Reverse Cholesterol Transport in Diabetes

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Atherosclerotic cardiovascular disease is the most common cause of mortality and morbidity in both types 1 and 2 diabetes. There is an inverse relationship between plasma high-density (HDL) levels and cardiovascular risk, implying that factors associated with HDL metabolism are cardioprotective. Studies showing that HDL particles are abnormal in diabetes suggest that dysfunctional HDL metabolism contributes 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. The cellular ATP-binding cassette transporters ABCA1 and ABCG1 act in concert to rid macrophages of excess cholesterol and to generate cholesterol-rich HDL particles. Ablation of ABCA1 or ABCG1 in mice increases deposition of cholesterol in tissue macrophages, and mutations in ABCA1 cause a severe HDL deficiency syndrome characterized by deposition of cholesterol in tissue macrophages and prevalent cardiovascular disease. We found that glucose oxidation products and free fatty acids, metabolic factors associated with diabetes, markedly reduce ABCA1 and ABCG1 protein levels in cultured cells. Inducing diabetes in mice significantly decreased ABCA1 protein levels in macrophages, consistent with the hypothesis that impaired ABCdependent cholesterol export from macrophages contributes to the abnormal HDL and enhanced atherogenesis in diabetes. The overall objectives of this project are to characterize the mechanisms by which these metabolic factors impair the ABCA1 and ABCG1 pathways and to assess the contribution of impaired ABC transporters to the increased cardiovascular disease associated with diabetes and the metabolic syndrome. We propose to characterize the effects of glucose and glycoxidation products on the ABCA1 and ABCG1 pathways, determine how fatty acids impair the ABCA1 and ABCG1 pathways, and examine the effects of diabetes on expression and activity of ABCA1 and ABCG1 in vivo using diabetic mouse models. These studies will provide important insights into possible mechanisms by which the diabetic state promotes atherogenesis and will help design therapeutic interventions for treating cardiovascular disease.