The role of nicotinamide N-methyltransferase in glucose and lipid homeostasis

烟酰胺N-甲基转移酶在葡萄糖和脂质稳态中的作用

• 批准号: 7887952
• 负责人: Pavlos Pissios
• 金额: $ 37.05万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 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/7887952
• 关键词: 3T3-L1 Cells; Adipocytes; Adipose tissue; Affect; Apolipoprotein A-I; Biological; Blood Pressure; Calories; Candidate Disease Gene; Cardiovascular Diseases; Cell physiology; Cholesterol; Cholesterol Homeostasis; Deacetylase; Development; Diabetes Mellitus; Diabetic mouse; Diet; Dietary Intervention; Disease; Disease model; Dyslipidemias; Enzymes; Epoprostenol; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Genetic Models; Glucose; Glucose Intolerance; Hepatic; Hepatocyte; High Density Lipoproteins; Homeostasis; Hypertension; In Vitro; Individual; Inflammatory Response; Insulin Resistance; Investigation; Knowledge; LXRalpha protein; Life Style; Lipids; Lipolysis; Liver; Liver diseases; Low-Density Lipoproteins; Measures; Mediating; Mediator of activation protein; Messenger RNA; Metabolic; Metabolic Pathway; Metabolic syndrome; Metabolism; Mission; Modeling; Mouse Strains; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Niacinamide; Nicotinamide N-Methyltransferase; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; PPAR alpha; Pathway interactions; Phenotype; Play; Process; Production; Prostaglandin Production; Prostaglandins; Prostaglandins I; Proteins; Public Health; Reaction; Regulation; Research; Risk; Role; Serum; Sirtuins; System; Testing; Therapeutic Intervention; Tissues; Variant; Weight Gain; blood glucose regulation; cyclooxygenase 2; db/db mouse; fatty acid oxidation; feeding; hepatic gluconeogenesis; high risk; improved; in vivo; inhibitor/antagonist; ketogenic diet; lipid biosynthesis; lipid metabolism; mouse model; novel; novel therapeutics; nutrient metabolism; overexpression; public health relevance; sedentary; transcription factor; waist circumference

DESCRIPTION (provided by applicant): Metabolic syndrome is characterized by a group of factors, such as increased waist circumference, dyslipidemia (low HDL, high LDL), increased blood pressure and increased insulin resistance or glucose intolerance. It is estimated that 50 million people in the US suffer from metabolic syndrome. People with metabolic syndrome are at higher risk for developing cardiovascular disease and type-2 diabetes (T2D). We have identified the enzyme Nicotinamide N-methyltransferase (NNMT) as a novel regulator of glucose and lipid homeostasis. NNMT methylates nicotinamide. Both compounds nicotinamide and N1-methylnicotinamide have biological activity. Nicotinamide is a potent inhibitor of sirtuins, recently recognized important metabolic regulators in the liver and other tissues. N1-methylnicotinamide increases the production of prostaglandins, which among other actions have profound effects on the function of adipose tissue. We hypothesize that NNMT activity regulates hepatic and fat glucose and lipid metabolism through sirtuin-dependent and independent pathways. The aims are: 1) To assess the in vivo role of NNMT in glucose and lipid homeostasis. We will investigate the effects of NNMT overexpression or knockdown on glucose, lipid and cholesterol metabolism in mouse models of obesity and diabetes. 2) To investigate the mechanisms by which NNMT regulates pathways of lipid and cholesterol metabolism in vitro. We will use primary hepatocytes with targeted NNMT overexpression or knockdown to directly assess the activity of pathways in lipid and cholesterol metabolism. We will assess the activity of the master transcriptional regulators LXRa and PPARa to provide a mechanistic explanation for the observed changes. 3) To evaluate the role of NNMT in adipogenesis of 3T3-L1 cells. We will investigate the pathways regulated by NNMT and nicotinamide during adipogenesis to provide evidence that vitamin B3 plays an essential role during the development of adipose tissue. This proposal has direct relevance to the NIDDK mission and will establish NNMT as a potential new candidate gene for the treatment of the metabolic syndrome. PUBLIC HEALTH RELEVANCE: Type-2 diabetes and fatty liver disease have become a major public health threat. We are discovering novel factors and pathways regulating glucose and lipid metabolism. The knowledge gained from this research might open new therapeutic options for these diseases.

描述（由申请人提供）：代谢综合征的特征在于一组因素，如腰围增加、血脂异常（低HDL、高LDL）、血压升高和胰岛素抵抗或葡萄糖耐受不良增加。据估计，美国有5000万人患有代谢综合征。患有代谢综合征的人患心血管疾病和2型糖尿病（T2 D）的风险更高。 我们已经确定了酶烟酰胺N-甲基转移酶（NNMT）作为一种新的调节葡萄糖和脂质体内平衡。NNMT甲基化烟酰胺。化合物烟酰胺和N1-甲基烟酰胺均具有生物活性。烟酰胺是一种有效的sirtuins抑制剂，最近被认为是肝脏和其他组织中重要的代谢调节剂。N1-methylnicotinamide增加生产的mesandins，其中除其他行动有深远的影响的功能的脂肪组织。我们推测NNMT活性通过沉默调节蛋白依赖性和非依赖性途径调节肝脏和脂肪的葡萄糖和脂质代谢。 目的是：1）评价NNMT在体内对糖和脂质稳态的作用。我们将研究NNMT过表达或敲低对肥胖和糖尿病小鼠模型中葡萄糖、脂质和胆固醇代谢的影响。2)研究NNMT在体外调节脂质和胆固醇代谢途径的机制。我们将使用具有靶向NNMT过表达或敲低的原代肝细胞来直接评估脂质和胆固醇代谢途径的活性。我们将评估主转录调节因子LXR α和PPARa的活性，为观察到的变化提供机制解释。3)观察NNMT对3 T3-L1细胞脂肪形成的影响。我们将研究脂肪形成过程中NNMT和烟酰胺调节的途径，以提供证据证明维生素B3在脂肪组织发育过程中起着重要作用。该建议与NIDDK使命直接相关，并将NNMT确立为治疗代谢综合征的潜在新候选基因。 公共卫生相关性：2型糖尿病和脂肪肝已成为主要的公共卫生威胁。我们正在发现调节葡萄糖和脂质代谢的新因子和途径。从这项研究中获得的知识可能为这些疾病开辟新的治疗选择。