Novel Aspects of Hepatic Mitochondrial Amino Acid Metabolism

肝线粒体氨基酸代谢的新方面

• 批准号: 10406922
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10406922
• 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.

项目总结/摘要 肝脏产生葡萄糖是一个重要的生理过程。肝脏葡萄糖生成作用 在调节饥饿期间的正常代谢，为骨骼肌提供葡萄糖中起重要作用 在运动期间，并有助于糖尿病的高血糖症。葡萄糖异生， 碳在丙酮酸、乳酸或氨基酸转化成新的葡萄糖时，起着重要的葡萄糖作用 由肝脏生产。葡萄糖异生需要丙酮酸或氨基酸跨膜转运， 不渗透的线粒体内膜（IMM）和随后的代谢酶排他 定位于线粒体基质。申请人的实验室最近的工作表明， 线粒体丙酮酸载体（MPC）复合物在从 丙酮酸/乳酸。然而，这些研究也表明，作为一种重要的代谢途径， 当MPC活动受损时的补偿机制。此外，虽然丙氨酸等氨基酸 被认为是一个重要的基板为eastogenesis，许多细节，关于他们的代谢是 缺乏这项研究的重要性在于，我们将剖析 在禁食、运动和糖尿病中调节这些过程。我们假设转录因子 ATF 4将调节丙氨酸转氨酶2（ALT 2）的表达，并且这种酶将发挥作用。 在调节丙氨酸刺激的糖尿病肝再生中的重要作用（具体目的1）。我们也 假设ALT 2缺乏对葡萄糖产生的影响将通过伴随的 MPC活性的丧失破坏了丙氨酸和丙酮酸的异生作用。（具体目标2）。我们也 提出第三个探索性的目标，有可能取得显著的科学进步。丙氨酸的转运 通过载体介导的过程穿过不可渗透的IMM是丙氨酸用于 异源发生然而，调解这一过程的载体的身份从未确定。 我们假设酵母Avt 5和它的哺乳动物同源物Slc 38 a10作为线粒体 这些蛋白质是线粒体丙氨酸代谢所需的（具体目标3）。我们 我相信这些研究将为我们理解肝脏疾病提供显著的科学进步。 氨基酸代谢，这一点尚未得到充分研究。此外，这些研究将提供 深入了解这些代谢途径对肝脏新生的影响， 药物开发新的药物来治疗糖尿病。