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

MGAT 在肝脏 TAG 合成和代谢疾病中的调控和功能

• 批准号: 8662247
• 负责人: Angela Marie Hall
• 金额: $ 11.11万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8662247
• 关键词: 2-acylglycerol O-acyltransferase; Acute; Adult; Affect; Animals; Automobile Driving; Data; Development; Elements; Enzymatic Biochemistry; Enzymes; Event; Fatty Liver; Gene Expression; Gene Expression Microarray Analysis; Genes; Hepatic; Homeostasis; Hyperlipidemia; Insulin Resistance; Lead; Lipid Biochemistry; Lipids; Lipodystrophy; Liver; Liver diseases; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolic syndrome; Metabolism; Modeling; Molecular; Molecular Profiling; Mus; Mutation; Obesity; Overweight; Pathogenesis; Pathologic; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Persons; Phenotype; Physiological; Physiology; Play; Prevalence; Regulation; Research; Research Personnel; Research Project Grants; Risk; Role; Time; Transcriptional Regulation; Transgenic Mice; Triglycerides; United States; United States National Institutes of Health; alpha-glycerophosphoric acid; base; career; career development; design; fatty acid metabolism; gain of function; interest; lipine; liver function; loss of function; mortality; mouse model; non-alcoholic fatty liver; novel therapeutic intervention; overexpression; promoter; research study; skills

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.

描述（由申请人提供）：非酒精性脂肪肝 (NAFLD) 影响着美国约 20% 的成年人。肥胖者的 NAFLD 患病率比瘦人高四到五倍，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稳态失衡显然在 NAFLD 的发展中起着致病作用。然而，肥胖症中驱动肝脏脂质积累的许多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，我们提出初步证据表明单酰基甘油酰基转移酶 1 (MGAT1) 可能参与肝脂肪变性的发生。 我们对 MGAT1 的兴趣源于我们最近使用无偏基因表达微阵列分析的观察，即与 WT 同窝对照小鼠相比，编码 MGAT1 (Mogat1) 的基因的表达在 fld 小鼠的肝脏中显着诱导。 fld 表型是由编码脂质 1 的基因突变引起的，导致脂肪营养不良、肝脂肪变性和高脂血症。脂质 1 编码 3-磷酸甘油 (G3P) 甘油三酯 (TAG) 合成途径中的关键酶，因此观察到的肝脏 TAG 积累有些出乎意料。我们假设缺乏脂质 1 的小鼠中 MGAT1 的激活通过促进 MGAT 途径的通量而在驱动 TAG 合成中发挥重要作用。我们还提供了其他肝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 表达的扰动会加剧许多脂肪肝疾病模型中的脂质积累。该提案旨在 [1] 表征 MGAT1 的转录调控，[2] 使用互补的功能获得和功能丧失方法阐明 MGAT1 对肝脏脂肪酸代谢的影响，[3] 评估 MGAT1 失活对小鼠模型中 NAFLD 发展的影响，以及 [4] 表征转基因小鼠的肝脏代谢表型 MGAT1 的肝脏特异性过度表达。