Glucose And BCAA Metabolism in the Heart

心脏中的葡萄糖和支链氨基酸代谢

基本信息

批准号：
9256515
负责人：
Rong Tian
金额：
$ 77.48万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9256515
关键词：
Amino Acids Animals Biogenesis Biology Blood Branched-Chain Amino Acids Cardiac Cardiovascular Diseases Cardiovascular system Catabolism Cell Culture System Chronic stress Coronary heart disease Data Development Diabetes Mellitus Diet Down-Regulation Enzymes Essential Amino Acids FRAP1 gene Fatty Acids GLUT4 gene Gene Expression Gene Targeting Genetic Transcription Glucose Glucose Transporter Heart Heart Diseases Heart failure High Fat Diet Homeostasis Hypertrophy Impairment Incidence Insulin Insulin Resistance Intervention Isoleucine Isotope Labeling Knockout Mice Kruppel-like transcription factors Leucine Link Liver Longevity Mammals Mass Spectrum Analysis Metabolic Metabolic Diseases Metabolic Pathway Metabolism Mitochondria Molecular Multinuclear NMR Mus Mutant Strains Mice Myocardial Myocardium NMR Spectroscopy Nutritional Study Obesity Outcome Pathologic Phenotype Physiology Play Regulation Resistance Role SLC2A1 gene Signal Transduction Skeletal Muscle Stress Supplementation Technology Testing Therapeutic Intervention Valine Workload blood glucose regulation cardiogenesis constriction glucose metabolism glucose transport glucose uptake heart metabolism insulin sensitivity interest lipid metabolism metabolomics mouse model mutant overexpression preference pressure protein phosphatase 2C public health relevance response transcription factor

项目摘要

DESCRIPTION (provided by applicant): Substrate metabolism is essential for the normal biology and physiology of the heart. The soaring incidence of obesity and diabetes has renewed and substantiated interest on cardiac metabolism, in particular, the glucose and lipids metabolism, in the ischemic and failing hearts. A large number of studies have focused on the shift of substrate preference between glucose and fatty acids in the development of heart diseases. However, metabolism of other classes of substrates in the heart, such as amino acids, has rarely been studied. Recently, emerging evidence suggests that the metabolism of branched-chain amino acids is significantly altered during the development of cardiovascular and metabolic diseases. Application of metabolomics technology has shown that blood levels of branched-chain amino acids (BCAA) and related metabolites are strongly associated with insulin resistance and coronary heart disease; the BCAA-related metabolites signature is predictive of intervention outcomes in patience with obesity and it is uniquely responsive to therapeutic interventions. In animal studies, BCAA supplementation promotes insulin resistance on high-fat diet background but increases average lifespan of mice on normal diet and enhances mitochondrial biogenesis and function in cardiac and skeletal muscle. These data, mostly generated by metabolomics and nutritional studies, raise the question of cellular metabolism of BCAA and its regulatory mechanisms. BCAAs, e.g. leucine, isoleucine and valine, are essential amino acids for mammals. Catabolism of BCAAs is a key step in maintaining BCAA homeostasis in the body. Impairment of BCAA catabolism in the heart due to the deletion of mitochondrial localized protein phosphatase 2C (PP2Cm), a key enzyme in activating BCAA catabolism, exacerbates cardiac responses to stress suggesting an important role of BCAA catabolism for cardiac response to stress. Little is known about the regulation of BCAA catabolism in the heart, nor of its relationship to the metabolism of other substrates. Using a mouse model with cardiac specific overexpression of insulin independent glucose transporter GLUT1 (GLUT1-TG) we have generated exciting preliminary data demonstrating that increased intracellular glucose down regulates BCAA catabolism through transcriptional mechanisms. This leads us to hypothesize that the metabolic homeostasis of glucose and BCAA is achieved via a reciprocal regulatory circuit involving Klf15 and insulin sensitivity. Here we propose to investigate the mechanistic link between glucose and BCAA metabolism in the heart through the following specific aims: 1) to test the hypothesis that glucose regulates BCAA catabolism via transcription factor Klf15 and its target genes; 2) To determine the global impact of altered glucose or BCAA utilization on cardiac substrate metabolism and to test the hypothesis that impaired BCAA catabolism promotes insulin resistance; 3) To test the hypothesis that defective BCAA catabolism accelerates the development of heart failure during chronic stress by impairing glucose metabolism and mitochondrial function.

描述（由申请人提供）：底物代谢对于心脏的正常生物学和生理学至关重要。肥胖和糖尿病发病率的飙升重新引起了人们对缺血和衰竭心脏中心脏代谢的兴趣，特别是葡萄糖和脂质代谢。大量研究集中在心脏病发展过程中葡萄糖和脂肪酸之间底物偏好的转变。然而，心脏中其他类别底物（例如氨基酸）的代谢却很少被研究。最近，新出现的证据表明，支链氨基酸的代谢在心血管和代谢疾病的发展过程中发生显着改变。代谢组学技术的应用表明，血液中支链氨基酸（BCAA）及相关代谢物的水平与胰岛素抵抗和冠心病密切相关；支链氨基酸相关代谢物特征可以预测肥胖患者的干预结果，并且它对治疗干预具有独特的反应。在动物研究中，补充 BCAA 会促进高脂肪饮食背景下的胰岛素抵抗，但会延长正常饮食小鼠的平均寿命，并增强心肌和骨骼肌中的线粒体生物发生和功能。这些数据主要由代谢组学和营养研究产生，提出了支链氨基酸的细胞代谢及其调节机制的问题。 BCAA，例如亮氨酸、异亮氨酸和缬氨酸是哺乳动物必需的氨基酸。支链氨基酸的分解代谢是维持体内支链氨基酸稳态的关键步骤。由于线粒体定位蛋白磷酸酶 2C (PP2Cm)（一种激活 BCAA 分解代谢的关键酶）的缺失，心脏中 BCAA 分解代谢受损，加剧了心脏对应激的反应，表明 BCAA 分解代谢在心脏对应激反应中发挥着重要作用。人们对心脏中 BCAA 分解代谢的调节及其与其他底物代谢的关系知之甚少。使用心脏特异性过度表达胰岛素依赖性葡萄糖转运蛋白 GLUT1 (GLUT1-TG) 的小鼠模型，我们生成了令人兴奋的初步数据，证明细胞内葡萄糖增加可通过转录机制下调 BCAA 分解代谢。这使我们假设葡萄糖和支链氨基酸的代谢稳态是通过涉及 Klf15 和胰岛素敏感性的相互调节回路实现的。在这里，我们建议通过以下具体目标来研究心脏中葡萄糖和支链氨基酸代谢之间的机制联系：1）检验葡萄糖通过转录因子Klf15及其靶基因调节支链氨基酸分解代谢的假设； 2) 确定葡萄糖或支链氨基酸利用改变对心脏底物代谢的总体影响，并检验支链氨基酸分解代谢受损会促进胰岛素抵抗的假设； 3) 检验以下假设：支链氨基酸分解代谢缺陷会损害葡萄糖代谢和线粒体功能，从而加速慢性应激期间心力衰竭的发展。