Plasma HDL cholesterol concentrations have been identified in epidemiological studies as being inversely correlated to the incidence of coronary heart disease. An inverse relationship between HDL and coronary artery atherosclerosis has always been identified in monkeys, although dietary polyunsaturated fat paradoxically lowers HDL in atherosclerosis. This proposal is to study the role of HDL and atherosclerosis as modified by dietary fat, and to determine mechanisms of HDL metabolism through which dietary fat effects occur. In African green monkeys, as in humans, monounsaturated fat compared to saturated fat in the diet induces lower LDL cholesterol concentrations (similar to polyunsaturated fat), but does not result in lower HDL cholesterol as does polyunsaturated fat. Plasma HDL consists of multiple subpopulations of particles that differ in size and composition, and animals fed monounsaturated and saturated fat have more of the larger, more cholesterol ester-rich particles than the animals fed polyunsaturated that have a predominance of intermediate-sized HDL. With correlation and regression analyses, the investigators will examine the relationships between dietary fat type, lipoproteins including detailed aspects of plasma HDL heterogeneity, and atherosclerosis in the coronary arteries, carotid arteries, and aorta. THe investigators will examine the hypothesis that intermediate-density HDL subfractions are the most effective components of HDL in protecting against atherosclerosis. Nascent HDL particles, deficient in cholesterol ester, are secreted by the primate liver and dietary fat effects on their composition will be determined and compared with the composition of plasma HDL. Hepatic secretion rates and mRNA abundance for APO AI, APO AII, and APO E will be determined to provide information about the relationship between apolipoprotein gene expression, plasma HDL heterogeneity, and dietary fatty acid type. Measurements of plasma and perfusate LCAT and CETP will also be done to learn the role of these lipoprotein metabolic factors in determination of plasma HDL subfraction composition, concentration, and distribution. In addition, dietary fat effects on the expression of the LCAT and CETP genes of the liver will be documented by assessing the mRNA abundance and the rate of hepatic secretion of these proteins. The roles of LCAT and CETP in modification of nascent HDL particles, as well as the roles of the lipids and apolipoproteins in determination of the physical state of nascent HDL particles will also be determined. Taken together, these studies will provide detailed information about the relationships between dietary fat type, HDL metabolism, and atherosclerosis. Observations will be made in non-human primates demonstrated to be relevant models for human beings with premature coronary heart disease. The ultimate goal is to provide information about the specific aspects of HDL metabolism that are related to atherosclerosis in order to provide clues about prevention of coronary heart disease in man.
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