Atherosclerosis is the major cause of morbidity and mortality in both insulin-dependent and insulin-independent diabetes. This may arise in part by an impaired HDL-mediated reverse cholesterol transport in diabetes, leading to accumulation of excess cholesterol in cells of the artery wall. Recent studies suggest that the removal of cholesterol from tissues is mediated by lipid poor apolipoproteins that are minor components of the total HDL particle population. The objectives of this proposal are to test how insulin-dependent diabetes affects the ability of HDL particles and lipid-poor apolipoproteins to remove lipids from cells and how diabetes-relevant molecules that may accumulate in the artery wall influence cholesterol excretory pathways in arterial cells. Studies are proposed to examine the functional, compositional, and physical properties of HDLl particles in insulin-dependent diabetic subjects; to determine if glucose-induced modifications of HDL apolipoproteins impair the ability of HDL particles to remove lipids from cells; and to test the regulatory effects of diabetes-relevant molecules on lipid efflux from a arterial smooth muscles cells and macrophages. Experiments will be conducted to compare the activities of serum and plasma from diabetic and normal subjects in removing cholesterol and phospholipid glycoxidation of HDL particles in vitro and in vivo reduces their lipid removal activities; and to examine the ability of insulin, TNF-alpha glycated and glycoxidated proteins, and macrophage derived apo E to modulate cholesterol and phospholipid excretion from cultured arterial smooth muscles cells and macrophages. These studies will provide important insights into possible mechanisms by which the diabetic state suppresses mobilization of excess cholesterol from cells of the artery wall and enhances atherogenesis.
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