Journal Article

Glucose promotes cell growth by suppressing branched-chain amino acid degradation

Ritterhoff, Julia, Djukovic, Danijel, Tian, Rong, Shao, Dan, Choi, Sung Won, Zhang, Zhen, Gu, Haiwei, Kolwicz, Stephen C., Yan, Jie, Raftery, Daniel, Villet, Outi, Christodoulou, Danos

2018

Overview

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. Hypertrophic cardiomyocytes switch their metabolism from fatty acid oxidation to glucose use, but the functional role of this change is unclear. Here the authors show that high intracellular glucose inhibits the degradation of branched-chain amino acids, which is required for the activation of pro-growth mTOR signaling.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/95 / 14/19 / 38/15 / 38/39 / 38/61 / 42/44 / 631/443/319 / 631/80/83/2359 / 64/110 / 64/60 / 692/4019/592/1540 / 82/29 / 82/51 / 82/80 / Amino acids / Amino Acids, Branched-Chain - metabolism / Animals / Cardiomyocytes / Catabolism / Cell Cycle - drug effects / Cell growth / Cell Proliferation - drug effects / Chain branching / Chains / Computational Biology / Cyclic AMP response element-binding protein / Degradation / Echocardiography / Essential nutrients / Gene expression / Gene regulation / Glucose / Glucose - pharmacology / Glucose metabolism / HEK293 Cells / Humanities and Social Sciences / Humans / Hypertrophy / Male / Metabolism / Mice / multidisciplinary / Nutrients / Restoration / Science / Science (multidisciplinary) / Signal Transduction - drug effects / TOR protein / Transcription