CELLULAR DISORDERS IN FAMILIAL HDL DEFICIENCIES

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Population studies have shown an inverse correlation between plasma HDL levels and risk for coronary heart disease, suggesting that HDL protects against atherosclerosis. This protection may be related to the ability of HDL to stimulate clearance of cholesterol from peripheral cells, particularly those of the artery wall. Lipid-poor HDL apolipoproteins such as apoAI remove excess cholesterol and phospholipids from cells by an active process that may account for the cardioprotective effects of HDL. This pathway is virtually absent in fibroblasts from subjects with Tangier disease (TD), a genetic disorder characterized by extremely low plasma levels of HDL, deposition of cholesteryl esters in tissue macrophages, and a high prevalence of cardiovascular disease. Other forms of familial HDL deficiency (FHD) have a less severe impairment of the same pathway. Thus a failure of apoAI to acquire cellular lipids may account for the rapid catabolism of nascent HDL particles, low HDL levels, and increased atherosclerosis in TD and other FHDs. Using microarray gene expression technology, we identified the probable TD gene product, called ABC1 , that appears to play a critical role in the apolipoprotein-mediated lipid removal pathway. We have prepared the necessary cell lines, cDNAs, antibodies, and assays for studying this protein and its gene. With these tools, we will characterize the biologic properties of ABC1 and other newly-discovered proteins using cultured cells, and we will establish the role of ABC1 in whole-body lipoprotein metabolism and atherogenesis using genetically-manipulated mouse models. Characterization of ABC1 and related proteins will advance significantly our understanding of cellular processes involved in clearing excess cholesterol from tissues by HDL apolipoproteins. These studies will help design therapeutic approaches for correcting cellular disorders associated with low plasma HDL and increased risk for heart disease.