Regulation of Hepatic Gluconeogenesis by the Mitochondrial Pyruvate Carrier

线粒体丙酮酸载体对肝糖异生的调节

• 批准号: 9229032
• 负责人: Eric B Taylor
• 金额: $ 37.17万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9229032
• 关键词: Address; Automobile Driving; Blood Glucose; Carbon; Citric Acid Cycle; Cytoplasm; Data; Diffuse; Fasting; Genetic Transcription; Glucagon; Gluconeogenesis; Glucose; Goals; Health; Hepatocyte; High Fat Diet; Hormonal; Hyperglycemia; Inner mitochondrial membrane; Investigation; Knock-out; Knowledge; Link; Liver; Metabolic; Metabolism; Mission; Mitochondria; Mitochondrial Matrix; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Outer Mitochondrial Membrane; Oxaloacetates; Oxidative Phosphorylation; Pathologic; Pathway interactions; Phosphoenolpyruvate; Protons; Public Health; Pyruvate; Pyruvate Carboxylase; Regulation; Research; Role; Route; Source; Testing; Therapeutic; Therapeutic Effect; Tracer; United States National Institutes of Health; base; glucose production; hepatic gluconeogenesis; in vivo; innovation; insulin sensitivity; mitochondrial membrane; mitochondrial metabolism; novel; paralogous gene; public health relevance; pyruvate carrier; response; stoichiometry; uptake

 DESCRIPTION (provided by applicant): Before entering the canonical gluconeogenic pathway, the vast majority of gluconeogenic carbon flux is routed through the TCA cycle within the mitochondrial matrix. Under normal conditions, mitochondrial pyruvate is the key metabolic intermediate supporting gluconeogenesis. To reach the matrix and drive gluconeogenesis, pyruvate requires a specific carrier, the Mitochondrial Pyruvate Carrier (MPC). Thus, the MPC occupies a central node linking cytosolic with mitochondrial metabolism and gluconeogenesis. The mechanisms regulating the function of the MPC in the liver have remained unexplained. The recent identification of the MPC molecule now enables the investigation of these mechanisms. The overall goal of this proposal is to understand the relationship between MPC function in the liver and the pathologically elevated gluconeogenesis during T2D. This goal will be addressed by pursuing two specific aims: 1) Determine the mechanisms that regulate liver MPC function in response to fasting and refeeding and in T2D states; and 2) Determine the therapeutic effect of decreasing Liver MPC activity on hyperglycemia during T2D states. The studies in aim 1 will test the hypothesis that the MPC is transcriptionally and post-translationall regulated by hormonal mechanisms during fasting and refeeding that increase and decrease MPC activity, respectively, and that misregulation of the MPC in T2D states increases its activity thereby increasing mitochondrial pyruvate uptake and gluconeogenesis. The studies in aim 2 will test the hypothesis that decreasing liver MPC activity in vivo during T2D states will decrease gluconeogenesis and ameliorate hyperglycemia. They will also define how liver-specific MPC knockout alters gluconeogenic and TCA cycle carbon flux using metabolic tracers in normal and T2D mice and primary hepatocytes. This research is significant because successful completion will provide fundamental information on the role of the MPC in driving elevated hepatic gluconeogenesis and resultant hyperglycemia in T2D. This research is innovative because completion will generate novel, and now only recently obtainable, knowledge on the regulation and function of the MPC molecule as a critical node linking cytosolic and mitochondrial metabolism with gluconeogenesis. We expect our studies will unveil a new paradigm for explaining and potentially decreasing the excessive gluconeogenesis that characterizes T2D.

 描述（由申请人提供）：在进入经典的生烃途径之前，绝大多数生烃碳通量通过线粒体基质内的TCA循环。在正常条件下，线粒体丙酮酸是支持线粒体异生的关键代谢中间体。为了到达基质并驱动线粒体异生，丙酮酸需要特定的载体，线粒体丙酮酸载体（MPC）。因此，MPC占据了连接胞质与线粒体代谢和线粒体异生的中心节点。调节肝脏中MPC功能的机制仍然无法解释。最近对MPC分子的鉴定现在使这些机制的研究成为可能。该提案的总体目标是了解T2 D期间肝脏中MPC功能与病理性升高的肝脏异生之间的关系。这一目标将通过追求两个具体目标来实现：1）确定响应于禁食和再喂养以及在T2 D状态下调节肝脏MPC功能的机制;以及2）确定降低肝脏MPC活性对T2 D状态期间高血糖症的治疗效果。目标1中的研究将检验以下假设：MPC在禁食和再喂养期间分别由增加和降低MPC活性的激素机制转录和后调节，并且T2 D状态中MPC的误调节增加其活性，从而增加线粒体丙酮酸摄取和线粒体异生。目标2中的研究将检验以下假设：T2 D状态期间体内肝脏MPC活性降低将降低 促进造血，改善高血糖。他们还将定义肝脏特异性MPC敲除如何使用代谢示踪剂在正常和T2 D小鼠和原代肝细胞中改变促生和TCA循环碳通量。这项研究是重要的，因为成功完成将提供关于MPC在T2 D中驱动肝脏增生升高和由此产生的高血糖症中的作用的基本信息。这项研究是创新性的，因为完成将产生新的，现在只是最近才获得的，关于MPC分子的调节和功能的知识，作为连接细胞溶质和线粒体代谢与代谢的关键节点。我们预计我们的研究将揭示一种新的范式，用于解释并可能减少T2 D特征的过度糖异生。