Glucose And BCAA Metabolism in the Heart

描述(由申请人提供)：底物代谢对心脏的正常生物学和生理学是必不可少的。肥胖和糖尿病发病率的飙升重新引起了人们对心脏代谢的兴趣，特别是在缺血和衰竭的心脏中的葡萄糖和脂类代谢。大量研究表明，在心脏病的发生发展过程中，葡萄糖和脂肪酸之间的底物偏好发生了转变。然而，其他种类的底物在心脏中的新陈代谢，如氨基酸，很少被研究。近年来，越来越多的证据表明，在心血管和代谢性疾病的发生发展过程中，支链氨基酸的代谢发生了显著的变化。代谢组学技术的应用表明，血液中支链氨基酸(BCAA)和相关代谢物的水平与胰岛素抵抗和冠心病密切相关；BCAA相关代谢物的特征可以预测对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，补充支链氨基酸可促进高脂饮食背景下的胰岛素抵抗，但延长正常饮食小鼠的平均寿命，并增强心肌和骨骼肌中线粒体的生物合成和功能。这些数据主要是由代谢组学和营养研究产生的，提出了支链氨基酸的细胞代谢及其调节机制的问题。支链氨基酸，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动态平衡的关键步骤。线粒体定位蛋白磷酸酶2C(PP2Cm)是激活支链氨基酸分解代谢的关键酶，其缺失导致心脏支链氨基酸分解代谢障碍，加剧了心脏对应激的反应，提示支链氨基酸分解代谢在心脏应激反应中起重要作用。关于支链氨基酸在心脏中分解代谢的调节，以及它与其他底物代谢的关系，人们知之甚少。利用心脏特异性过表达胰岛素非依赖性葡萄糖转运体GLUT1(GLUT1-TG)的小鼠模型，我们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支链氨基酸的分解代谢。这导致我们假设葡萄糖和支链氨基酸的代谢动态平衡是通过涉及Klf15和胰岛素敏感性的相互调节电路实现的。在这里，我们建议通过以下特定目的来研究葡萄糖和BCAA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BCAA分解代谢的假说；2)确定葡萄糖或BCAA利用改变对心脏底物代谢的整体影响，并检验BCAA分解代谢受损促进胰岛素抵抗的假说；3)检验BCAA分解代谢缺陷通过损害糖代谢和线粒体功能而加速慢性应激时心力衰竭的发展的假说。

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.