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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：
9789259
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 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9789259
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.

项目总结/文摘