Glucose promotes membrane cholesterol crystalline domain formation by lipid peroxidation

Abstract

Oxidative damage to vascular cell membrane phospholipids causes physicochemical changes in membrane structure and lipid organization, contributing to atherogenesis. Oxidative stress combined with hyperglycemia has been shown to further increase the risk of vascular and metabolic diseases. In this study, the effects of glucose on oxidative stress-induced cholesterol domain formation were tested in model membranes containing polyunsaturated fatty acids and physiologic levels of cholesterol. Membrane structural changes, including cholesterol domain formation, were characterized by small angle X-ray scattering (SAXS) analysis and correlated with spectrophotometrically-determined lipid hydroperoxide levels. Glucose treatment resulted in a concentration-dependent increase in lipid hydroperoxide formation, which correlated with the formation of highly-ordered cholesterol crystalline domains (unit cell periodicity of 34 A) as well as a decrease in overall membrane bilayer width. The effect of glucose on lipid peroxidation was further enhanced by increased levels of cholesterol. Treatment with free radical-scavenging agents inhibited the biochemical and structural effects of glucose, even at elevated cholesterol levels. These data demonstrate that glucose promotes changes in membrane organization, including cholesterol crystal formation, through lipid peroxidation.

Eicosapentaenoic acid inhibits glucose-induced membrane cholesterol crystalline domain formation through a potent antioxidant mechanism

“…The biophysical consequences of lipid peroxidation have been well characterized and include changes in membrane fluidity, increased membrane permeability, and changes in membrane protein activity [40][41][42][43][44]. Oxidative modification of PUFAs also causes a marked reduction in membrane d-space (i.e., bilayer width plus surface hydration) associated with interdigitation of the phospholipid acyl chain terminal methyl segments [3,45]. These alterations in the intermolecular packing characteristics of membrane phospholipids promote the displacement of cholesterol into discrete domains (d-space of 34 Å) within the phospholipid bilayer environment [4,46].…”

“…We have also reported that glucose promotes similar changes in membrane structural organization by increasing lipid peroxidation [3]. In this study, we used small angle x-ray diffraction to characterize the structural properties of model membranes treated with glucose and prepared in the absence or presence of the various test agents (each at 1:30 drug-to-phospholipid mole ratio), before and after exposure to oxidative conditions (Fig.…”

“…Oxidative stress and AGEs have been implicated in both microvascular and macrovascular complications of diabetes and other metabolic disorders [1,2]. In membranes enriched with polyunsaturated fatty acids (PUFAs), hyperglycemia promotes the formation of free radicals and cholesterol crystalline domains associated with atherosclerosis [3][4][5][6]. The non-enzymatic effects of glucose on cholesterol crystalline domain formation were shown to be enhanced under conditions of high cholesterol and could not be reproduced by mannitol [3].…”

“…In membranes enriched with polyunsaturated fatty acids (PUFAs), hyperglycemia promotes the formation of free radicals and cholesterol crystalline domains associated with atherosclerosis [3][4][5][6]. The non-enzymatic effects of glucose on cholesterol crystalline domain formation were shown to be enhanced under conditions of high cholesterol and could not be reproduced by mannitol [3]. Oxidative damage to PUFAs with glucose is of particular interest given its role in the propagation of free radicals during vascular injury and insulin resistance [1,7,8].…”

The Deleterious Effects of Oxidative and Nitrosative Stress on Palmitoylation, Membrane Lipid Rafts and Lipid-Based Cellular Signalling: New Drug Targets in Neuroimmune Disorders

“…Cholesterol is essentially the molecular glue which maintains the structural and functional integrity of lipid rafts, and hence, its depletion and altered distribution kinetics have serious consequences for membrane-based cellular signalling [79,177]. Moreover, the presence of lipid hydroperoxidases within the PM provokes the formation of crystalline membrane-restricted cholesterol domains with a concomitant reduction in the width of cholesterol-poor regions ultimately changing the internal structure of the bilayer and another element contributing to profound changes in function [179,180]. The presence of oxidised cholesterol and other lipids in the membrane further contributes to increased membrane permeability and adverse structural and functional changes [181].…”