Reverse Cholesterol Transport in Diabetes

University Of Washington, Seattle WA

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Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): Atherosclerotic cardiovascular disease is the most common cause of mortality and morbidity in diabetes. Abnormal HDL metabolism may contribute to diabetes-induced atherogenesis. It is believed that HDL is cardioprotective because of its role in reverse cholesterol transport, a pathway whereby HDL transports cholesterol from tissues to the liver for elimination from the body. A cellular ATP-binding cassette transporter called ABCA1 mediates the first step of this pathway by transferring cellular cholesterol and phospholipids to HDL apolipoproteins. Mutations in ABCAl impair this transfer, causing a severe HDL deficiency syndrome characterized by deposition of cholesterol in tissue macrophages and prevalent cardiovascular disease. We found that free fatty acids and glucose oxidation products, metabolic factors associated with diabetes, markedly suppress the activity of the ABCA1 lipid secretory pathway in cultured cells. This may contribute to the low HDL levels and enhanced atherogenesis associated with diabetes and other metabolic disorders. The overall objectives of this project are to characterize the mechanisms by which these metabolic factors impair the ABCAl pathway and to assess their roles in diabetes-induced atherosclerosis. Studies will characterize the processes by which fatty acids reduce ABCA1 protein expression, examine the role of nuclear receptors in the coordinate regulation of the ABCA1 pathway, identify the mechanisms by which reactive carbonyls inhibit ABCA1 expression and activity, and characterize the effects of these diabetes factors on ABCA1 expression in humans and animal models. These studies will provide important insights into possible mechanisms by which the diabetic state promotes cardiovascular disease and will help design therapeutic interventions for preventing diabetes-induced atherogenesis.