Lipid Peroxidation Induces Cholesterol Domain Formation in Model Membranes

Abstract

Numerous reports have established that lipid peroxidation contributes to cell injury by altering the basic physical properties and structural organization of membrane components. Oxidative modification of polyunsaturated phospholipids has been shown, in particular, to alter the intermolecular packing, thermodynamic, and phase parameters of the membrane bilayer. In this study, the effects of oxidative stress on membrane phospholipid and sterol organization were measured using small angle x-ray diffraction approaches. Model membranes enriched in dilinoleoylphosphatidylcholine were prepared at various concentrations of cholesterol and subjected to lipid peroxidation at physiologic conditions. At cholesterol-to-phospholipid mole ratios (C/P) as low as 0.4, lipid peroxidation induced the formation of discrete, membrane-restricted cholesterol domains having a unit cell periodicity or d-space value of 34 Å. The formation of cholesterol domains correlated directly with lipid hydroperoxide levels and was inhibited by treatment with vitamin E. In the absence of oxidative stress, similar cholesterol domains were observed only at C/P ratios of 1.0 or higher. In addition to changes in sterol organization, lipid peroxidation also caused reproducible changes in overall membrane structure, including a 10 Å reduction in the width of the surrounding, sterolpoor membrane bilayer. These data provided direct evidence that lipid peroxidation alters the essential organization and structure of membrane lipids in a manner that may contribute to changes in membrane function during aging and oxidative stress-related disorders.Lipid peroxidation is a degenerative process that affects unsaturated membrane lipids under conditions of oxidative stress (1). This complex process is believed to contribute to human aging and disease by disrupting the structural conformation, the packing of lipid components and, ultimately, the function of biological membranes. The polyunsaturated fatty acids of membrane phospholipids are particularly susceptible to peroxidation and undergo significant modifications, including the rearrangement or loss of double bonds and, in some cases, the reductive degradation of lipid acyl side chains (2-4). Lipid hydroperoxides, prominent intermediates of peroxidative reactions, also accumulate in the bilayer and further contribute to changes in the structural organization and packing of membrane lipid components (1). Many of the biophysical consequences of these structural modifications have been well characterized and include changes in membrane fluidity (5-7), increased membrane permeability (6, 8 -10), alteration of membrane thermotropic phase properties (11-13), and changes in membrane protein activity (14 -20).Recent studies conducted in our laboratory have provided direct evidence for changes in the molecular organization of membrane lipid bilayers following exposure to oxidative stress. Using small angle x-ray diffraction approaches, we examined model membranes composed of dilinoleoylphosphatidylcholine (DLPC), 2 befor...

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