Novel Aspects of Hepatic Mitochondrial Amino Acid Metabolism

肝线粒体氨基酸代谢的新方面

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要肝脏产生葡萄糖是一个重要的生理过程。肝葡萄糖生成发挥作用在饥饿期间调节正常血糖方面发挥重要作用，为骨骼肌提供葡萄糖运动时，会导致糖尿病的高血糖。糖异生，转化过程将丙酮酸、乳酸或氨基酸中的碳转化为新的葡萄糖，在葡萄糖中起着重要作用由肝脏产生。糖异生需要丙酮酸或氨基酸跨过不可渗透的线粒体内膜（IMM）和随后仅通过酶进行的代谢定位于线粒体基质。申请人实验室最近的工作表明线粒体丙酮酸载体（MPC）复合物在糖异生中的重要作用丙酮酸/乳酸。然而，这些研究也表明丙酮酸-丙氨酸循环作为一种重要的作用 MPC活性受损时的补偿机制。此外，虽然像丙氨酸这样的氨基酸被认为是糖异生的重要底物，有关其代谢的许多细节缺乏。所提出的研究的意义在于我们将剖析分子机制在禁食、运动和糖尿病中介导这些过程。我们假设转录因子 ATF4 将调节丙氨酸转氨酶 2 (ALT2) 的表达，并且该酶将发挥在调节糖尿病肝脏中丙氨酸刺激的糖异生中发挥重要作用（具体目标 1）。我们也假设 ALT2 缺乏对葡萄糖产生的影响会因同时服用而增强 MPC 活性丧失，破坏丙氨酸和丙酮酸的糖异生。（具体目标 2）。我们也提出第三个探索性目标，该目标有可能取得显着的科学进步。丙氨酸的运输丙氨酸需要通过载体介导的过程穿过不可渗透的 IMM 糖异生。然而，调解这一过程的载体的身份从未确定。我们假设酵母 Avt5 及其哺乳动物同源物 Slc38a10 充当线粒体丙氨酸载体，并且这些蛋白质是线粒体丙氨酸代谢所必需的（具体目标 3）。我们相信所提出的研究将为我们对肝脏的理解提供显着的科学进步氨基酸代谢，目前尚未得到充分研究。此外，这些研究将提供深入了解这些代谢途径对肝糖异生的影响，并可能影响治疗糖尿病新药的药物开发。