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

Dan Shao, Outi Villet, Zhen Zhang, Sung Won Choi, Jie Yan, Julia Ritterhoff, Haiwei Gu, Danijel Djukovic, Danos Christodoulou, Stephen C. Kolwicz, Daniel Raftery and Rong Tian ()
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Dan Shao: University of Washington
Outi Villet: University of Washington
Zhen Zhang: University of Washington
Sung Won Choi: University of Washington
Jie Yan: Brigham and Women’s Hospital
Julia Ritterhoff: University of Washington
Haiwei Gu: University of Washington
Danijel Djukovic: University of Washington
Danos Christodoulou: Brigham and Women’s Hospital
Stephen C. Kolwicz: University of Washington
Daniel Raftery: University of Washington
Rong Tian: University of Washington

Nature Communications, 2018, vol. 9, issue 1, 1-17

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-05362-7

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