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。肥胖者NAFLD的患病率是瘦人的4 - 5倍，并且与胰岛素抵抗和代谢综合征有关。在肥胖症中发生的整体全身脂质稳态的不平衡在NAFLD的发展中明显起致病作用。然而，许多驱动肥胖症肝脏脂质蓄积的分子机制以及导致肝功能致病性重塑的事件仍然难以捉摸。下面，我们提出了初步证据，单酰基甘油酰基转移酶1（MGAT 1）可能参与肝脂肪变性的发展。 我们对MGAT 1的兴趣来自于我们最近的观察，使用无偏的基因表达微阵列分析，与WT同窝对照小鼠相比，编码MGAT 1的基因（Mogat 1）在fld小鼠的肝脏中的表达被显著诱导。fld表型是由于编码脂蛋白1的基因突变导致脂肪代谢障碍、肝脂肪变性和高脂血症。Lipin 1编码甘油3-磷酸（G3 P）甘油三酯（TAG）合成途径中的关键酶，因此观察到的肝脏TAG蓄积有些出乎意料。我们推测，在缺乏lipin 1的小鼠中，MGAT 1的激活通过促进MGAT途径的通量而在驱动TAG合成中起重要作用。我们还提供了在其他肝脂肪变性模型中高度诱导MGAT 1表达的数据。因此，我们还假设MGAT 1表达的扰动会加剧许多脂肪肝模型中的脂质蓄积。该提案旨在[1]表征MGAT 1的转录调控，[2]使用互补的功能获得和功能丧失方法阐明MGAT 1对肝脂肪酸代谢的影响，[3]评估MGAT 1失活对小鼠模型中NAFLD发展的影响，和[4]表征肝脏特异性过表达MGAT 1的转基因小鼠的肝脏代谢表型。

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.