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.
BCAAs, e.g. leucine, isoleucine and valine, are essential amino acids for mammals, and recent studies have suggested that BCAA catabolism play a critical role in insulin resistance and heart disease. The proposed study will define the molecular mechanisms linking glucose utilization and BCAA catabolism and determine the contributions of these metabolic pathways to cardiac response to stresses.
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