METABOLIC RELATIONSHIP AMONG TRIGLYCERIDE-RICH LIPOPROTEINS AND HDLS

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There exists a close inverse relationship between the plasma levels of triglycerides (TG) and HDL-cholesterol (HDL-chol) suggesting that the metabolism of one of these lipids affects that of the other. By all the available evidence, it is the metabolism of triglyceride-rich lipoproteins (TGRL) which controls association between HDL-chol and not vice versa. Therefore, the powerful negative association between HDL-chol and coronary artery disease (CAD) may in reality be a positive relationship between CAD and the metabolism of TGRL. Rapid catabolism of TGRL, as reflected in modest postprandial lipemia, limits the time available for their enrichment with cholesteryl esters and provides surface phospholipids from nascent TGRL required for the anabolic formation of HDL2. By contrast, pronounced alimentary lipemia leads to cholesteryl ester enrichment of TGRL and accelerates the catabolism of HDL. The aim of this proposal is to test the above hypotheses through three major objectives: i)to separate postprandial lipoproteins of hepatic and intestinal origins at various time points of the alimentary cycle and characterize their physiochemical properties, lipid and apoprotein composition, and to study their ability to affect the metabolism of fibroblasts, macrophages and liver and endothelial cells in culture; ii)to identify HDL subfractions which are essential for or indicative of defined metabolic events of TGRL in vivo; to develop and apply an in vitro model system that allows identification of factors which determine the rates of conversion of HDL3 subfractions into HDL2 and vice versa; to determine the effects of these interconversions on cellular cholesterol metabolism and cholesterol routing among lipoproteins; iii)to measure the contribution of genetic factors to postprandial lipid metabolism in family studies and determine their co-aggregation with CAD and candidate genes involved in lipid metabolism; to study the relationship of insulin resistance and alimentary lipemia in subjects before and after therapeutic interventions known to enhance insulin sensitivity, in order to identify a potential role of trans-activating factors in the expression of genes relevant for the metabolism of TGRL. These studies represent a logical extension of our previous work on lipoprotein metabolism, postprandial lipemia and its association with CAD and should elucidate the mechanisms underlying the relationships among CAD, HDL-chol, and plasma triglycerides.