LOW DENSITY LIPOPROTEIN (LDL) METABOLISM IN NONHUMAN PRIMATE ATHEROSCLEROSIS

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The hypothesis behind these studies is that the type of dietary fat influences atherosclerosis development through effects on LDL concentration and composition. To test this hypothesis, we will study two nonhuman primate species, the hyper-responsive cynomolgus monkey and the hypo-responsive African green monkey, fed cholesterol together with four different dietary fats [saturated, monounsaturated, polyunsaturated (n-6), and polyunsaturated (n-3)]. Measurements of plasma lipoproteins and hepatic cholesterol metabolism will be correlated with the extent and severity of coronary artery atherosclerosis. The plasma lipoprotein measurements to be made include cholesterol concentrations among classes, including LDL, HDL, and VLDL, concentrations of four apolipoproteins including apoA-I, apoA-II, apoB, and apoE, concentration of Lp(a), particle heterogeneity of LDL and HDL, and plasma cholesteryl esterification and transfer. To detect differences in the regulation of hepatic cholesterol metabolism that may be directly related to dietary modification of plasma LDL concentrations, we will measure hepatic lipoprotein and cholesterol secretion and cholesterol secretion into bile using the isolated, perfused liver. In addition, we will attempt to inhibit the cholesterol esterifying enzyme in the liver, acyl- CoA:cholesterol acyltransferase(ACAT), with specific compounds to determine the effects of this enzyme on lipoprotein particle cholesteryl ester and apoB secretion. Preliminary evidence suggests that this enzyme may be contributing cholesteryl esters to the LDL particle that increase its atherogenicity, and that some dietary fats, such as n-3 polyunsaturated fat, effectively decrease the activity of this enzyme thereby decreasing LDL atherogenicity. We will also measure the extent of cholesterol absorption in each of the animals and we will estimate the level of LDL receptor function in each of the animals with LDL turnover studies in vivo. With these measurements, we can document specific dietary effects on individual aspects of cholesterol metabolism. Each of these will then be correlated to the extent of coronary artery atherosclerosis in each of the animals. In this way, we will learn about specific aspects of lipoprotein metabolism that are correlated to atherosclerosis and are likely to play an important role in lipoprotein- mediated development of the disease. The perturbations induced by dietary fat and study of two different primate species should allow more sensitive detection of regulatory factors. Development of this information will assist in designing strategies for prevention and treatment of coronary heart disease in man, which is the overall goal of this research.