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; Zheng Chen

doi:10.1038/s41467-022-32163-w

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

Nat Commun. 2022 Aug 4;13(1):4549. doi: 10.1038/s41467-022-32163-w.

Authors

Xinzhi Li^#¹, Kaixin Ding^#¹, Xueying Li¹, Bingchuan Yuan¹, Yuqin Wang¹, Zhicheng Yao², Shuaikang Wang³, He Huang³, Bolin Xu⁴, Liwei Xie⁵, Tuo Deng⁶, Xiao-Wei Chen⁴, Zheng Chen⁷

Affiliations

¹ HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin, 150001, China.
² Department of General Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
³ Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai, 200438, China.
⁴ State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, College of Future Technology, and Center for Life Sciences, Peking University, Beijing, 100871, China.
⁵ Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, State Key Laboratory of Applied Microbiology Southern China, Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, 510070, China.
⁶ National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China.
⁷ HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin, 150001, China. chenzheng@hit.edu.cn.

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
CD36 Antigens / metabolism
Cell Cycle Proteins / metabolism
Disease Models, Animal
Fatty Acids, Nonesterified / metabolism
Hepatocytes / metabolism
Humans
Inflammation / pathology
Lipodystrophy* / metabolism
Liver / metabolism
Non-alcoholic Fatty Liver Disease* / metabolism
RNA Splicing Factors / metabolism

Substances

CD36 Antigens
Cell Cycle Proteins
Fatty Acids, Nonesterified
RNA Splicing Factors
WTAP protein, human