Novel Aspects of Hepatic Mitochondrial Amino Acid Metabolism

肝线粒体氨基酸代谢的新方面

• 批准号: 10170348
• 负责人: Brian N Finck
• 金额: $ 38.13万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-22 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10170348
• 关键词: Address; Alanine; Alanine Transaminase; Amino Acids; Blood; Carbohydrates; Carbon; Carrier Proteins; Catabolism; Complex; Cytosol; Data; Defect; Development; Diabetes Mellitus; Enzymes; Exercise; Fasting; Gene Deletion; Gene Expression; Gluconeogenesis; Glucose; Glycerol; Goals; Hepatic; Hepatocyte; Homologous Gene; Hyperglycemia; Impairment; Inner mitochondrial membrane; Insulin Resistance; Knock-out; Knowledge; Laboratories; Liver; Liver Mitochondria; Mediating; Metabolic Pathway; Metabolism; Mitochondria; Mitochondrial Matrix; Molecular; Mus; Organism; Orthologous Gene; Pathway interactions; Pharmacologic Substance; Physiological; Physiological Processes; Play; Process; Proteins; Pyruvate; Pyruvate Metabolism Pathway; Regulation; Role; Scientific Advances and Accomplishments; Skeletal Muscle; Source; Starvation; Techniques; Testing; Work; Yeasts; activating transcription factor; activating transcription factor 4; amino acid metabolism; clinical development; design; diabetic; endoplasmic reticulum stress; glucose production; glycogenolysis; hepatic gluconeogenesis; insight; metabolic phenotype; mitochondrial metabolism; novel; novel therapeutics; nutrient metabolism; pyruvate carrier; transamination

Project Summary/Abstract The production of glucose by the liver is a vital physiological process. Hepatic glucose production plays an important role in regulating normoglycemia during starvation, providing skeletal muscle with glucose during exercise, and contributing to hyperglycemia of diabetes. Gluconeogenesis, the process of converting the carbon in pyruvate, lactate, or amino acids into new glucose, plays an important role in glucose production by the liver. Gluconeogenesis requires the transport of pyruvate or amino acids across the impermeable inner mitochondrial membrane (IMM) and subsequent metabolism by enzymes exclusively localized to the mitochondrial matrix. Recent work from the laboratory of the applicant has demonstrated an important role for the mitochondrial pyruvate carrier (MPC) complex in gluconeogenesis from pyruvate/lactate. However, these studies also suggested an important role for pyruvate-alanine cycling as a compensatory mechanism when MPC activity was impaired. In addition, while amino acids like alanine are believed to be an important substrate for gluconeogenesis, many details regarding their metabolism are lacking. The significance of the proposed studies is that we will dissect the molecular mechanisms that mediate these processes in fasting, exercise, and diabetes. We hypothesize that the transcription factor ATF4 will regulate the expression of alanine transaminase 2 (ALT2) and that this enzyme will play an important role in regulating alanine-stimulated gluconeogenesis in diabetic liver (Specific Aim 1). We also hypothesize that that the effects of ALT2 deficiency on glucose production will be enhanced by concomitant loss of MPC activity to disrupt gluconeogenesis from both alanine and pyruvate. (Specific Aim 2). We also propose a third, exploratory Aim that has the potential for marked scientific advance. The transport of alanine across the impermeable IMM by a carrier-mediated process is required for alanine to be used for gluconeogenesis. However, the identity of the carrier that mediates this process has never been determined. We hypothesize that the yeast Avt5 and its mammalian homolog Slc38a10 serve as the mitochondrial alanine carrier and that these proteins are required for mitochondrial alanine metabolism (Specific Aim 3). We believe that the proposed studies will provide marked scientific advance towards our understanding of hepatic amino acid metabolism, which has been understudied to this point. In addition, these studies will provide insight into the effects of these metabolic pathways on hepatic gluconeogenesis and could impact pharmaceutical development of new drugs to treat diabetes.

项目摘要/摘要 肝脏的葡萄糖产生是一个重要的生理过程。肝葡萄糖生产 饥饿期间调节正常血糖的重要作用，为骨骼肌肉提供葡萄糖 在运动过程中，并导致糖尿病高血糖。糖异生，转化的过程 丙酮酸，乳酸或氨基酸中的碳进入新葡萄糖，在葡萄糖中起重要作用 肝脏的生产。糖异生需要丙酮酸或氨基酸在整个 不可渗透的内部线粒体膜（IMM）和随后的代谢仅由酶进行 位于线粒体基质中。申请人实验室的最新工作证明了 线粒体丙酮酸载体（MPC）复合物在糖异生中的重要作用 丙酮酸/乳酸。但是，这些研究还表明，丙酮酸 - 丙氨酸循环作为一种重要作用 MPC活性受损时的补偿机制。另外，氨基酸像丙氨酸 认为这是糖异生的重要底物，有关其代谢的许多细节是 缺乏。拟议的研究的意义在于，我们将剖析分子机制 在禁食，运动和糖尿病中调解这些过程。我们假设转录因子 ATF4将调节丙氨酸转氨酶2（ALT2）的表达，该酶将发挥作用 在调节丙氨酸刺激的糖尿病肝脏中糖异生中的重要作用（特定目标1）。我们也是 假设Alt2缺乏对葡萄糖产生的影响将通过同时增强 MPC活性的丧失，破坏丙氨酸和丙酮酸的糖异生。 （特定目标2）。我们也是 提出第三个探索性目标，具有明显的科学进步。丙氨酸的运输 在载体介导的过程中，丙氨酸需要​​使用载体介导的过程 糖异生。但是，从未确定介导该过程的载体的身份。 我们假设酵母AVT5及其哺乳动物同源性SLC38A10用作线粒体 丙氨酸载体，这些蛋白质是线粒体丙氨酸代谢所必需的（特定目标3）。我们 相信拟议的研究将为我们对肝的理解提供明显的科学进步 氨基酸代谢，至今已被研究了。此外，这些研究将提供 深入了解这些代谢途径对肝糖异生的影响，并可能影响 新药治疗糖尿病的药物开发。