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. Apo A-I, the major protein of plasma HDL, promotes cholesterol and phospholipid efflux and stimulates cholesteryl ester clearance from cultured cells. We found that these apo A-I-mediated lipid transport processes are virtually absent in fibroblasts from two patients with Tangier disease, a genetic disorder characterized by extremely low plasma levels of HDL, massive deposition of cholesterol esters in tissues, and a high prevalence of cardiovascular disease. We also found that the interaction of apo A-I with cell-surface binding sites is abnormal for Tangier fibroblasts, which may be the basis for the impaired lipid transport. Failure of apo A-I to acquire cellular cholesterol and phospholipids may account for the rapid catabolism of nascent HDL particles and the low plasma HDL levels in Tangier disease and other familial HDL deficiencies (FHDs). We propose to determine the prevalence of lipid transport disorders among different fibroblast lines from patients with Tangier disease and FHDs and to assess the involvement of the same or different genotypes using complementation analysis. We will also characterize the cellular processes defective in apolipoprotein-mediated removal of lipids from Tangier fibroblasts by comparing properties of cell-surface apolipoprotein binding sites between normal and Tangier fibroblasts and by determining if apolipoprotein- mediated signalling events are abnormal in Tangier cells. Lastly, we will identify gene products differentially expressed between normal and Tangier cells by 2-D gel electrophoresis and mRNA differential display. These studies will generate important information about the cellular phenotypes and genotypes that underlie Tangier disease and other FHDs and will provide insight into the molecular properties of the HDL apolipoprotein-mediated cholesterol excretory pathways in cells. A greater understanding of this pathway may suggest therapeutic approaches for correcting acquired and genetic cellular disorders associated with low plasma HDL levels and increased risk for heart disease.