Glycerolipid synthesis in liver

Univ Of North Carolina Chapel Hill, Chapel Hill NC

Investigators

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Abstract

Our long term goal is to understand how the excess synthesis of triacylglycerol (TAG) results in chronic disorders such as the metabolic syndrome, insulin resistance, nonalcoholic fatty liver disease, and cardiovascular disease. TAG metabolism is directly linked to two markers of the metabolic syndrome: increased waist size (excess visceral fat stores) and dyslipidemia, particularly high serum TAG which is an independent risk factor for cardiovascular disease. To achieve our goal, we need to answer questions of how TAG synthesis is normally regulated, how the enzymes in the pathway of TAG synthesis contribute to hepatic fatty acid metabolism, and how lipid intermediates of the TAG pathway control hepatic pathologies. The initial and rate-limiting step in hepatic TAG synthesis is catalyzed by three independent glycerol-3-phosphate acyltransferase (GPAT) isoenzymes which appear to differ in their ability to target their lipid products towards specific downstream pathways, thereby altering the rate of TAG synthesis under differing physiological conditions, reducing the rate of fatty acid oxidation, adjusting the fatty acid composition of phospholipids, regulating nutrient-mediated signaling cascades, and blocking adipogenesis in human BSCL2 congenital lipodystrophy. Because the GPAT isoforms are intimately involved in processes involving the development of hepatic steatosis, VLDL biosynthesis, insulin resistance, and adipogenesis, we believe that identifying the independent functions and regulation of the GPAT isoforms will allow potential targeting of their pathogenic outcomes by identifying new targets and strategies for the diagnosis and treatment of fatty liver, dyslipidemia, and the BSCL2 congenital lipodystrophy.