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

• 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
• 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

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.

非酒精性脂肪性肝病（NAFLD）影响约25%的世界人口，并且是肝脏胰岛素抵抗和2型糖尿病（T2 D）发病机制的关键因素。NAFLD是非酒精性脂肪性肝炎（NASH）和肝细胞癌的易感因素，也是心血管疾病的独立风险因素。然而，目前还没有批准的治疗NAFLD的疗法。为了解决这一未满足的需求，我们计划研究胰高血糖素在体内改变肝线粒体脂肪氧化和肝回补通量的细胞和分子机制，以及三磷酸肌醇受体-1（InsP 3R-1）在介导这些效应中的潜在作用。这些问题将由一个成熟的跨学科研究人员团队使用最先进的核磁共振光谱（NMR）-气相色谱-质谱（GC-MS）方法来解决，我们最近开发了该方法，以首次在清醒的肝脏特异性InsP 3R-1敲除小鼠中评估肝脏线粒体脂肪酸氧化，肝脏葡萄糖氧化和肝脏丙酮酸羧化酶通量的体内速率。这些方法将被应用于解决以下具体目的：1）检查InsP 3R-1在介导胰高血糖素促进肝线粒体氧化和肝再生的作用中的作用。2)研究IP 3R-I在介导运动诱导的肝线粒体脂肪氧化增加和NAFLD和NAFLD相关肝胰岛素抵抗减少中的作用。3)检查胰高血糖素对IP 3R-I的慢性刺激是否会增加肝脏线粒体氧化并逆转NAFLD和NAFLD相关的肝脏胰岛素抵抗。总之，本授权申请中提出的研究旨在全面了解胰高血糖素对体内肝线粒体脂肪氧化和肝丙酮酸羧化酶通量的影响以及InsP 3R-I在介导胰高血糖素对肝线粒体功能的影响中的作用。此外，预计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，并可能将InsP 3R-I鉴定为治疗NAFLD/NASH和T2 D的新型治疗靶标。