Structures of Biologically Active Oxysterols Determine Their Differential Effects on Phospholipid Membranes^†

Oxysterols, derivatives of cholesterol that contain a second oxygen moiety, are intermediates in cholesterol catabolism, regulators of lipid metabolism, and toxic sterols with proatherogenic effects. In model membranes, cholesterol and eight selected oxysterols were compared by fluorescence probe techniques that measure changes in bilayer order and phase behavior and by the formation of detergent-resistant membranes (DRM). The oxysterols were modified on the sterol nucleus or on the isooctyl side chain. The model membranes consisted of dipalmitoyl phosphatidylcholine (DPPC) and mixtures of dioleoyl phosphatidylcholine with DPPC and with sphingomyelin. The different oxysterols induced changes in membrane properties according to the differences in their structures. Whereas the effects of some oxysterols on membrane order, fluorescence probe microenvironment, and DRM formation were similar to those of cholesterol, others had little or no effect. An empirical correlation ranking the oxysterols by their ability to modify membrane biophysical properties when compared to cholesterol led to a significant structure/function relationship between the biophysical measurements and an important cellular phenomenon, apoptosis. 7β-Hydroxycholesterol, which is the most cytotoxic of the eight selected oxysterols, was one of the least cholesterol-like with respect to modification of membrane properties. The results suggest that an underlying mechanism for oxysterol-induced apoptosis in cells, e.g., monocyte/macrophages, should include their biophysical effects on membranes, such as the regulation of the formation and composition of sterol-rich membrane domains.