Hypertriglyceridemia (HTG) is a common disorder of lipoprotein metabolism and a potential risk factor for coronary heart disease. An interaction between bile acids and plasma very low density lipoprotein (VLDL) triglyceride has been recognized for many years. The central hypothesis of these studies is that bile acid flux through the liver in the enterohepatic circulation influences VLDL triglyceride production. The overall goals of the proposed research are to test the hypothesis that inherited defects in genes responsible for intestinal bile acid absorption can cause FHTG, and to examine the mechanism by which bile acids can regulate hepatic VLDL triglyceride production. Information obtained from these studies will increase our understanding of the underlying mechanism(s) of hypertriglyceridemia and assist in designing new therapies for this important health problem. The following questions will be addressed: 1. Are inherited dysfunctional mutations in the ileal Na+/bile acid co- transporter responsible for a subset of Familial Hypertriglyceridemia? A candidate gene for FHTG is the ileal Na+/bile acid co-transporter (ISBT) that is responsible for intestinal reclamation of bile acids. The ISBT gene has been cloned and a dysfunctional mutation was recently identified in a FHTG patient. To answer this question, the association of the ISBT gene and HTG will be examine din FHTG families by linkage analysis and the ISBT gene will be screened for mutations in FHTG subjects with bile acid malabsorption. 2. Does a decreased bile acid flux through the liver directly stimulate VLDL production? Studies in cholestyramine-treated patients suggest that a decreased return of bile acids to the liver stimulate production of VLDL triglyceride. To directly test this hypothesis, hepatic secretion of VLDL apolipoprotein B-100 (apo B) and triglyceride will be measured in isolated perfused livers obtained from African green monkeys fed control or cholestyramine-containing diets. 3. What is the molecular mechanism by which bile acid affect hepatic VLDL triglyceride production? The interaction between bile aids and VLDL production will be studied in primary culture of African green monkey hepatocytes. Bile acid effects on the synthesis and secretion of VLDL triglyceride and apo B will be determined using pulse-chase protocols to determine the regulated step(s).
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