We propose an integrated series of clinical and biochemical investigations to better delineate the effects of specific dietary lipids on lipid and lipoprotein metabolism in human subjects. The influence of diets in which monounsaturated fatty acids represent the main source of fat will be investigated in terms of their lipid lowering effects compared to similar diets containing 30% of calories from omega-6 polyunsaturated fatty acids or primarily saturated fatty acids and both of these compared to a low fat diet. All diets will be fed to subjects with primary hypercholesterolemia and parameters of lipoprotein metabolism to be studied will include 125I-LDL turnover, cholesterol homeostasis assessed by serum and urinary excretion of mevalonic acid and cholesterol synthesis in freshly isolated mononuclear leukocytes. These four diets will be fed to subjects consuming a cholesterol-free diet and in the presence of 600 mg/day of dietary cholesterol. The metabolic effects of long chain polyunsaturated fatty acids derived from fish oil will be examined in studies outlined in Project 2. These studies aim to examine whether the hypotriglyceridemic effects of long-chain omega-3 polyunsaturated fatty acids are due primarily to eicosapentaenoic acid or docosahexaenoic acid by determining if these purified fatty acids (as dietary constituents) prevent carbohydrate induced hypertriglyceridemia. The mechanisms responsible for the reduction of HDL concentrations in hypercholesterolemic subjects fed a low cholesterol fish oil will be examined by performing kinetic studies with 125I-labeled HDL. The influence of fish oils on prostanoid formation will be examined in collaborative studies. These studies should further our knowledge concerning the anti-atherosclerotic effects of long chain omega-3 fatty acids. The influence of sterols on plasma lipid and lipoprotein concentrations will be examined in normal and hypercholesterolemic subjects fed diets supplemented with seafood sterols. Finally, the fourth project aims to examine the hypocholesterolemic effects of three phases of a prudent diet in volunteer subjects, establish a recipe development laboratory, and prospectively assess the effectiveness of dietary counseling as an adjunct to long-term control of plasma lipids in an outpatient setting. Overall, these studies should enhance our knowledge concerning the clinical and metabolic effects of specific dietary lipids and have direct therapeutic application to treatment of subjects with hypercholesterolemia.
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