Glucose And BCAA Metabolism in the Heart

心脏中的葡萄糖和支链氨基酸代谢

• 批准号: 8711853
• 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
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8711853
• 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; Fatty Acids; Fatty acid glycerol esters; GLUT4 gene; Gene Expression; Gene Targeting; Glucose; Glucose Transporter; Heart; Heart Diseases; Heart failure; Homeostasis; Hypertrophy; Impairment; Incidence; Insulin; Insulin Resistance; Intervention; Isoleucine; Isotope Labeling; Kruppel-like transcription factors; Leucine; Link; Liver; Longevity; Mammals; Mass Spectrum Analysis; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Mitochondria; Molecular; Mus; Mutant Strains Mice; Myocardial; Myocardium; NMR Spectroscopy; Nuclear; Nutritional Study; Obesity; Outcome; Phenotype; Physiology; Play; Regulation; Resistance; Role; SLC2A1 gene; Signal Transduction; Skeletal Muscle; Stress; Supplementation; Technology; Testing; Therapeutic Intervention; Valine; Workload; blood glucose regulation; constriction; glucose metabolism; glucose transport; glucose uptake; heart metabolism; human FRAP1 protein; insulin sensitivity; interest; lipid metabolism; metabolomics; mouse model; mutant; overexpression; preference; pressure; protein phosphatase 2C; public health relevance; response; transcription factor

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（由申请方提供）：底物代谢对心脏的正常生物学和生理学至关重要。肥胖症和糖尿病发病率的不断上升重新引起并证实了人们对缺血性和衰竭性心脏的心脏代谢，特别是葡萄糖和脂质代谢的兴趣。大量的研究集中在葡萄糖和脂肪酸之间的底物偏好在心脏疾病的发展中的转变。然而，其他类型的底物在心脏中的代谢，如氨基酸，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性疾病的发展过程中发生了显着改变。代谢组学技术的应用表明，支链氨基酸（BCAA）和相关代谢物的血液水平与胰岛素抵抗和冠心病密切相关; BCAA相关代谢物特征可预测肥胖患者的干预结果，并且对治疗干预具有独特的响应性。在动物研究中，BCAA补充剂在高脂肪饮食背景下促进胰岛素抵抗，但增加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合成和功能。这些数据，主要是由代谢组学和营养研究产生的，提出了BCAA的细胞代谢及其调节机制的问题。支链氨基酸，例如亮氨酸、异亮氨酸和缬氨酸，是哺乳动物的必需氨基酸。BCAAs的Catalination是维持体内BCAA稳态的关键步骤。由于线粒体局部蛋白磷酸酶2C（PP 2Cm）（激活BCAA分解代谢的关键酶）的缺失，心脏中的BCAA分解代谢受损，加剧了心脏对应激的反应，这表明BCAA分解代谢在心脏对应激的反应中发挥着重要作用。人们对BCAA在心脏中的调节知之甚少，也不知道它与其他底物代谢的关系。使用心脏特异性过表达胰岛素非依赖性葡萄糖转运蛋白GLUT 1（GLUT 1-TG）的小鼠模型，我们已经产生了令人兴奋的初步数据，表明细胞内葡萄糖增加通过转录机制下调BCAA催化剂。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Klf 15和胰岛素敏感性的相互调节回路实现的。本研究拟通过以下具体目的探讨葡萄糖与BCAA代谢之间的机制联系：1）验证葡萄糖通过转录因子Klf 15及其靶基因调节BCAA代谢的假说; 2）确定葡萄糖或BCAA利用改变对心脏底物代谢的总体影响，并验证BCAA代谢受损促进胰岛素抵抗的假说; 3）验证BCAA催化剂缺陷通过损害葡萄糖代谢和线粒体功能加速慢性应激期间心力衰竭发展的假设。