Deficiency of WTAP in hepatocytes induces lipoatrophy and non-alcoholic steatohepatitis (NASH)

Xinzhi Li, Kaixin Ding, Xueying Li, Bingchuan Yuan, Yuqin Wang, Zhicheng Yao, Shuaikang Wang, He Huang, Bolin Xu, Liwei Xie, Tuo Deng, Xiao-wei Chen and Zheng Chen ()
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Xinzhi Li: Harbin Institute of Technology
Kaixin Ding: Harbin Institute of Technology
Xueying Li: Harbin Institute of Technology
Bingchuan Yuan: Harbin Institute of Technology
Yuqin Wang: Harbin Institute of Technology
Zhicheng Yao: The Third Affiliated Hospital of Sun Yat-sen University
Shuaikang Wang: Fudan University
He Huang: Fudan University
Bolin Xu: Peking University
Liwei Xie: Guangdong Academy of Sciences
Tuo Deng: The Second Xiangya Hospital of Central South University
Xiao-wei Chen: Peking University
Zheng Chen: Harbin Institute of Technology

Nature Communications, 2022, vol. 13, issue 1, 1-19

Abstract: Abstract Ectopic lipid accumulation and inflammation are the essential signs of NASH. However, the molecular mechanisms of ectopic lipid accumulation and inflammation during NASH progression are not fully understood. Here we reported that hepatic Wilms' tumor 1-associating protein (WTAP) is a key integrative regulator of ectopic lipid accumulation and inflammation during NASH progression. Hepatic deletion of Wtap leads to NASH due to the increased lipolysis in white adipose tissue, enhanced hepatic free fatty acids uptake and induced inflammation, all of which are mediated by IGFBP1, CD36 and cytochemokines such as CCL2, respectively. WTAP binds to specific DNA motifs which are enriched in the promoters and suppresses gene expression (e.g., Igfbp1, Cd36 and Ccl2) with the involvement of HDAC1. In NASH, WTAP is tranlocated from nucleus to cytosol, which is related to CDK9-mediated phosphorylation. These data uncover a mechanism by which hepatic WTAP regulates ectopic lipid accumulation and inflammation during NASH progression.

Date: 2022
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DOI: 10.1038/s41467-022-32163-w

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