Regulation and Function of MGAT in Hepatic TAG Synthesis and Metabolic Disease

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DESCRIPTION (provided by applicant): Nonalcoholic fatty liver disease (NAFLD) affects about 20% of adults in the United States. The prevalence of NAFLD is four to five times higher in obese than in lean persons and is associated with insulin resistance and the metabolic syndrome. The imbalance in overall whole body lipid homeostasis that occurs in obesity clearly plays a pathogenic role in the development of NAFLD. However, many of the molecular mechanisms that drive hepatic lipid accumulation in obesity and the events that lead to pathogenic remodeling of liver function remain elusive. Below, we present preliminary evidence that monoacylglycerol acyltransferase 1 (MGAT1) could be involved in the development of hepatic steatosis. Our interest in MGAT1 arose from our recent observation, using unbiased gene expression microarray analysis, that the expression of the gene encoding MGAT1 (Mogat1) was markedly induced in liver of fld mice compared to WT littermate control mice. The fld phenotype results from mutations in the gene encoding lipin 1 leading to lipodystrophy, hepatic steatosis, and hyperlipidemia. Lipin 1 encodes a key enzyme in the glycerol 3-phosphate (G3P) triglyceride (TAG) synthesis pathway and therefore the observed hepatic TAG accumulation is somewhat unexpected. We hypothesize that the activation of MGAT1 in mice lacking lipin 1 plays an important role in driving TAG synthesis by promoting flux through the MGAT pathway. We also present data that MGAT1 expression is highly induced in other models of hepatic steatosis. We therefore also postulate that perturbations of MGAT1 expression exacerbate lipid accumulation in many models of fatty liver disease. This proposal is designed to [1] characterize the transcriptional regulation of MGAT1, [2] elucidate the effects of MGAT1 on hepatic fatty acid metabolism using complementary gain-of-function and loss-of-function approaches, [3] to evaluate the effects of MGAT1 deactivation on the development of NAFLD in mouse models, and [4] to characterize the hepatic metabolic phenotype of transgenic mice with liver-specific overexpression of MGAT1. PUBLIC HEALTH RELEVANCE: About two-thirds of adults in the US are overweight, and one-third are obese. The prevalence of Nonalcoholic fatty liver disease (NAFLD) is four to five times higher in obese than in lean persons and affects about 20% of adults in the US. NAFLD and is associated with insulin resistance, the metabolic syndrome, and an increased risk of mortality. These studies seek to understand the molecular mechanism of this pathologic condition in order to develop new therapeutic interventions.