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)在美国大约20%的成年人中受到影响。肥胖者NAFLD的患病率是瘦者的四到五倍，并与胰岛素抵抗和代谢综合征有关。肥胖引起的全身脂肪平衡失衡在NAFLD的发生发展中起着明显的致病作用。然而，许多导致肥胖时肝脏脂肪堆积的分子机制以及导致肝功能病理性重构的事件仍不清楚。下面，我们提出了单甘油酰基转移酶1(MGAT1)可能参与肝脏脂肪变性发生的初步证据。 我们对MGAT1的兴趣源于我们最近使用无偏向基因表达微阵列分析观察到，与WT斜发对照小鼠相比，编码MGAT1(Mogat1)的基因在FLD小鼠的肝脏中显著诱导表达。FLD表型是由编码脂蛋白1的基因突变导致的，导致脂肪营养不良、肝脏脂肪变性和高脂血症。Lipin 1编码3-磷酸甘油(G3P)甘油三酯(Tag)合成途径中的一个关键酶，因此观察到的肝脏Tag的积累有些出乎意料。我们推测，在缺乏Lipin 1的小鼠中，MGAT1的激活通过促进MGAT途径的通量，在推动Tag合成方面发挥了重要作用。我们还提供了在其他肝脏脂肪变性模型中高度诱导MGAT1表达的数据。因此，我们还假设，MGAT1表达的紊乱会加剧许多脂肪肝模型中的脂肪堆积。这项建议旨在[1]表征MGAT1的转录调控，[2]通过功能获得和功能丧失互补的方法阐明MGAT1对肝脏脂肪酸代谢的影响，[3]评估MGAT1失活对小鼠NAFLD发展的影响，以及[4]表征肝脏特异性MGAT1过表达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.