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. 2020 Feb 11;30(6):1835-1847.e9.
doi: 10.1016/j.celrep.2020.01.043.

Hepatic DNAJB9 Drives Anabolic Biasing to Reduce Steatosis and Obesity

Fangfang Sun  1 , Yilie Liao  2 , Xingfan Qu  1 , Xia Xiao  3 , Shaocong Hou  4 , Zheqin Chen  5 , Haipeng Huang  5 , Pingping Li  4 , Suneng Fu  6
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Free article

Hepatic DNAJB9 Drives Anabolic Biasing to Reduce Steatosis and Obesity

Fangfang Sun et al. Cell Rep. .
Free article

Abstract

Nutrients stimulate the anabolic synthesis of proteins and lipids, but selective insulin resistance in obesity biases the anabolic program toward lipogenesis. Here, we report the identification of a DNAJB9-driven program that favors protein synthesis and energy production over lipid accumulation. We show there are two pools of DNAJB9 cochaperone. DNAJB9 in the ER lumen promotes the degradation of the lipogenic transcription factor SREBP1c through ERAD, whereas its counterpart on the ER membrane promotes the assembly of mTORC2 in the cytosol and stimulates the synthesis of proteins and ATP. The expression of Dnajb9 is induced by nutrients and downregulated in the obese mouse liver. Restoration of hepatic DNAJB9 expression effectively improves insulin sensitivity, restores protein synthesis, and suppresses food intake, accompanied by reduced hepatic steatosis and adiposity in multiple mouse models of obesity. Therefore, targeting the anabolic balance may provide a unique opportunity to tackle obesity and diabetes.

Keywords: Dnajb9; SREBP1c degradation; anabolic biasing; appetite regulation; energy homeostasis; hepatic steatosis; mTORC2 assembly; obesity; selective insulin resistance; topology.

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Conflict of interest statement

Declaration of Interests The authors declare no competing interests.

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