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: 9792043
• 负责人: MARK A HERMAN
• 金额: $ 70.86万
• 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/9792043
• 关键词: ATP Citrate (pro-S)-Lyase; Affect; Attenuated; Behavioral; Branched-Chain Amino Acids; Carbohydrates; Chronic; Complex; Consumption; Development; Diabetes Mellitus; Diet; Dietary Intervention; Disease; 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; cardiometabolism; 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; 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.

.项目摘要 – R01 Newgard/Herman 。 我们小组进行的研究帮助确定支链氨基酸 (BCAA) 和相关 代谢物与胰岛素抵抗和 T2D 相关，可预测糖尿病的发展和干预 结果，并对治疗干预高度敏感。该提案的目标是充分了解 支链氨基酸、葡萄糖和脂质代谢协同失调之间的代谢和分子机制。 当我们改变支链酮酸脱氢酶时，导致这一提议的最新关键发现出现了 (BCKDH) 通过其调节激酶 (BDK) 的药理学和分子操作实现复合活性，以及 肥胖和代谢疾病啮齿动物模型中的磷酸酶（PPM1K）。 Zucker 肥胖大鼠的治疗 BT2、BDK 的小分子抑制剂或表达 PPM1K 的重组腺病毒可降低循环 支链氨基酸和支链酮酸水平，改善葡萄糖耐量和胰岛素敏感性，并增加 脂肪酸氧化同时显着降低肝脏甘油三酯。磷酸化蛋白质组学分析表明， 除了调节 BCKDH 活性外，BDK 和 PPM1K 还调节 BCKDH 的磷酸化。 关键的脂肪生成酶，ATP-柠檬酸裂解酶（ACL）。而 BCKDH 的磷酸化会抑制其活性， ACL 的磷酸化是一种激活性翻译后修饰，可导致 de novo 增加 脂肪生成。我们还证明，营养过剩或果糖喂养会激活碳水化合物感应 转录因子 ChREBP，上调 BDK 和 ACL 表达，同时抑制 PPM1K。 总而言之，这些研究定义了一个整合葡萄糖、脂质和支链氨基酸代谢的新型调节节点， 参与代谢性疾病的进展。目前的研究旨在了解慢性病的影响 在多种饮食环境中操纵 ChREBP/BDK/PPM1K 调节节点，并扩展我们的人类 研究包括对遗传和饮食变量的评估，通过以下具体目标：1）测试 假设慢性肝脏 BDK 过度表达会加剧代谢性疾病表型； 2）测试 慢性肝脏 PPM1K 过度表达或 ChREBP 抑制将减弱或预防的假设 代谢疾病表型的发展； 3) 判断食用糖是否加甜 饮料 (SSB) 与循环支链氨基酸 (BCAA) 水平相关，以及饮料中的遗传变异是否与 ChREBP/BDK/PPM1K 调节节点与糖消耗相互作用，调节 BCAA 水平和其他 人群的代谢特征。