This Program Project is designed to develop specific information about the role of lipoprotein metabolism, as modified by diet, in coronary heart disease )CHD). In our society, modification of the type and amount of dietary fat has taken on increasing importance as a means for reduction of plasma cholesterol and premature CHD. The bulk of the evidence purporting to show benefits in CHD outcome for substitution of polyunsaturated or monounsaturated fat for saturated fat is based on the changes in plasma cholesterol concentrations. Unfortunately, this information is insufficient to establish a major health benefit, and information about the primary disease endpoint, coronary artery atherosclerosis, is needed. The nonhuman primate is the ideal animal model in which to derive this type of information since diet responses and atherogenesis are similar to those in man. In this Program Project, evidence on the effects of four types of dietary fats [saturated, monounsaturated, monounsaturated, polyunsaturated (n-6) and polyunsaturated )n-3)] directly on coronary artery atherosclerosis will be obtained, and information bearing on the mechanisms by which these dietary fats may exert effects on lipoprotein metabolism and atherosclerosis will be obtained, and information bearing on the mechanisms by which these dietary fats may exert effects on lipoprotein metabolism and atherosclerosis will be derived. In project 1, the effects of diet on both LDL composition and concentration will be examined and directly correlated to atherosclerosis. In project 3, the effects of diet on LDL oxidation will be quantitated and directly correlated to atherosclerosis. In project 4, the effects of diet on HDL composition and concentration will quantitated and directly correlated to atherosclerosis. In each case, the role of diet in lipoprotein metabolism as it affects atherosclerosis will be directly tested. The potential molecular mechanisms by which such effects could occur will be examined: in project 1, where regulation of hepatic cholesterol metabolism as it influences plasma LDL will be will be examined, in project 2, where the synthesis and assembly of apolipoprotein B in lipoprotein particles will be studied, in project 4, where the effects of the lipid composition of HDL on particle structure and metabolism will be quantitated, and in project 5, where the specific aspects of apolipoprotein A-I structure that influence plasma cholesteryl ester will be examined. The results of the studies of this Program Project should provide evidence for mechanisms by which different dietary fat influence lipoprotein metabolism in atherosclerosis. This information will be useful in future attempts at prevention and treatment of premature CHD in man since it provides basic information on the fundamental aspects of coronary artery atherogenesis.
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