A major risk factor for development of atherosclerosis is the concentration of circulating low density lipoprotein (LDL)-cholesterol (C). The concentration of this lipoprotein is determined by at lest four major factors: a) the rate of LDL-C production (Jt), b) the rate of maximal receptor-dependent LDL-C transport (Jm), c) the affinity of the LDL particle for its receptor (Km), and the rate of receptor-independent LDL-C transport (P). Using new quantitative techniques to measure each of these processes, in vivo, these studies will determine how dietary lipids alter these processes and elucidate the underlying physiological differences that account for variability in the response of the plasma LDL-C. One group of studies will investigate the effects of dietary additions on each of these parameters in the hamster and, in particular, will explore the relationships between dietary cholesterol and different triacylglycerols. The specific effect of chain-length in saturated fatty acids and the number of double bonds in unsaturated fatty acids will be examined. After feeding the various experimental diets, absolute rates of cholesterol synthesis and receptor-dependent and receptor-independent LDL transport will be measured in every organ and other regulated metabolic pathways will be undertaken in different animal species intestine. A second group of experiments will be undertaken in different animal species in which the liver contributes a variable proportion of total-body cholesterol synthesis. by making detailed measurements of each transport process, it will be possible to determine the reasons for the variable response of the LDL-C concentration to identical dietary lipid intakes in the different species. Finally, a third group of studies will characterize in detail cholesterol and LDL-C transport in responding and nonresponding Cynomolgus monkeys. If this difference is proven to reside within the intestine, then measurements also will be made of unstirred layer resistance and microvillus hydrophobicity. Overall, these very detailed, quantitative investigations should provide important new insights into how different dietary components alter the specific parameters of LDL-C metabolism and should elucidate what factors are responsible for variability in the response of the plasma LDL-C concentrations to similar dietary intakes between different animal species as well as between different individuals of the same species.
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