Post-translational regulation of lipogenesis via AMPK-dependent phosphorylation of insulin-induced gene

Yamei Han, Zhimin Hu, Aoyuan Cui, Zhengshuai Liu, Fengguang Ma, Yaqian Xue, Yuxiao Liu, Feifei Zhang, Zehua Zhao, Yanyan Yu, Jing Gao, Chun Wei, Jingya Li, Jing Fang, Jia Li, Jian-Gao Fan, Bao-Liang Song and Yu Li ()
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Yamei Han: Chinese Academy of Sciences
Zhimin Hu: Chinese Academy of Sciences
Aoyuan Cui: Chinese Academy of Sciences
Zhengshuai Liu: Chinese Academy of Sciences
Fengguang Ma: Chinese Academy of Sciences
Yaqian Xue: Chinese Academy of Sciences
Yuxiao Liu: Chinese Academy of Sciences
Feifei Zhang: Chinese Academy of Sciences
Zehua Zhao: Shanghai Jiaotong University School of Medicine
Yanyan Yu: Chinese Academy of Sciences
Jing Gao: Chinese Academy of Sciences
Chun Wei: Zhejiang University of Technology
Jingya Li: Chinese Academy of Sciences
Jing Fang: Chinese Academy of Sciences
Jia Li: Chinese Academy of Sciences
Jian-Gao Fan: Shanghai Jiaotong University School of Medicine
Bao-Liang Song: Wuhan University
Yu Li: Chinese Academy of Sciences

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: Abstract Insulin-induced gene (Insig) negatively regulates SREBP-mediated de novo fatty acid synthesis in the liver. However, the upstream regulation of Insig is incompletely understood. Here we report that AMPK interacts with and mediates phosphorylation of Insig. Thr222 phosphorylation following AMPK activation is required for protein stabilization of Insig-1, inhibition of cleavage and processing of SREBP-1, and lipogenic gene expression in response to metformin or A769662. AMPK-dependent phosphorylation ablates Insig’s interaction with E3 ubiquitin ligase gp78 and represses its ubiquitination and degradation, whereas AMPK deficiency shows opposite effects. Interestingly, activation of AMPK by metformin causes an augmentation of Insig stability and reduction of lipogenic gene expression, and leads to the attenuation of hepatic steatosis in HFHS diet-fed mice. Moreover, hepatic overexpression of Insig-1 rescues hepatic steatosis in liver-specific AMPKα2 knockout mice fed with HFHS diet. These findings uncover a novel effector of AMPK. Targeting Insig may have the therapeutic potential for treating fatty liver disease and related disorders.

Date: 2019
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DOI: 10.1038/s41467-019-08585-4

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