To better understand the biologic phenomenae responsible for the inverse relationship between circulating levels of HDL cholesterol and the risk of coronary artery disease we wish to continue our studies of HDL metabolism in the rat adrenal cortex, a tissue in which HDL serves a physiologic, hormonally regulated function-delivery of substrate cholesterol for steroidogenesis. We have previously shown that (1) rat adrenocortical cells possess distinctive ACTH regulated membrane recognition sites for HDL and (2) adrenal uptake of HDL cholesterol is not coupled to lysosomal degradation of the HDL particle. We have observed that (1) LDL is a partial competitor for HDL binding, (2) that apo A-I binds to the putative HDL receptor but with much reduced affinity compared to native HDL, (3) full binding activity requires native lipoprotein structure, (4) unesterified cholesterol (UC) and cholesterol esters (CE) from HDL are both taken up and converted to steroid hormones but by different mechanisms, (5) similar processes occur in the swine adrenal as well as swine and rat ovary. We are proposing to continue in our studies in two related areas. We will further characterize the HDL receptor specificity, (ii) regulation, and (iii) structure. We also wish to elucidate the nature and regulation of the cellular processes responsible for (1) uptake of UC from HDL, (2) uptake of CE from HDL, (3) adrenal mediated changes in HDL structure and (4) HDL mediated cholesterol egress. We will employ native and modified HDL as well as lipid free apoproteins and apoprotein particles to explore reception specificity and relate receptor accompany to HDL metabolism by cells in culture. Radiolabeled and modified HDL particles, in conjunction with cell fractionation, will be used to explore HDL metabolism. Studies of HDL metabolism in the rat adrenal will provide information essential to understanding general cell metabolism of HDL and its role in artherosclerosis. Such understanding could provide the basis for new therapies to prevent or reverse the atherosclerotic process.
