KINETICS OF HUMAN POSTPRANDIAL LIPOPROTEIN METABOLISM

流行病学研究和实验室正在积累证据

Evidence is building from epidemiological studies and laboratory investigations to support the hypothesis that abnormalities in lipoprotein metabolism during the postprandial period promote atherosclerosis. Technological advances in lipoprotein tracer studies now make it possible to study at a new level of sophistication the plasma lipoproteins that are formed postprandially in the intestine and the liver. The overall goal of the proposed research is to uncover postprandial lipoprotein pathways that are likely to influence the development of atherosclerosis, to study these pathways in normal and hypertriglyceridemic persons, and to test the effect of dietary manipulation. We will determine the fundamental metabolic pathways of the intestinal and hepatic lipoprotein particle system in plasma as traced by apolipoprotein B48 and B100; that is, what sizes of particles are produced, the extent of a lipolytic cascade, the residence times, and the existence of slowly metabolized remnant particles that are potentially atherogenic. We will study whether the presence of apolipoproteins E and C-III modulates the residence times, clearance rates and interconversions of VLDL and IDL of intestinal and hepatic origin, or whether they are markers of atherogenic remnant particles. The kinetics of apo E and C-III transfer between HDL and VLDL/IDL will be quantified. Specific Aim 1 will compare postprandial lipoprotein kinetics during intake of a Step 1 diet with fasting lipoprotein kinetics in hypertriglyceridemic and normolipidemic subjects. Specific Aim 2 will study the effect of substituting carbohydrate or monounsaturated fat for saturated fat on postprandial lipoprotein metabolism. Diurnal concentration patterns of lipoproteins of intestinal and hepatic origin, as well as tracer kinetics will be studied. The diurnal concentration and tracer kinetic studies are complementary, the latter delineating the mechanisms responsible for producing the peak postprandial concentrations. These studies will increase our understanding of the metabolic pathways that are activated or suppressed postprandially, and could lead to treatments for reducing the development of atherosclerosis.