This research program concerns 15-oxygenated sterols wich have been found to be extraordinarily potent inhibitors of cholesterol synthesis in cultured mammalian cells. Several of these compounds have been shown to have significant hypocholesterolemic activity in rats. In the course of these studies we have obtained rather striking results in preliminary studies in two species of nonhuman primates. The potential importance of these findings, coupled with our continuing fundamental studies of the chemistry and mechanisms of action of these compounds, forms the basis and justification of the renewal request. Briefly, oral administration of 5Alpha-cholest-8(14)-en-3Beta-ol-15-one to baboons caused significant lowering of serum cholesterol levels and of the levels of cholesterol in lipoprotein fraction containing low density lipoproteins (LDL) and very low density lipoproteins (VLDL). Moreover, and elevation of the levels of high density lipoprotein (HDL) cholesterol was described in animals whose initial values of HDL cholesterol were low (or in which the percentage of total serum cholesterol in the HDL fraction was low). Even more striking findings have been observed upon administration of the compound to rhesus monkeys maintained on a diet of moderate cholesterol content. LDL cholesterol and protein levels reduced markedly while HDL cholesterol and protein levels were increased. The HDL profiles were shifted to one in which the HDL2 species dominated. We now seek funds required to extend and confirm these observations in baboons and monkeys and to undertake studies to explore the mechanisms involved in the actions of the Delta8(14)-15-ketosterol in lowering serum cholesterol levels and altering the distribution of cholesterol in lipoproteins in baboons. In addition, we propose to investigate the effects of the inhibitor on serum cholesterol and plasma lipoprotein in rhesus monkeys and most importantly, to study the effect of the compound on coronary artery atherosclerosis. We also propose to extend our studies on the effects, metabolism, and mechanisms of action of 15-oxygenated sterols in cultured mammalian cells and in intact small animals and to continue our studies on the chemistry of 15-oxygenated sterols and their derivatives. The proposal involves a collaborative effort between this laboratory and two NHLBI Primate Resource Centers with additional important collaborations with investigators at a number of other institutions.
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