Basic Study
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 14, 2022; 28(26): 3201-3217
Published online Jul 14, 2022. doi: 10.3748/wjg.v28.i26.3201
Intracellular alpha-fetoprotein mitigates hepatocyte apoptosis and necroptosis by inhibiting endoplasmic reticulum stress
Yun-Fen Chen, Si-Ying Liu, Qi-Jiao Cheng, Yu-Jiao Wang, Shuang Chen, Yi-Yang Zhou, Xia Liu, Zhi-Gang Jiang, Wei-Wei Zhong, Yi-Huai He
Yun-Fen Chen, Si-Ying Liu, Qi-Jiao Cheng, Shuang Chen, Yi-Yang Zhou, Xia Liu, Yi-Huai He, Department of Infectious Diseases, The Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
Yu-Jiao Wang, Department of General Medicine, The Affiliated Hospital of Zunyi Medical University, Zunyi 563000, Guizhou Province, China
Zhi-Gang Jiang, School of Public Health, Zunyi Medical University, Zunyi 563099, Guizhou Province, China
Wei-Wei Zhong, Department of Endoscopy, Jingmen No.1 People’s Hospital, Jingmen 448000, Hubei Province, China
Author contributions: Chen YF, Liu SY, and Cheng QJ contributed equally to this work; Chen YF, Liu SY, Cheng QJ, and He YH conceived and designed research; Chen YF, Liu SY, Wang YJ, Chen S, Zhou YY, and Liu X collected data and conducted research; Jiang ZG, Chen YF, and Zhong WW analyzed and interpreted data; Chen YF, Liu SY, and Cheng QJ wrote the initial paper; He YH and Zhong WW revised the paper; He YH had primary responsibility for final content; all authors read and approved the final manuscript.
Supported by the National Natural Science Foundation of China, No. 81560110; Tian Qing Liver Disease Research Fund Project of the Chinese Foundation for Hepatitis Prevention and Control, No. TQGB20200001; and the Science and Technology Planning Projects of Guizhou Province and Zunyi City, No. QKH·ZC[2019] 2803, No. QKHJC-ZK[2022]YB642, No. QKH·PTRC[2017]5733-013, No. gzwjkj2020-1-041, No. ZSKHSZ[2020]230, and No. ZMC·YZ[2018]38.
Institutional review board statement: The study was reviewed and approved by the Ethics Committee of Affiliated Hospital of Zunyi Medical University (ZYFYLS[2018] 28).
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Animal Experiment Ethics Committee of Zunyi Medical University (LS[2020] 2-231).
Conflict-of-interest statement: There are no conflicts of interest to report.
Data sharing statement: The datasets generated 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: Yi-Huai He, MM, Director, Department of Infectious Diseases, The Affiliated Hospital of Zunyi Medical University, No. 201 Dalian Street, Zunyi 563000, Guizhou Province, China. 993565989@qq.com
Received: January 13, 2022
Peer-review started: January 13, 2022
First decision: March 8, 2022
Revised: March 22, 2022
Accepted: May 13, 2022
Article in press: May 13, 2022
Published online: July 14, 2022
ARTICLE HIGHLIGHTS
Research background

Endoplasmic reticulum (ER) stress plays an important role in the pathogenesis of chronic liver diseases, but how hepatocytes respond to ER stress has not been clarified. Alpha-fetoprotein (AFP) is secreted by hepatoma cells and elevated levels of serum AFP are associated with development of liver malignancies.

Research motivation

Anti-injury response is an important force for hepatocytes to resist liver injury mediated by various reasons, which has a close relationship to the progress and prognosis of liver injury. Studying the anti-injury mechanism of hepatocytes is important for the diagnosis and treatment of liver injury in the clinic.

Research objectives

To investigate whether and how AFP could regulate ER stress and hepatocyte injury.

Research methods

The distribution of AFP and the degrees of ER stress in liver tissues were characterized by histology, immunohistochemistry, and Western blot in biopsied human liver specimens, two mouse models of liver injury and a cellular model. The levels of AFP in sera and the supernatants of cultured cells were quantified by chemiluminescence.

Research results

ER stress induces liver injury and increases intracellular AFP expression in hepatocytes. ER stress up-regulates intracellular AFP expression by up-regulating activating transcription factor-6 (ATF6). Upregulated AFP feedback attenuates ER stress, forming a regulatory loop. Upregulated AFP mitigates the ER stress-induced hepatocyte apoptosis and necroptosis.

Research conclusions

ER stress upregulated intracellular AFP expression in hepatocytes by up-regulating ATF6 during the process of liver injury and intracellular AFP feedback-attenuated hepatocyte apoptosis and necroptosis by alleviating ER stress.

Research perspectives

Intracellular AFP induced by ER stress alleviates hepatocyte apoptosis and necroptosis by activating ATF6.