardial infarction, coronary artery bypass graft, positive coronary angiography, atherosclerotic plaques in the carotid arteries and CAD (p<0.01) than patients with FDB. CAD was present in 33% and plaques in the carotid arteries in 82% of the patients with LDLR defects. No patient with FDB had severe CAD, while only 52% had plaques in the carotid arteries (p<0.05). Thus in our study, hypercholesterolemia and premature atherosclerosis were more common in LDLR patients than in FDB patients. We believe that the striking difference in CHD incidence is not sufficiently explained by the higher LDL levels in LDLR patients. A possible explanation may be that in LDLR patients, the metabolism of low density lipoproteins, intermediate density lipoproteins and very low density lipoproteins is disrupted, whereas in FDB patients there is only disruption in apo B-containing LDL.
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      Ishibashi, S.; Brown, M. S.; Goldstein, J. L.; Gerard, R. D.; Hammer, R. E.; Herz, J. Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery J. Clin. Invest. 1993, 92, 883– 893
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      Hypercholesterolemia in low density lipoprotein receptor knockout mice and its reversal by adenovirus-mediated gene delivery
      Ishibashi, Shun; Brown, Michael S.; Goldstein, Joseph L.; Gerard, Robert D.; Hammer, Robert E.; Herz, Joachim
      Journal of Clinical Investigation (1993), 92 (2), 883-93CODEN: JCINAO; ISSN:0021-9738.
      The authors employed homologous recombination in embryonic stem cells to produce mice lacking functional LDL receptor genes. Homozygous male and female mice lacking LDL receptors (LDLR-/- mice) were viable and fertile. Total plasma cholesterol levels were twofold higher than those of wild-type littermates, owing to a seven- to ninefold increase in intermediate d. lipoproteins (IDL) and LDL without a significant change in HDL. Plasma triglyceride levels were normal. The half-lives for i.v. administered 125I-VLDL and 125I-LDL were prolonged by 30-fold and 2.5-fold, resp., but the clearance of 125I-HDL was normal in the LDLR-/1 mice. Unlike wild-type mice, LDLR-/- mice responded to moderate amts. of dietary cholesterol (0.2% cholesterol/10% coconut oil) with a major increase in the cholesterol content of IDL and LDL particles. The elevated IDL/LDL level of LDLR-/- mice was reduced to normal 4 d after the i.v. injection of a recombinant replication-defective adenovirus encoding the human LDL receptor driven by the cytomegalovirus promoter. The virus restored expression of LDL receptor protein in the liver and increased the clearance of 125I-VLDL. The authors conclude that the LDL receptor is responsible in part for the low levels of VLDL, IDL, and LDL in wild-type mice and that adenovirus-encoded LDL receptors can acutely reverse the hypercholesterolemic effects of LDL receptor deficiency.
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      Twisk, J.; Gillian-Daniel, D. L.; Tebon, A.; Wang, L.; Barrett, P. H.; Attie, A. D. The role of the LDL receptor in apolipoprotein B secretion J. Clin. Invest. 2000, 105, 521– 532
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      The role of the LDL receptor in apolipoprotein B secretion
      Twisk, Jaap; Gillian-Daniel, Donald L.; Tebon, Angie; Wang, Lin; Barrett, P. Hugh R.; Attie, Alan D.
      Journal of Clinical Investigation (2000), 105 (4), 521-532CODEN: JCINAO; ISSN:0021-9738. (American Society for Clinical Investigation)
      Familial hypercholesterolemia is caused by mutations in the LDL receptor gene (Ldlr). Elevated plasma LDL levels result from slower LDL catabolism and a paradoxical lipoprotein overprodn. We explored the relationship between the presence of the LDL receptor and lipoprotein secretion in hepatocytes from both wild-type and LDL receptor-deficient mice. Ldlr-/- hepatocytes secreted apoB100 at a 3.5-fold higher rate than did wild-type hepatocytes. ApoB mRNA abundance, initial apoB synthetic rate, and abundance of the microsomal triglyceride transfer protein 97-kDa subunit did not differ between wild-type and Ldlr-/- cells. Pulse-chase anal. and multicompartmental modeling revealed that in wild-type hepatocytes, approx. 55% of newly synthesized apoB100 was degraded. However, in Ldlr-/- cells, less than 20% of apoB was degraded. In wild-type hepatocytes, approx. equal amts. of LDL receptor-dependent apoB100 degrdn. occurred via reuptake and presecretory mechanisms. Adenovirus-mediated overexpression of the LDL receptor in Ldlr-/- cells resulted in degrdn. of approx. 90% of newly synthesized apoB100. These studies show that the LDL receptor alters the proportion of apoB that escapes co- or post-translational presecretory degrdn. and mediates the reuptake of newly secreted apoB-contg. lipoprotein particles.
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      Hussain, M. M. Structural, biochemical and signaling properties of the low-density lipoprotein receptor gene family Front. Biosci. 2001, 6, D417– D428
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      Structural, biochemical and signaling properties of the low-density lipoprotein receptor gene family
      Hussain, M. Mahmood
      Frontiers in Bioscience [online computer file] (2001), 6 (), D417-D428CODEN: FRBIF6; ISSN:1093-4715. (Frontiers in Bioscience)
      A review, with refs. The low-d. lipoprotein (LDL) receptor (LDL-R) family members (LDL-R, LRP, megalin, VLDL-R, apoER2) bind several extra-cellular structurally dissimilar ligands and internalize them for degrdn. by lysosomes by a process called receptor-mediated endocytosis. The receptor-mediated endocytosis involves immobilization of circulating ligands onto the cell-surface followed by their internalization and degrdn. All the receptors can perform both of these functions. However, in the majority of the cases, other proteins immobilize ligands on to the cell-surface and subsequent internalization is mediated by these receptors. The LDL-R and LRP play important roles in plasma cholesterol homeostasis and fetal development. Megalin is an antigenic determinant for Heymann nephritis in rats and may be important for re-absorption of various mols. by the kidney. VLDL-R homolog in chicken is essential for female fertility. This receptor and apoER2 are crit. for the proper development of the brain in mice. The members of the LDL-R gene family contain several complement-type and EGF precursor-like repeats, and single transmembrane and cytoplasmic domain. Cysteine-rich complement-type repeats contg. DxSDE sequences at the C-termini constitute ligand-binding domains. In contrast to the ligand binding domains, receptor-binding domains in different ligands do not share sequence homol. It has been proposed that pos. electrostatic surface potentials, not the primary sequences, in different ligands constitute receptor-binding domains. The EGF precursor homol. repeats in receptors are important for the dissocn. of ligands from receptors in endocytic vesicles. The transmembrane domain is necessary for anchoring to membranes and the cytoplasmic domain is required for their targeting to coated pits and subsequent internalization. The receptor-mediated endocytosis involves recognition of the NPXY motif by clathrin. Recently, this motif has also been implicated in signaling pathways that are crucial in brain development. The signaling process involves the recognition of the NPXY motif by Disabled-1 protein and possibly other proteins involved in intracellular signaling cascade. The LDL-R gene family has provided important insights into the mechanisms of ligand catabolism and may serve as new targets for the treatment of different cardiovascular and neuronal disorders. In the future, their role in signaling may provide novel insights into brain development and neuronal layering.
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      Castoreno, A. B.; Wang, Y.; Stockinger, W.; Jarzylo, L. A.; Du, H.; Pagnon, J. C.; Shieh, E. C.; Nohturfft, A. Transcriptional regulation of phagocytosis-induced membrane biogenesis by sterol regulatory element binding proteins Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 13129– 13134
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      Transcriptional regulation of phagocytosis-induced membrane biogenesis by sterol regulatory element binding proteins
      Castoreno, Adam B.; Wang, Yan; Stockinger, Walter; Jarzylo, Larissa A.; Du, Hong; Pagnon, Joanne C.; Shieh, Eugenie C.; Nohturfft, Axel
      Proceedings of the National Academy of Sciences of the United States of America (2005), 102 (37), 13129-13134CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      In the process of membrane biogenesis several dozen proteins must operate in precise concert to generate ≈100 lipids at appropriate concns. To study the regulation of bilayer assembly in a cell cycle-independent manner, we have exploited the fact that phagocytes replenish membranes expended during particle engulfment in a rapid phase of lipid synthesis. In response to phagocytosis of latex beads, human embryonic kidney 293 cells synthesized cholesterol and phospholipids at amts. equiv. to the surface area of the internalized particles. Lipid synthesis was accompanied by increased transcription of several lipogenic proteins, including the low-d. lipoprotein receptor, enzymes required for cholesterol synthesis (3-hydroxy-3-methylglutaryl CoA synthase, 3-hydroxy-3-methylglutaryl CoA reductase), and fatty acid synthase. Phagocytosis triggered the proteolytic activation of two lipogenic transcription factors, sterol regulatory element binding protein-1a (SREBP-1a) and SREBP-2. Proteolysis of SREBPs coincided with the appearance of their transcriptionally active N termini in the nucleus and 3-fold activation of an SREBP-specific reporter gene. In previous studies with cultured cells, proteolytic activation of SREBP-1a and SREBP-2 has been obsd. in response to selective starvation of cells for cholesterol and unsatd. fatty acids. However, under the current conditions, SREBP-1a and SREBP-2 are induced without lipid deprivation. SREBP activation is inhibited by high levels of the SREBP-interacting proteins Insig1 or the cytosolic domain of SREBP cleavage-activating protein. Upon overexpression of these proteins, phagocytosis-induced transcription and lipid synthesis were blocked. These results identify SREBPs as essential regulators of membrane biogenesis and provide a useful system for further studies on membrane homeostasis.
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      Horton, J. D.; Shimomura, I.; Brown, M. S.; Hammer, R. E.; Goldstein, J. L.; Shimano, H. Activation of cholesterol synthesis in preference to fatty acid synthesis in liver and adipose tissue of transgenic mice overproducing sterol regulatory element-binding protein-2 J. Clin. Invest. 1998, 101, 2331– 2339
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      Activation of cholesterol synthesis in preference to fatty acid synthesis in liver and adipose tissue of transgenic mice overproducing sterol regulatory element-binding protein-2
      Horton, Jay D.; Shimomura, Iichiro; Brown, Michael S.; Hammer, Robert E.; Goldstein, Joseph L.; Shimano, Hitoshi
      Journal of Clinical Investigation (1998), 101 (11), 2331-2339CODEN: JCINAO; ISSN:0021-9738. (Rockefeller University Press)
      We produced transgenic mice that express a dominant-pos. truncated form of sterol regulatory element-binding protein-2 (SREBP-2) in liver and adipose tissue. The encoded protein lacks the membrane-binding and COOH-terminal regulatory domains, and it is therefore not susceptible to neg. regulation by cholesterol. Livers from the transgenic mice showed increases in mRNAs encoding multiple enzymes of cholesterol biosynthesis, the LDL receptor, and fatty acid biosynthesis. The elevations in mRNA for 3-hydroxy-3-methylglutaryl CoA (HMG CoA) synthase and HMG CoA reductase were esp. marked (13-fold and 75-fold, resp.). As a result, the transgenic livers showed a 28-fold increase in the rate of cholesterol synthesis and a lesser fourfold increase in fatty acid synthesis, as measured by i.p. injection of [3H]water. These results contrast with previously reported effects of dominant-pos. SREBP-1a, which activated fatty acid synthesis more than cholesterol synthesis. In adipose tissue of the SREBP-2 transgenics, the mRNAs for cholesterol biosynthetic enzymes were elevated, but the mRNAs for fatty acid biosynthetic enzymes were not. We conclude that SREBP-2 is a relatively selective activator of cholesterol synthesis, as opposed to fatty acid synthesis, in liver and adipose tissue of mice.
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      Brown, M. S.; Goldstein, J. L. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor Cell 1997, 89, 331– 340
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      The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor
      Brown, Michael S.; Goldstein, Joseph L.
      Cell (Cambridge, Massachusetts) (1997), 89 (3), 331-340CODEN: CELLB5; ISSN:0092-8674. (Cell Press)
      A review with 62 refs. End-product regulation of cholesterol metab. is achieved predominantly through repression of transcription of genes that govern the synthesis of cholesterol and its receptor-mediated uptake from plasma lipoproteins. As an end-product repressor, cholesterol presents a special problem because it is an insol. lipid that resides almost exclusively in cell membranes. How does the cell sense the level of a membrane-embedded lipid, and how is that information transmitted to the nucleus to regulate transcription. Answers are emerging from studies of a novel family of membrane-bound transcription factors called sterol regulatory element-binding proteins (SREBPs) that regulate multiple genes involved in cholesterol biosynthesis and uptake. Here, the SREBPs are reviewed, focusing on the novel way in which sterols regulate their proteolytic release from membranes. For SREBP-2, release from the membrane is accomplished by a two-step proteolytic cascade that is regulated by sterols. Insight into this processing pathway may shed light on Alzheimer's disease and coronary artery disease.
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      Luu, W.; Sharpe, L. J.; Stevenson, J.; Brown, A. J. Akt acutely activates the cholesterogenic transcription factor SREBP-2 Biochim. Biophys. Acta 2012, 1823, 458– 464
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      Akt acutely activates the cholesterogenic transcription factor SREBP-2
      Luu, Winnie; Sharpe, Laura J.; Stevenson, Julian; Brown, Andrew J.
      Biochimica et Biophysica Acta, Molecular Cell Research (2012), 1823 (2), 458-464CODEN: BBAMCO; ISSN:0167-4889. (Elsevier B.V.)
      Akt is an essential protein kinase for cell growth, proliferation, and survival. Perturbed Akt regulation is assocd. with a no. of human diseases, such as cancer and diabetes. Recently, evidence has emerged that Akt is involved in the regulation of the sterol-regulatory element binding proteins, which are master transcriptional regulators of lipid metab. This offers a means by which synthesis of new membrane can be coordinated with cell growth and proliferation. However, the link between Akt and sterol-regulatory element binding protein-2, the major isoform participating in cholesterol regulation, is relatively unexplored. In the present study, we employed insulin-like growth factor-1 as an inducer of Akt signalling, and showed that it increased sterol-regulatory element binding protein-2 activation acutely (within 1 h). This insulin-like growth factor-1-induced sterol-regulatory element binding protein-2 activation was blunted when Akt was inhibited pharmacol. or molecularly with small interfering RNA. Furthermore, we employed a rapalog heterodimerization system to specifically and rapidly activate Akt, and found that sterol-regulatory element binding protein-2 activation was increased in response to Akt activation. Together, this study provides compelling evidence that Akt contributes to the acute regulation of cholesterol metab. through activating sterol-regulatory element binding protein-2.
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      Annual Review of Cell and Developmental Biology (2009), 25 (), 539-566CODEN: ARDBF8; ISSN:1081-0706. (Annual Reviews Inc.)
      A review. Bilayer synthesis during membrane biogenesis involves the concerted assembly of multiple lipid species, requiring coordination of the level of lipid synthesis, uptake, turnover, and subcellular distribution. Here, the authors discuss some of the salient conclusions regarding the coordination of lipid synthesis that have emerged from work in mammalian and yeast cells. The principal instruments of global control are a small no. of transcription factors that target a wide range of genes encoding enzymes that operate in a given metabolic pathway. Crit. in mammalian cells are sterol regulatory element-binding proteins (SREBPs) that stimulate the expression of genes for the uptake and synthesis of cholesterol and fatty acids. From work with Saccharomyces cerevisiae, much has been learned about glycerophospholipid and ergosterol regulation through Ino2p/Ino4p and Upc2p transcription factors, resp. Lipid supply is fine-tuned through a multitude of neg. feedback circuits initiated by both end products and intermediates of lipid synthesis pathways. Moreover, there is evidence that the diversity of membrane lipids is maintained through cross-regulatory effects, whereby classes of lipids activate the activity of enzymes operating in another metabolic branch.
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      Trends in Endocrinology and Metabolism (2002), 13 (10), 444-451CODEN: TENME4; ISSN:1043-2760. (Elsevier Science Ltd.)
      A review. Since its discovery more than a decade ago, the Ser/Thr kinase Akt/PKB (protein kinase B) has been recognized as being remarkably well conserved across a broad range of species and involved in a diverse array of cellular processes. Among its many roles, Akt appears to be common to signaling pathways that mediate the metabolic effects of insulin in several physiol. important target tissues. Refining our understanding of those pivotal mol. components that normally coordinate insulin action throughout the body is essential for a full understanding of insulin resistance in diabetes mellitus and ultimately the successful treatment of this disease.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADC%252BD38XosFCmsrw%253D&md5=63791865269698c59fa64feac0be5440
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      Journal of Cellular and Molecular Medicine (2005), 9 (1), 59-71CODEN: JCMMC9; ISSN:1582-1838. ("Carol Davila" University Press)
      A review. Akt/PKB is a serine/threonine protein kinase that functions as a crit. regulator of cell survival and proliferation. Akt/PKB family comprises 3 highly homologous members known as PKBα/Akt1, PKBβ/Akt2, and PKBγ/Akt3 in mammalian cells. Similar to many other protein kinases, Akt/PKB contains a conserved domain structure including a specific PH domain, central kinase domain, and C-terminal regulatory domain that mediates the interaction between signaling mols. Akt/PKB plays important roles in the signaling pathways in response to growth factors and other extracellular stimuli to regulate several cellular functions including nutrient metab., cell growth, apoptosis, and survival. This review surveys recent developments in understanding the mol. mechanisms of Akt/PKB activation and its roles in cell survival in normal and cancer cells.
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      A review. Phosphatidylinositol 3'-kinase (PI3K) and Akt are signaling kinases involved in cell survival and proliferation. Recent evidence suggests that PI3K/Akt activates the sterol-regulatory element-binding proteins (SREBPs), master transcriptional regulators of lipid metab. The precise mol. mechanisms are controversial and differ between SREBP isoforms; proposed mechanisms include increased trafficking and processing of SREBP, reduced degrdn., and involvement of the downstream signaling hub, mammalian target of rapamycin complex 1 (mTORC1). In this report, we explore the various mechanistic links between Akt and SREBP. We consider this relationship in diseases where Akt and lipids play crucial roles, including diabetes, viral infections and cancer, suggesting that this Akt-SREBP link provides fresh insights into human health and disease.
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      Du, X.; Kristiana, I.; Wong, J.; Brown, A. J. Involvement of Akt in ER-to-Golgi transport of SCAP/SREBP: a link between a key cell proliferative pathway and membrane synthesis Mol. Biol. Cell 2006, 17, 2735– 2745
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      Du, Ximing; Kristiana, Ika; Wong, Jenny; Brown, Andrew J.
      Molecular Biology of the Cell (2006), 17 (6), 2735-2745CODEN: MBCEEV; ISSN:1059-1524. (American Society for Cell Biology)
      Akt is a crit. regulator of cell growth, proliferation, and survival that is activated by phosphatidylinositol 3-kinase (PI3K). We investigated the effect of PI3K inhibition on activation of sterol regulatory element binding protein-2 (SREBP-2), a master regulator of cholesterol homeostasis. SREBP-2 processing increased in response to various cholesterol depletion approaches (including statin treatment) and this increase was blunted by treatment with a potent and specific inhibitor of PI3K, LY294002, or when a plasmid encoding a dominant-neg. form of Akt (DN-Akt) was expressed. LY294002 also suppressed SREBP-2 processing induced by insulin-like growth factor-1. Furthermore, LY294002 treatment down-regulated SREBP-2 or -1c gene targets and decreased cholesterol and fatty acid synthesis. Fluorescence microscopy studies indicated that LY294002 disrupts transport of the SREBP escort protein, SCAP, from the endoplasmic reticulum to the Golgi. This disruption was also shown by immunofluorescence staining when DN-Akt was expressed. Taken together, our studies indicate that the PI3K/Akt pathway is involved in SREBP-2 transport to the Golgi, contributing to the control of SREBP-2 activation. These results provide a crucial mechanistic link between the SREBP and PI3K/Akt pathways that may be reconciled teleol. because synthesis of new membrane is an abs. requirement for cell growth and proliferation.
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      Food Chemistry (2014), 145 (), 34-40CODEN: FOCHDJ; ISSN:0308-8146. (Elsevier Ltd.)
      The objective of this investigation was to compare the angiotensin converting enzyme (ACE)-inhibitory activity of the hydrolyzates obtained by pepsin digestion of proteins of some legumes, such as chickpea, common bean, lentil, lupine, pea, and soybean, by using the same exptl. procedure. The ACE-inhibitory activity was measured by using the tripeptide hippuryl-histidyl-leucine (HHL), as model peptide, and HPLC-DAD, as anal. method. The peptide mixts. of all legumes were active, with soybean and lupine the most efficient, with IC50 values of 224 and 226 μg/mL, resp. Considering the promising results obtained with lupine, and aiming to identify the protein(s) that release(s) the peptides responsible for the activity, the peptides obtained from the pepsin digestion of some industrial lupine protein isolates and purified protein fractions were tested. The most active mixt., showing an IC50 value of 138 μg/mL, was obtained hydrolyzing a mixt. of lupine α + β conglutin.
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      In this paper, the authors pioneer application of a unique method of protein detn. by coloring peptide bonds for anal. of a variety of biomols. with different grades of purity (e.g., oligopeptides, membrane, and glycol proteins). The authors demonstrated that the calibration curve for all studied mols. is universal and linear within 0.1 to 1.2 mg protein content range. The assay thus can be used to analyze peptides without preliminary dilns. and calibration in up to 1 g/mL solns. of peptides, which is crucial for many biotechnol. processes, such as development of coatings, scaffolds, and biocompatible materials.
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      A review with 117 refs. on the development of HMG-CoA reductase inhibitors as anticholesterolemics.
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      https://chemport.cas.org/services/resolver?origin=ACS&resolution=options&coi=1%3ACAS%3A528%3ADyaK3sXhsFOhuw%253D%253D&md5=cf348ef767a7a8275a61216a36ed913f
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      Cold Spring Harbor Symposia on Quantitative Biology (2002), 67 (), 491-498CODEN: CSHSAZ; ISSN:0091-7451. (Cold Spring Harbor Laboratory Press)
      A review focuses on the transcriptional activating properties of each sterol regulatory element binding protein (SREBP) family member, and how the regulation of each SREBP isoform provides a mechanism for cells to coordinately and independently regulate the lipid biosynthetic pathways.
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      Edwards, P. A.; Tabor, D.; Kast, H. R.; Venkateswaran, A. Regulation of gene expression by SREBP and SCAP Biochim. Biophys. Acta 2000, 1529, 103– 113
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      A review with 77 refs. Sterol regulatory element binding proteins (SREBPs) function as transcription factors that activate specific genes involved in cholesterol synthesis, endocytosis of low d. lipoproteins, the synthesis of both satd. and unsatd. fatty acids and glucose metab. As such, these proteins provide a link between lipid and carbohydrate metab. There are three SREBPs, SREBP-1a, SREBP-1c and SREBP-2, that are encoded by two genes. SREBPs are synthesized as 125 kDa precursor proteins that are localized to the endoplasmic reticulum. The precursor is transported to the Golgi by a chaperone protein (SREBP-cleavage activating protein) and then cleaved by two proteases to release the mature, transcriptionally active 68 kDa amino terminal domain. Recent studies have shown that formation of mature SREBP is controlled at multiple levels in response to changes in the levels of oxysterols, insulin/glucose and polyunsatd. fatty acids. These recent findings have important clin. implications relevant to hyperlipidemia and diabetes and are the topic of this review.
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      Demoulin, J. B.; Ericsson, J.; Kallin, A.; Rorsman, C.; Rönnstrand, L.; Heldin, C. H. Platelet-derived growth factor stimulates membrane lipid synthesis through activation of phosphatidylinositol 3-kinase and sterol regulatory element-binding proteins J. Biol. Chem. 2004, 279, 35392– 35402
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      Journal of Biological Chemistry (2004), 279 (34), 35392-35402CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
      We analyzed the transcriptional program elicited by stimulation of normal human fibroblasts with platelet-derived growth factor (PDGF) using cDNA microarrays. 103 Significantly regulated transcripts that had not been previously linked to PDGF signaling were identified. Among them, a cluster of genes involved in fatty acid and cholesterol biosynthesis, including stearoyl-CoA desaturase (SCD), fatty acid synthase, and hydroxymethylglutaryl-CoA synthase (HMGCS), was up-regulated by PDGF after 24 h of treatment, and their expression correlated with increased membrane lipid prodn. These genes are known to be controlled by sterol regulatory element-binding proteins (SREBP). PDGF increased the amt. of mature SREBP-1 and regulated the promoters of SCD and HMGCS in an SREBP-dependent manner. In line with these results, blocking SREBP processing by addn. of 25-hydroxycholesterol blunted the effects of PDGF on lipogenic enzymes. SREBP activation was dependent on the phosphatidylinositol 3-kinase (PI3K) pathway, as judged from the effects of the inhibitor LY294002 and mutation of the PDGFβ receptor tyrosines that bind the PI3K adaptor subunit p85. Fibroblast growth factors (FGF-2 and FGF-4) and other growth factors mimicked the effects of PDGF on NIH3T3 and human fibroblasts. In conclusion, our results suggest that growth factors induce membrane lipid synthesis via the activation SREBP and PI3K.
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      Zhou, R. H.; Yao, M.; Lee, T. S.; Zhu, Y.; Martins-Green, M.; Shyy, J. Y. Vascular endothelial growth factor activation of sterol regulatory element binding protein: a potential role in angiogenesis Circ. Res. 2004, 95, 471– 478
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      Zhou, Rui-Hai; Yao, Min; Lee, Tzong-Shyuan; Zhu, Yi; Martins-Green, Manuela; Shyy, John Y.-J.
      Circulation Research (2004), 95 (5), 471-478CODEN: CIRUAL; ISSN:0009-7330. (Lippincott Williams & Wilkins)
      By stimulating the migration and proliferation of endothelial cells (ECs), vascular endothelial growth factor (VEGF) is a potent angiogenic factor. However, the mol. mechanism involved in the VEGF-induced angiogenesis remains elusive. We hypothesized that sterol regulatory element binding proteins (SREBPs), transcription factors governing cellular lipid homeostasis, play an important role in regulating angiogenesis in response to VEGF. VEGF activated SREBP1 and SREBP2 in ECs, as demonstrated by the increased SREBPs, their cleavage products, and the upregulation of the targeted genes. VEGF-induced SREBP activation depended on SREBP cleavage-activating protein (SCAP), because knocking down SCAP by RNA interference (RNAi) inhibited SREBP activation in response to VEGF. SREBP activation was also blocked by 25-hydroxycholesterol (25-HC). To verify the functional implication of SREBPs in VEGF-induced angiogenesis, we tested the role of SREBPs in EC migration and proliferation. SCAP RNAi or 25-HC inhibited VEGF-induced pseudopodia extension and migration of ECs. Both treatments inhibited VEGF-induced EC proliferation, with cell growth arrested at the G0/G1 phase and a concomitant decrease of the S phase. Blocking the PI3K-Akt pathway inhibited the VEGF-activated SREBPs, demonstrating that PI3K-Akt regulates SREBPs. Consistent with our in vitro data, SREBP1 was detected in newly developed microvasculatures in a rabbit skin partial-thickness wound-healing model. SREBP inhibition also markedly suppressed VEGF-induced angiogenesis in chick embryos. In summary, this study identifies SREBPs as the key mols. in regulating angiogenesis in response to VEGF.
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      Hegarty, B. D.; Bobard, A.; Hainault, I.; Ferré, P.; Bossard, P.; Foufelle, F. Distinct roles of insulin and liver X receptor in the induction and cleavage of sterol regulatory element-binding protein-1c Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 791– 796
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      Distinct roles of insulin and liver X receptor in the induction and cleavage of sterol regulatory element-binding protein-1c
      Hegarty, Bronwyn D.; Bobard, Alexandre; Hainault, Isabelle; Ferre, Pascal; Bossard, Pascale; Foufelle, Fabienne
      Proceedings of the National Academy of Sciences of the United States of America (2005), 102 (3), 791-796CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      Sterol regulatory element-binding proteins (SREBPs) are transcription factors central to the regulation of lipid metab. The SREBPs are synthesized as precursor proteins that require proteolytic processing to become transcriptionally active. Whereas the regulation of SREBP-1a and -2 cleavage by cellular sterol content is well defined, much less is known about the regulation of SREBP-1c, the predominant SREBP isoform in the liver. Both insulin and liver X receptor α (LXRα) induce SREBP-1c transcription; however, the resp. roles of these factors and the mechanism responsible for proteolytic cleavage of this SREBP isoform are not known. In this study, the authors compare the effects of insulin and LXR agonist TO-901317 on SREBP-1c expression and transcriptional activity in isolated rat hepatocytes. The authors report that full induction of the mature and transcriptionally active form of SREBP-1c protein requires insulin. Although activation of LXR leads to the induction of SREBP-1c gene expression and precursor protein, it has a very poor effect in inducing the mature nuclear form of the transcription factor. This may be due to the induction of insulin-induced gene-2a mRNA and protein by LXR activation. The LXR-induced SREBP-1c precursor, however, is rapidly cleaved on acute exposure to insulin via a phosphatidylinositol 3-kinase-dependent mechanism. Finally, the authors show through expts. in suckling mice that this acute action of insulin to stimulate the proteolytic processing of SREBP-1c is functional in vivo.
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      Eberlé, D.; Hegarty, B.; Bossard, P.; Ferré, P.; Foufelle, F. SREBP transcription factors: master regulators of lipid homeostasis Biochimie 2004, 86, 839– 848
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      SREBP transcription factors: master regulators of lipid homeostasis
      Eberle, Delphine; Hegarty, Bronwyn; Bossard, Pascale; Ferre, Pascal; Foufelle, Fabienne
      Biochimie (2004), 86 (11), 839-848CODEN: BICMBE; ISSN:0300-9084. (Elsevier B.V.)
      Sterol regulatory element binding proteins (SREBPs) are a family of transcription factors that regulate lipid homeostasis by controlling the expression of a range of enzymes required for endogenous cholesterol, fatty acid (FA), triacylglycerol and phospholipid synthesis. The three SREBP isoforms, SREBP-1a, SREBP-1c and SREBP-2, have different roles in lipid synthesis. In vivo studies using transgenic and knockout mice suggest that SREBP-1c is involved in FA synthesis and insulin-induced glucose metab. (particularly in lipogenesis), whereas SREBP-2 is relatively specific to cholesterol synthesis. The SREBP-1a isoform seems to be implicated in both pathways. SREBP transcription factors are synthesized as inactive precursors bound to the endoplasmic reticulum (ER) membranes. Upon activation, the precursor undergoes a sequential two-step cleavage process to release the NH2-terminal active domain in the nucleus (designated nSREBPs). SREBP processing is mainly controlled by cellular sterol content. When sterol levels decrease, the precursor is cleaved to activate cholesterogenic genes and maintain cholesterol homeostasis. This sterol-sensitive process appears to be a major point of regulation for the SREBP-1a and SREBP-2 isoforms but not for SREBP-1c. Moreover, the SREBP-1c isoform seems to be mainly regulated at the transcriptional level by insulin. The unique regulation and activation properties of each SREBP isoform facilitate the coordinate regulation of lipid metab.; however, further studies are needed to understand the detailed regulation pathways that specifically regulate each SREBP isoform.
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