Our long term goal is to determine the metabolic and molecular mechanisms by which individuals in a population respond differently to dietary cholesterol and how dietary fat modulates this response. We hypothesize that dietary cholesterol interacts with type of fat in determining plasma lipoprotein variables in a given genetic background. We will test this hytpothesis in selectively bred high and low responding baboons. The first experiment will use a factorial design to determine the interactions of four levels of dietary cholesterol intake, two types of fat (saturated and unsaturated), and two genetic backgrounds (high and low responders) on plasma lipoprotein heterogeneity and concentrations, and on factors in plasma (lecithin cholesterol acyl transferase and cholesteryl ester transfer protein) and liver (mRNA for apoproteins and LDL receptor), that affect plasma lipoprotein concentrations. The second experiment, designed to determine mechanisms accounting for the effects abserved in the first experiment, will use high and low responding baboons maintained on two levels of cholesterol (high and low) with either saturated or unsaturated fat. In these we will measure cholesterol absorption and the synthesis and catabolic rates of apo-B in VLDL, LDL and their subfractions. Turnover rates of apo-AI will be measured to determine whether changes are due to synthesis or catabolism. The HDL metabolic variables and clearance of post-prandial lipoproteins will be correlated with each other and with activities of post-heparin plasma hepatic triglyceride (HTGL) and lipoprotein lipases (LPL) and mRNA for apo-AI and HTGL in liver and LPL in adipose tissues. Apo-E turnover studies will be conducted and the metabolic variables will be correlated with mRNA for apo-E in liver. We will determine whether triglyceride-rich lipoproteins induced by dietary cholesterol promote cholesterol ester synthesis in macrophages. Using primary cultures of baboon hepatocytes, we will study the interaction of chylomicron remnant and fasting lipoproteins with hepatocytes to determine how these lipoproteins affect lipid metabolism in the liver. Using hep G2 cells, we will investigate the down regulation of hepatic LDL receptor by the lipoproteins from high and low responding animals maintained on different diets. These studies will enable us to understand why some indiviuals are susceptible and others resistant to dietary cholesterol.
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