Basic Study
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jun 21, 2022; 28(23): 2569-2581
Published online Jun 21, 2022. doi: 10.3748/wjg.v28.i23.2569
Family with sequence similarity 134 member B-mediated reticulophagy ameliorates hepatocyte apoptosis induced by dithiothreitol
Yi-Xin Guo, Bing Han, Ting Yang, Yu-Si Chen, Yi Yang, Jia-Yao Li, Qin Yang, Ru-Jia Xie
Yi-Xin Guo, Jia-Yao Li, Department of Pathophysiology, Guizhou Provincial Key Laboratory of Pathogenesis and Drug Research on Common Chronic Diseases, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
Bing Han, Ting Yang, Yu-Si Chen, Yi Yang, Qin Yang, Ru-Jia Xie, Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, Guiyang 550025, Guizhou Province, China
Author contributions: Yang Q and Xie RJ designed and coordinated the study; Guo YX, Han B and Yang T performed the experiments and acquired data; Chen YS, Yang Y and Li JY analyzed and interpreted data; Guo YX and Xie RJ drafted the manuscript; all authors approved the final version of the article.
Supported by National Natural Science Foundation of China, No. 81560105; Science and Technology Foundation of Guizhou Province, No. Qiankehe Jichu-ZK[2021]365, and No. Qiankehe Pingtai Rencai[2019]5801; and National Natural Science Foundation Cultivation Project of Guizhou Medical University, No. 20NSP016.
Institutional review board statement: This study did not involve human subjects or living animals.
Institutional animal care and use committee statement: This study did not involve human subjects or living animals.
Conflict-of-interest statement: The authors declare no conflicts of interest.
Data sharing statement: The data used to support the findings of this study are available from the corresponding author at 592153968@qq.com upon request.
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: Ru-Jia Xie, MD, Academic Research, Department of Pathophysiology, College of Basic Medical Sciences, Guizhou Medical University, Dongqing Road, Guiyang 550025, Guizhou Province, China. 592153968@qq.com
Received: January 5, 2022
Peer-review started: January 5, 2022
First decision: March 9, 2022
Revised: March 23, 2022
Accepted: April 29, 2022
Article in press: April 29, 2022
Published online: June 21, 2022
Processing time: 162 Days and 7.6 Hours
ARTICLE HIGHLIGHTS
Research background

Hepatocyte apoptosis induced by endoplasmic reticulum (ER) stress has a strong association with the development of fibrosis, cirrhosis, and hepatocellular carcinoma. Previous studies have revealed that endoplasmic reticulophagy (ER-phagy) promotes the selective clearance of damaged ER fragments during ER stress, playing a crucial role in maintaining ER homeostasis and inhibiting apoptosis. However, the precise regulatory mechanisms remain unclear.

Research motivation

Defects in ER-phagy pathways are associated with multiple human pathologies, including infectious and neurodegenerative diseases, aging and cancer. However, whether ER-phagy is involved in the regulation of ER homeostasis in hepatocytes under ER stress remains elusive.

Research objectives

To elucidate the effect of family with sequence similarity 134 member B (FAM134B)-mediated ER-phagy on normal buffalo rat hepatocytes apoptosis induced by dithiothreitol (DTT) and explore the potential regulatory mechanism.

Research methods

A model of ER stress was established by DTT. The levels of proteins related to ER stress and ER-phagy were determined by western blot. An interaction between FAM134B, calnexin (CNX), and microtubule-associated protein 1 light chain 3 (LC3) was investigated by co-immunoprecipitation. ER-Tracker Red probe and Lyso-Tracker Green probe were used to detect the colocalization of ER with lysosome in cells. Mito-Tracker Green and Rhod-2 AM probes were used to detect the level of mitochondrial Ca2+ under the confocal microscopy. Flow cytometry was conducted to analyze the effect of DTT treatment on cell cycle distribution and apoptosis. The small interfering RNA against FAM134B was used to knockdown FAM134B in buffalo rat liver 3A (BRL-3A) cells.

Research results

DTT treatment upregulated glucose-regulated protein 78 (GRP78), CNX, FAM134B, and autophagy related gene 12 (ATG12) protein levels and increased the ratio of LC3II/LC3I in BRL-3A cells. FAM134B-mediated reticulophagy maintains ER homeostasis in ER-stressed hepatocytes via the clearance of damaged ER fragments. FAM134B-mediated reticulophagy ameliorates DTT-induced hepatocyte apoptosis. Knockdown of FAM134B enhanced ER stress-mediated apoptosis in BRL-3A cells.

Research conclusions

FAM134B-mediated ER-phagy attenuates hepatocyte apoptosis by suppressing the mitochondrial apoptotic pathway.

Research perspectives

FAM134B-mediated reticulophagy may be a novel therapeutic target, and our findings provide emerging evidence demonstrating the prominence of ER-phagy in ER stress-related hepatocyte apoptosis. Alleviation of the ER stress-mediated hepatocyte apoptosis via restoring ER homeostasis is critical in the treatment of liver diseases.