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，是肝脏胰岛素抵抗发病机制的关键因素，而 2 型糖尿病 (T2D) 是非酒精性脂肪性肝炎 (NASH) 和肝细胞性肝炎的诱发因素。癌症和心血管疾病的独立危险因素然而，目前尚无批准的治疗 NAFLD 的疗法，为了解决这一未满足的需求，我们计划：检查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，以及肌醇三磷酸受体-1 (InsP3R-1) 在介导这些作用中的潜在作用。使用最先进的核磁共振波谱（NMR）-气相色谱-质谱（GC-MS）建立了跨学科研究人员团队我们最近开发的方法首次用于评估清醒肝脏特异性 InsP3R-1 敲除小鼠体内肝线粒体脂肪酸氧化、肝葡萄糖氧化和肝丙酮酸羧化酶通量的速率。具体目标如下： 1) 检查 InsP3R-1 在介导胰高血糖素促进肝线粒体氧化和2) 检查IP3R-I 在介导运动引起的肝脏线粒体脂肪氧化增加和NAFLD 和NAFLD 相关肝脏胰岛素抵抗的减少中的作用。 3) 检查胰高血糖素对IP3R-I 的慢性刺激是否会影响肝脏糖异生。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 综上所述，本拨款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 InsP3R-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，并有可能确定InsP3R-I 作为治疗 NAFLD/NASH 和 T2D 的新型治疗靶点。