The overall objective of these studies is to understand how dietary fish oil regulates plasma lipoprotein concentrations. Such information would bear on the important problem of atherosclerosis and coronary heart disease. Dietary fish oil is known to lower plasma LDL and VLDL levels in humans and in several animal species including the rat. The first group of studies will be undertaken to quantitate and compare the effect of fish oil, polyunsaturated vegetable triglyceride and saturated vegetable triglyceride on the synthesis and catabolism of LDL. Rates of LDL synthesis and rates of receptor-dependent and receptor-independent LDL transport will be measured in animals fed varying amounts of these three triglycerides in the presence or absence of varying amounts of cholesterol. Studies will also be done to examine the effect of these three triglycerides on the synthesis and catabolism of VLDL. The second group of studies will be undertaken to elucidate the mechanism by which fish oil regulates the synthesis or catabolism of LDL and VLDL. Studies will first be done to determine if fish oil alters gross cholesterol balance across the liver and whole body. The main determinants of total body sterol balance are cholesterol absorption, de novo cholesterol synthesis and the secretion of cholesterol into bile either as such or after conversion into bile acids. Accordingly, these three pathways will be quantitated in vivo in animals fed fish oil, polyunsaturated vegetable triglyceride and saturated triglyceride. The effect of each of these dietary manipulations on the fatty acid profile of lipoprotein and membrane lipids will be monitored. Depending on the outcome of these studies, experiments will be undertaken to try to define the mechanism of action of dietary fish oil at the molecular level. Since fish oil contains considerable amounts of cholesterol and saturated fatty acids, in some studies, relatively pure omega-3 fatty acids will be isolated from fish oil by preparative HPLC and the efficacy and mechanism of action of these fatty acids examined as described above. Finally, certain hypolipidemic drugs in combination with fish oil may produce additive effects on plasma lipoprotein levels and this possibility will be explored. Taken together, the results of these studies will provide a much better understanding of how fish oil regulates cholesterol balance and LDL metabolism in the intact animal.
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