Mechanisms connecting dysregulated BCAA, glucose & lipid metabolism in the pathogenesis of metabolic disease

连接支链氨基酸失调、葡萄糖的机制

• 批准号: 10457911
• 负责人: MARK A HERMAN
• 金额: $ 65.12万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-19 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10457911
• 关键词: ATP Citrate (pro-S)-Lyase; Affect; Attenuated; Behavioral; Branched-Chain Amino Acids; Carbohydrates; Cardiometabolic Disease; Chronic; Complex; Consumption; Development; Diabetes Mellitus; Diet; Dietary Intervention; Enzymes; Evaluation; Fatty Acids; Fructose; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Genetic study; Genomics; Glucose; Goals; Healthcare; Hepatic; High Fat Diet; Homeostasis; Human; Human Genetics; Institutes; Insulin Resistance; Intervention; Keto Acids; Laboratories; Light; Link; Lipids; Liver; Metabolic; Metabolic Diseases; Modeling; Molecular; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity associated disease; Outcome; Overnutrition; Oxidoreductase; Pathogenesis; Pathway interactions; Pharmacology; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Physiology; Population; Post-Translational Protein Processing; Program Research Project Grants; Protein Dephosphorylation; Proteomics; Rattus; Resource Sharing; Rodent Model; Supplementation; Testing; Therapeutic Intervention; Triglycerides; United States National Institutes of Health; Weight; Work; amino acid metabolism; bariatric surgery; blood glucose regulation; diabetes pathogenesis; dietary; disease phenotype; enzyme activity; experience; fatty acid oxidation; feeding; genetic variant; global health; glucose metabolism; glucose tolerance; human subject; improved; insulin sensitivity; lifestyle intervention; lipid biosynthesis; lipid metabolism; metabolomics; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; obese person; obesity treatment; overexpression; phosphoproteomics; prevent; prognostic; recombinant adenovirus; response; small molecule inhibitor; sugar; sweetened beverage; tool; trait; transcription factor

.PROJECT SUMMARY – R01 Newgard/Herman . Studies performed by our group have helped establish that branched-chain amino acids (BCAA) and related metabolites are associated with insulin resistance and T2D, predictive of diabetes development and intervention outcomes, and highly responsive to therapeutic interventions. The goal of this proposal is to fully understand the metabolic and molecular mechanisms linking concerted dysregulation of BCAA, glucose and lipid metabolism. Key recent findings leading to this proposal emerged when we altered branched-chain ketoacid dehydrogenase (BCKDH) complex activity via pharmacologic and molecular manipulation of its regulatory kinase (BDK) and phosphatase (PPM1K) in rodent models of obesity and metabolic disease. Treatment of Zucker-obese rats with BT2, a small molecule inhibitor of BDK, or a recombinant adenovirus expressing PPM1K lowered circulating BCAA and branched chain ketoacid levels, improved glucose tolerance and insulin sensitivity, and increased fatty acid oxidation while markedly decreasing liver triglycerides. Phosphoproteomics analysis revealed that in addition to their function to modify BCKDH activity, BDK and PPM1K also regulate the phosphorylation of the key lipogenic enzyme, ATP-citrate lyase (ACL). Whereas phosphorylation of BCKDH inhibits its activity, phosphorylation of ACL is an activating post-translational modification that leads to increased de novo lipogenesis. We also demonstrated that overnutrition or fructose feeding activates the carbohydrate sensing transcription factor, ChREBP, which upregulates both BDK and ACL expression while suppressing PPM1K. Altogether, these studies define a novel regulatory node integrating glucose, lipid, and BCAA metabolism that participates in the progression of metabolic disease. The current study seeks to understand the impact of chronic manipulation of the ChREBP/BDK/PPM1K regulatory node in multiple dietary contexts, and to expand our human studies to include evaluation of genetic and dietary variables, via the following specific aims: 1) To test the hypothesis that chronic hepatic BDK overexpression will exacerbate metabolic disease phenotypes; 2) To test the hypotheses that chronic hepatic PPM1K overexpression or ChREBP suppression will attenuate or prevent development of metabolic disease phenotypes; 3) To determine whether consumption of sugar-sweetened beverages (SSB) associates with circulating BCAA levels, and whether genetic variants in the ChREBP/BDK/PPM1K regulatory node interact with sugar consumption to regulate BCAA levels and other metabolic traits in human populations.

．项目总结- R01 Newgard/Herman。