The proposed project is intended to promote further understanding of the physiologic effects of high density lipoproteins (HDL) in humans, and of the roles played by specific cell-surface receptors for HDL in these effects. It is ultimately hoped that these studies will yield fundamental information which will provide insights into the inverse relationship between HDL-cholesterol and atherogenesis, and that this information will be of benefit in developing effective therapeutic and preventive interventions. Such broad goals will be approached by addressing specific questions about HDL physiology and the attendant roles of HDL receptors. These questions include: 1) whether HDL-promoted net efflux of cholesterol from human fibroblasts, and net uptake of cholesterol into Hep G2 cells (a minimal-deviation human hepatoma cell line) is mediated by specific cell-surface receptors (net cholesterol flux due to HDL will be measured at baseline and when the HDL receptors are blocked or ablated); 2) whether hepatic and steroidogenic tissue HDL receptors serve to bring HDL into contact with hepatic lipase and thereby promote cholesterol uptake by these tissues (the conversion of C14-choline-labeled phosphatidylcholine within HDL to lysophosphatidylcholine will be used to assay the interaction of hepatic lipase with HDL); 3) whether HDL-cholesterol delivered to the liver through HDL receptors affects the synthesis of cholesterol and lipoproteins (Hep G2 cells will be used); 4) whether the binding of HDL to their receptors inhibits the uptake of LDL by the low affinity LDL receptor in human fibroblasts (high-affinity LDL receptor-negative cells - GM 2000 - will be used); 5) whether hepatic and fibroblast HDL receptors are under hormonal regulation; and 6) whether individual subspecies of HDL, isolated from human serum by the newly developed technique of selected-affinity immunosorption, can be assigned specific physiologic (receptor-mediated) functions which correlate with their structures.
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