EFFECT OF FISH OIL ON LIPOPROTEIN METABOLISM

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The overall objective of these studies is to understand how dietary fatty acids regulate the concentration of LDL in plasma. The concentration of LDL in plasma is determined by at least four factors including 1) the rate of LDL production (J-t ) , 2) the maximal rate of receptor dependent LDL transport (J-max ), 3) the affinity if the LDL particle; for the LDL receptor (K-m) and 4) the rate of receptor independent LDL transport (P). Using new quantitative techniques to measure each of these processes in vivo, we have recently shown that the type of fatty acids in the diet can markedly affect both the! production and the receptor dependent catabolism of LDL by the liver. These effects will be studied in much greater detail in hamsters and Cynomolgus monkeys using diets designed to evaluate the effect of number and configuration of double bonds, saturated fatty acid chain length and level of dietary fat. One group of studies will then investigate the mechanism by which dietary fatty acids regulate the LDL receptor pathway. Since changes in cholesterol availability are known to regulate the LDL receptor pathway, fatty acid-induced changes in receptor dependent LDL transport will be correlated with changes in tissue and whole body cholesterol balance and with changes in', receptor protein and mRNA levels; changes in receptor dependent uptake will also be correlated with changes in the composition and physical properties of liver membranes. A second group of studies will be carried out to determine how dietary fatty acids regulate the rate of LDL production. Since LDL are formed during the metabolism of VLDL, studies will be done to determine how dietary fatty acids regulate the rate of VLDL synthesis by the liver, the activities of hepatic and lipoprotein lipase in metabolizing VLDL to LDL particles and VLDL remnants, and the rate at which VLDL remnants are cleared by the liver. A third group of studies will be undertaken to determine if dietary fatty acids affect chylomicron remnant transport and, if so, whether this could account for changes in receptor dependent LDL transport. A final group of studies will be undertaken to determine if diet-induced changes in the composition and physical properties of LDL affect the affinity of LDL for its receptor in vivo. Overall, these detailed and quantitative studies should provide basic information on how specific dietary fatty acids regulate plasma LDL concentrations (and thus the risk of coronary heart disease) both at the physiological and cell biological level.