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©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
Mechanism and therapeutic strategy of hepatic TM6SF2-deficient non-alcoholic fatty liver diseases via in vivo and in vitro experiments
Zu-Yin Li, Gang Wu, Chen Qiu, Zhi-Jie Zhou, Yu-Peng Wang, Guo-He Song, Chao Xiao, Xin Zhang, Gui-Long Deng, Rui-Tao Wang, Yu-Long Yang, Xiao-Liang Wang
Zu-Yin Li, Department of Hepatobiliary Surgery, Peking University People’s Hospital, Beijing 100034, China
Gang Wu, Department of Gastrointestinal Surgery, Henan Provincial People’s Hospital, Zhengzhou 450003, Henan Province, China
Chen Qiu, Institute of Gallstone Disease, Shanghai East Hospital, Shanghai 200120, China
Zhi-Jie Zhou, Department of General Surgery, Huashan Hospital North, Shanghai 201907, China
Yu-Peng Wang, Guo-He Song, Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China
Chao Xiao, Department of General Surgery, Huashan Hospital, Fudan University, Shanghai 200041, China
Xin Zhang, Xiao-Liang Wang, Department of General Surgery, Qingpu Branch of Zhongshan Hospital Affiliated to Fudan University, Shanghai 201700, China
Gui-Long Deng, Rui-Tao Wang, Department of General Surgery, Shanghai General Hospital, Shanghai 201600, China
Yu-Long Yang, Institute of Gallstone Disease, Center of Gallbladder Disease, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, China
Xiao-Liang Wang, Department of Hepatobiliary Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, China
Author contributions: Li ZY and Wu G contributed equally to the work, Li ZY and Wu G performed the in vitro and in vivo experiments; Qiu C, Zhou ZJ, Wang YP, Song GH and Xiao C performed the analysis of GEO data; Deng GL and Wang RT provided the technical supports; Zhang X interpreted the data; Li ZY wrote the manuscript; Wang XL and Yang YL contributed equally, Wang XL and Yang YL conceived and supervised the study; all authors critically reviewed and edited the manuscript.
Supported by National Natural Science Foundation of China, No. 81670514 and No. 81702337; Scientific Research Project of Shanghai Municipal Health Commission, No. 202040065; and Natural Science Foundation of Shanghai Scientific and Technological Project of Innovative Action, No. 20ZR1411900.
Institutional review board statement: The study was reviewed and approved by the Shanghai First People's Hospital Institutional Review Board, No. 2016KY074.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of the Shanghai First People's Hospital, No. 2020-A0072-01.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: The data used and analyzed during the current study are available from the corresponding author on reasonable request.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Xiao-Liang Wang, PhD, Chief Doctor, Department of Hepatobiliary Surgery, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, No. 2800 Gongwei Road, Huinan Town, Pudong New Area, Shanghai 201399, China. xiaoliangwang2018@163.com
Received: December 21, 2021
Peer-review started: December 21, 2021
First decision: March 10, 2022
Revised: April 15, 2022
Accepted: May 22, 2022
Article in press: May 22, 2022
Published online: July 7, 2022
ARTICLE HIGHLIGHTS
Research background
Previously, we found that the TM6SF2 E167K mutation was associated with susceptibility to nonalcoholic fatty liver disease (NAFLD) in a Chinese cohort, but the underlying mechanism is poorly understood.
Research motivation
Because existing evidence has shown that TM6SF2 gene mutation would reduce its expression at the protein level, we used NAFLD mouse models to explore the causes of NAFLD caused by TM6SF2 deficiency in the context of high-fat feeding and test possible treatment strategies. This would benefit our understanding of the mechanisms underlying NAFLD in humans.
Research objectives
Mechanism and therapeutic strategy of hepatic TM6SF2-deficient NAFLD via in vivo and in vitro experiments.
Research methods
This study mainly involved the knockdown and overexpression of the hepatic TM6SF2 gene in NAFLD mice and cell models to explore its effects on pathological changes in the liver. In addition, RNA-seq, oxygen consumption rate technology, western blotting, and pathological examination were performed to investigate the underlying mechanisms of NALFD caused by TM6SF2 deficiency.
Research results
Hepatic TM6SF2 expression was upregulated in patients with NAFLD and high-fat diet (HFD)-fed mice. Overexpression of TM6SF2 mitigated hepatic lipid accumulation in HFD-fed mouse models. Knockdown of TM6SF2 promoted hepatic lipid accumulation and inflammation. TM6SF2 deficiency promotes hepatic lipid accumulation through the dysregulation of fatty acid metabolism. MK-4074 administration may serve as a potential drug to improve NAFLD caused by TM6SF2 deficiency.
Research conclusions
In this study, we found that the reactive overexpression of TM6SF2 under HFD conditions could alleviate hepatic lipid accumulation, the loss of which accelerated the NALFD phenotypes under HFD feeding. We also found that dysregulated fatty acid metabolism occurs in the context of TM6SF2 deficiency under overnutrition conditions. Therapeutics aimed at abnormal fatty acid metabolism may be a promising strategy for improving the hepatic lipid profile of patients with the TM6SF2 E167K variant in the clinical setting. Our study suggests that MK-4074 could be a potential drug for lowering hepatic lipid content in a TM6SF2-knockdown NAFLD mouse model.
Research perspectives
TM6SF2 plays a protective role in the HFD condition; its deficiency enhanced hepatic lipid accumulation through dysregulated fatty acid metabolism, and MK-4074 treatment could alleviate the NAFLD phenotypes caused by TM6SF2 deficiency. The next step was to investigate whether MK-4074 has a therapeutic effect in patients with NAFLD harboring the TM6SF2 E167K mutation.
