Macrophages derived from blood monocytes play a role in the development of atherosclerotic lesions and are themselves precursors of many arterial foam cells. Foam cells characteristically contain cholesteryl esters which account for more than 50% of the total cellular cholesterol content. One objective of this program project will be to elucidate the mechanisms leading to cholesteryl ester accumulation in these cells. This will be approached in Project I by defining the molecular determinants promoting recognition of negatively charged LDL by the scavenger receptor of macrophages. In project II we will determine the roles of the scavenger and Beta-VLDL receptors in foam cell formation and we will isolate and study substances produced by lymphocytes (lymphokines) that are extraordinarily potent inhibitors of these receptor activities, protecting the cells against cholesteryl ester accumulation in vitro. Project III will determine the mechanisms of monocyte and lipoprotein accumulation in the intima-subintima complex. We will also study the mechanisms regulating hepatic cholesterol synthesis and cell division. Project IV will attempt to identify (1) the putative repressor of HMB-CoA reductase generated through the metabolism of mevalonate and (2) the mitogen generated through the metabolism of mevalonate and the interaction between lymphocytes and other leukocytes. Project V proposes to test the hypothesis that cholesterol synthesis is regulated prior to the formation of mevalonate but sites of regulation other than HMG-CoA reductase exist under certain conditions (e.g. fat feeding). It is proposed that the cytoplasmic enzyme acetoacetyl-CoA synthetase is such a regulatory site and acetoacetate produced in the mitochondria of the liver is exported to liver cytoplasm where it is acted upon by this enzyme and utilized preferentially for cholesterol biosynthesis. Project VI proposes to characterize the subunits of HMG-CoA reductase; directly determine the rates of synthesis and degradation of HMG-CoA reductase; quantitate mRNA levels for HMG-CoA reductase; determine if HMG-CoA reductase must be co-translationally inserted into the membranes and proteolytically modified or whether such events can occur post-translationally; determined the mechanism of action of the derivative of mevalonate isolated in project III that regulates the reductase. The information obtained from these studies should substantially increase our understanding of lipid and liporotein metabolism in atherosclerosis.
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