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

基本信息

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
项目类别：
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

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

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项目摘要

.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有助于确定分支链氨基酸（BCAA）及其相关的研究代谢物与胰岛素抵抗和T2D有关，可预测糖尿病的发育和干预措施结果，对治疗干预措施的反应很高。该提议的目的是完全了解将BCAA，葡萄糖和脂质代谢的协同失调连接的代谢和分子机制。当我们改变分支链酮酸脱氢酶时，导致该建议的主要发现出现了（BCKDH）通过对其调节激酶（BDK）和分子操纵的复杂活性和肥胖和代谢疾病啮齿动物模型中的磷酸酶（PPM1K）。用 BT2，BDK的小分子抑制剂或表达PPM1K的重组腺病毒降低的循环 BCAA和分支链酮酸水平，提高葡萄糖耐受性和胰岛素敏感性，并提高脂肪酸氧化，同时显着降低了肝甘油三酸酯。磷酸蛋白质组学分析表明， BDK和PPM1K的功能增加了BCKDH活性，还调节了磷酸化的磷酸化关键的脂肪生物酶，ATP-CITRATE裂解酶（ACL）。而BCKDH的磷酸化抑制其活性，而 ACL的磷酸化是一种激活的翻译后修饰，导致从头开始增加脂肪生成。我们还证明了营养或果糖喂养激活碳水化的感应转录因子Chrebp，在抑制PPM1K时上调BDK和ACL表达。 Altogether, these studies define a novel regulatory node integrating glucose, lipid, and BCAA metabolism that 参与代谢疾病的进展。当前的研究试图了解慢性的影响在多种饮食环境中操纵CHREBP/BDK/PPM1K调节节点，并扩大我们的人类通过以下特定目的包括评估遗传和饮食变量的研究：1）测试假设慢性肝BDK过表达会加剧代谢疾病表型。 2）测试慢性肝PPM1K过表达或CHREBP抑制的假设将减弱或预防代谢疾病表型的发展； 3）确定是否消耗糖味床位（SSB）与循环BCAA水平相关联，以及遗传变异是否存在 CHREBP/BDK/PPM1K调节节点与糖消耗相互作用，以调节BCAA水平和其他人口中的代谢特征。