Glucose and branched-chain amino acids (BCAAs) are essential nutrients and key determinants of cell growth and stress responses. High BCAA level inhibits glucose metabolism but reciprocal regulation of BCAA metabolism by glucose has not been demonstrated.
Here we show that glucose suppresses BCAA catabolism in cardiomyocytes to promote hypertrophic response. High glucose inhibits CREB stimulated KLF15 transcription resulting in downregulation of enzymes in the BCAA catabolism pathway. Accumulation of BCAA through the glucose-KLF15-BCAA degradation axis is required for the activation of mTOR signaling during the hypertrophic growth of cardiomyocytes. Restoration of KLF15 prevents cardiac hypertrophy in response to pressure overload in wildtype mice but not in mutant mice deficient of BCAA degradation gene.
Thus, regulation of KLF15 transcription by glucose is critical for the glucose-BCAA circuit which controls a cascade of obligatory metabolic responses previously unrecognized for cell growth. Disruption of this regulatory cascade alleviates cardiomyocyte hypertrophy during pressure overload in mice, demonstrating that this mechanism plays a critical role in cellular growth response in disease. Importantly, identification of the glucose and BCAA circuit adds to the fundamental principle of metabolic regulation, which has significant implications beyond cell growth.
Citation & Full Text
Shao, D., Villet, O., Zhang, Z., Choi, S.W., Yan, J., Ritterhoff, J., Gu, H., Djukovic, D., Christodoulou, D., Kolwicz, S.C., Raftery, D., Tian, R.: Glucose Promotes Cell Growth by Suppressing Branched-Chain Amino Acid Degradation, Nature Comm. 9:2935 (2018), PCMID: PMC6062555.