Basic Study
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Nov 21, 2015; 21(43): 12381-12391
Published online Nov 21, 2015. doi: 10.3748/wjg.v21.i43.12381
Retinoic acid receptor α promotes autophagy to alleviate liver ischemia and reperfusion injury
Chen Zhong, Li-Yong Pu, Ming-Ming Fang, Zhen Gu, Jian-Hua Rao, Xue-Hao Wang
Chen Zhong, Li-Yong Pu, Jian-Hua Rao, Xue-Hao Wang, Key Laboratory of Living Donor Liver Transplantation of Chinese Ministry of Health, Liver Transplantation Center, First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
Ming-Ming Fang, Department of Neurology, Jiangsu Province Hospital on Integration of Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210028, Jiangsu Province, China
Zhen Gu, State Key Laboratory of Reproductive Medicine, Research Center for Bone and Stem Cells, Department of Human Anatomy, Nanjing Medical University, Nanjing 210029, Jiangsu Province, China
Author contributions: Zhong C and Pu LY contributed equally to this study; Zhong C, Pu LY, Gu Z, Rao JH and Wang XH were responsible for the study design and conception; Zhong C and Fang MM participated in data analysis and collection and manuscript preparation; Zhong C, Pu LY, Gu Z, Rao JH and Wang XH took part in the revision of this article.
Supported by National Natural Science Foundation of China, No. 81273261.
Institutional review board statement: The study was reviewed and approved by the Institutional Review Board of Nanjing Medical University.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and use Committee of Nanjing Medical University (NJMU, Protocol Number NJMU08-092).
Conflict-of-interest statement: All the authors declare no potential conflicts of interest.
Data sharing statement: Technical appendix, statistical code, and dataset available from the corresponding author at wangxh@njmu.edu.cn.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (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: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Xue-Hao Wang, MD, PhD, Key Laboratory of Living Donor Liver Transplantation of Chinese Ministry of Health, Liver Transplantation Center, First Affiliated Hospital of Nanjing Medical University, No. 300 Guangzhou Road, Nanjing 210029, Jiangsu Province, China. wangxh@njmu.edu.cn
Telephone: +86-25-83718836 Fax: +86-25-83672106
Received: March 12, 2015
Peer-review started: March 13, 2015
First decision: June 2, 2015
Revised: June 19, 2015
Accepted: August 25, 2015
Article in press: August 25, 2015
Published online: November 21, 2015
Abstract

AIM: To study the role of autophagy and the relationship between retinoic acid receptor α (RARα) and autophagy in liver ischemia and reperfusion (IR) injury.

METHODS: All-trans retinoic acid (ATRA) was administered to mice for two weeks before operation. Reverse transcription-polymerase chain reaction and Western blot were used to detect the expression levels of related factors. To demonstrate the role of RARα, LE540, a RARα inhibitor, was used to treat hepatocytes injured by H2O2in vitro.

RESULTS: ATRA pretreatment noticeably diminished levels of serum alanine aminotransferase and aspartate aminotransferase as well as the degree of histopathological changes. Apoptosis was also inhibited, whereas autophagy was promoted. In vitro, RARα was inhibited by LE540, which resulted in decreased autophagy and increased apoptosis. Similarly, the expression of Foxo3a and p-Akt was downregulated, but Foxo1 expression was upregulated.

CONCLUSION: This research provides evidence that ATRA can protect the liver from IR injury by promoting autophagy, which is dependent on Foxo3/p-Akt/Foxo1 signaling.

Keywords: Ischemia/reperfusion, Retinoic acid receptor α, Foxo3a, Foxo1, Autophagy

Core tip: To investigate the role of autophagy and the relationship between all-trans retinoic acid (ATRA) and autophagy in liver ischemia and reperfusion (IR) injury. We found that ATRA pretreatment alleviated liver IR injury by inducing autophagy and it may involves retinoic acid receptor α (RARα) activity. To clarify the mechanism of RARα, we used LE540 to inhibit RARα during reactive oxygen species-inducing cell damage in vitro. Our data showed that RARα activation enhanced Foxo3a and p-Akt expression except Foxo1. The Foxo3a/p-Akt/Foxo1 pathway has previously been proven to promote autophagy. Hence, we conclude that ATRA activates RARα to reduce liver IR injury by regulating the Foxo3a/p-Akt/Foxo1 pathway to promote autophagy.