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

描述（由申请人提供）：非酒精性脂肪性肝病（NAFLD）影响美国约20%的成年人。肥胖人群NAFLD的患病率是瘦人的四到五倍，并且与胰岛素抵抗和代谢综合征有关。肥胖引起的全身脂质平衡失衡显然在NAFLD的发生中起致病作用。然而，许多驱动肥胖中肝脏脂质积累的分子机制和导致肝功能致病性重塑的事件仍然是难以捉摸的。下面，我们提出初步证据，证明单酰基甘油酰基转移酶1 （MGAT1）可能参与肝脂肪变性的发展。

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.