Glucagon Regulation of Hepatic Mitochondrial Activity and Glucose Metabolism by InsP3R-1

InsP3R-1 对肝线粒体活性和葡萄糖代谢的胰高血糖素调节

基本信息

批准号：
10093992
负责人：
GERALD I SHULMAN
金额：
$ 41.88万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-01 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10093992
关键词：
Acute Address Affect Agonist American Applications Grants Calcium Signaling Cardiovascular Diseases Centers for Disease Control and Prevention (U.S.)Chronic Citrate (si)-Synthase Disease Resistance Dose Exercise Fasting Fatty Liver Fatty acid glycerol esters Gases Genetic Transcription Glucagon Gluconeogenesis Glucose Glucose Plasma Concentration Glycogen Hepatic Hyperglycemia ITPR1 gene Infusion procedures Inositol Insulin Insulin Resistance Knockout Mice Link Liver Liver Mitochondria Liver diseases Mass Spectrum Analysis Measurement Mediating Methodology Methods Molecular Muscle NMR Spectroscopy Non-Insulin-Dependent Diabetes Mellitus Non-Rodent Model Oxidation-Reduction Pathogenesis Patients Physiological Plasma Play Population Portal vein structure Predisposing Factor Primary carcinoma of the liver cells Process Pyruvate Carboxylase Rattus Regulation Research Personnel Role Signal Transduction Time Transcriptional Regulation awake cardiovascular risk factor design diet-induced obesity exercise training fatty acid oxidation glucose metabolism glucose production hepatic gluconeogenesis improved in vivo insight insulin sensitivity ketogenesis mouse model new therapeutic target non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel oxidation receptor tripolyphosphate

项目摘要

Non-alcoholic fatty liver disease (NAFLD) affects ~25% of the world’s population and is a key factor in the pathogenesis of hepatic insulin resistance and type 2 diabetes (T2D). NAFLD is a predisposing factor for nonalcoholic steatohepatitis (NASH) and hepatocellular cancer and an independent risk factor for cardiovascular disease. However, there are currently no approved therapies to treat NAFLD. In order to address this unmet need, we plan to examine the cellular and molecular mechanisms by which glucagon alters hepatic mitochondrial fatty oxidation and hepatic anaplerotic fluxes in vivo and the potential role of the Inositol Triphosphate Receptor-1 (InsP3R-1) in mediating these effects. These questions will be addressed by a well-established team of interdisciplinary investigators using state-of-the-art nuclear magnetic resonance spectroscopy (NMR)-gas chromatographic-mass spectrometry (GC-MS) methodologies that we have recently developed to assess in vivo rates of hepatic mitochondrial fatty acid oxidation, hepatic glucose oxidation, and hepatic pyruvate carboxylase flux for the first time in awake liver-specific InsP3R-1 knockout mice. These methods will be applied to address the following Specific Aims: 1) To examine the role of InsP3R-1 in mediating glucagon’s effect to promote hepatic mitochondrial oxidation and hepatic gluconeogenesis. 2) To examine the role of IP3R-I in mediating exercise-induced increases in hepatic mitochondrial fat oxidation and reductions in NAFLD and NAFLD-associated hepatic insulin resistance. 3) To examine whether chronic stimulation of IP3R-I by glucagon will increase hepatic mitochondrial oxidation and reverse NAFLD and NAFLD-associated hepatic insulin resistance. Taken together, the studies proposed in this grant application are designed to generate a comprehensive mechanistic understanding of the impact of glucagon on hepatic mitochondrial fat oxidation and hepatic pyruvate carboxylase flux in vivo and on the role of InsP3R-I in mediating glucagon’s effects on hepatic mitochondrial function. Furthermore, it is anticipated that the results of these studies will provide important new insights into the mechanism by which novel glucagon agonists might reverse NAFLD and hepatic insulin resistance as well as potentially identify InsP3R-I as a novel therapeutic target for the treatment of NAFLD/NASH and T2D.

非酒精性脂肪肝病（NAFLD）影响了世界人口的约25％，是肝胰岛素抵抗和2型糖尿病（T2D）发病机理的关键因素。 NAFLD是非酒精性脂肪性肝炎（NASH）和肝细胞癌的诱发因素，也是心血管疾病的独立危险因素。但是，目前尚无批准治疗NAFLD的疗法。为了满足这种未满足的需求，我们计划检查胰高血糖素在体内改变肝素线粒体脂肪氧化和肝硬化的肝脏氧化剂的细胞和分子机制。 These questions will be addressed by a well-established team of interdisciplinary investigators using state-of-the-art nuclear magnetic resonance spectroscopy (NMR)-gas chromatographic-mass spectrometry (GC-MS) methods That we have recently developed to assess in vivo rates of hepatitic mitochondrial fatty acid oxidation, hepatitic glucose oxidation, and hepatitic pyruvate carboxylase flux for第一次在醒肝特异性的INSP3R-1敲除小鼠中。这些方法将用于解决以下特定目的：1）检查INSP3R-1在介导胰高血糖素作用中的作用，以促进肝脏线粒体氧化和肝粘胶质分析。 2）检查IP3R-I在介导运动型肝炎线粒体脂肪氧化和NAFLD和NAFLD相关肝炎胰岛素耐药性的升高中的作用。 3）检查胰高血糖素对IP3R-I的慢性刺激是否会增加线粒体氧化以及反向NAFLD和NAFLD相关的肝炎胰岛素耐药性。综上所述，本赠款应用中提出的研究旨在对胰高血糖素对肝脏线粒体脂肪氧化和体内肝丙酮酸羧化酶的影响产生全面的机械理解，以及在体内以及INSP3R-I对胰高血糖素对肝脏线粒体效应的作用的作用。此外，可以预料，这些研究的结果将为新型胰高血糖素激动剂可能逆转NAFLD和肝胰岛素抵抗的机制提供重要的新见解，并有可能将INSP3R-I视为用于治疗NAFLD/NAFLD/NASH和T2D的新型治疗靶标。