This is an application to examine the role of trans fatty acids in the development of coronary artery atherosclerosis in African green monkeys, a relevant primate species with known similarities to humans in dietary cholesterol and fatty acid responsiveness. We will contrast the extent of coronary artery atherosclerosis in monkeys fed trans fatty acids substituted isocalorically for stearic acid, and we will compare the results to the atherosclerosis outcome in animals in a parallel project in which saturated (palmitate), cis monounsaturated (oleate), and n-6 polyunsaturated (linoleate) fat is fed. We will contrast the extent of atherosclerosis in coronary arteries with that in the aorta and carotid arteries. Through these multiple comparisons, the relative atherogenicity of trans fatty acids compared to other dietary fatty acids will be clearly indicated. We will carry out studies of plasma lipoprotein metabolism to determine if trans fatty acids raise LDL cholesterol concentrations, lower HDL concentrations, and promote atherosclerosis through their effects on the plasma cholesterol transport system. We have made the observation that dietary fat that cause an accumulation of cholesteryl oleate in LDL are the most atherogenic, and we will determine if trans fatty acids have this effect. We will examine plasma LDL for compositional differences in LDL particles that have been identified as atherogenic in earlier studies, i.e. particle enlargement, cholesteryl oleate enrichment, and increased apoE content. We will document the compositional changes and particle size differences in HDL, and we will measure the rates of HDL particle formation and clearance to learn if the movement of cholesteryl ester through the HDL pool can be altered by trans fatty acids. We will do in viva turnover studies with native and methylated LDL to estimate hepatic LDL receptor function, and we will take liver biopsies to measure the cholesteryl ester content and the state of acyl CoA:cholesterol acyltransferase. Finally, after the atherosclerosis induction period is complete, when the animals are killed for atherosclerosis evaluations, we will study the livers of the animals in an isolated perfusion system to determine if the rates and amount of cholesteryl esters secreted by the liver are elevated by trans fatty acids as a means to cause an accumulation of ACAT-derived cholesteryl oleate in the plasma LDL particles, as a primary component of dietary fatty acid-mediated atherosclerosis induction.
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