Basic Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Oct 14, 2019; 25(38): 5800-5813
Published online Oct 14, 2019. doi: 10.3748/wjg.v25.i38.5800
Sirtuin 1 alleviates endoplasmic reticulum stress-mediated apoptosis of intestinal epithelial cells in ulcerative colitis
Meng-Ting Ren, Meng-Li Gu, Xin-Xin Zhou, Mo-Sang Yu, Hang-Hai Pan, Feng Ji, Chen-Yan Ding
Meng-Ting Ren, Xin-Xin Zhou, Mo-Sang Yu, Feng Ji, Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
Meng-Li Gu, Department of Gastroenterology, Ningbo First Hospital, Ningbo 315000, Zhejiang Province, China
Hang-Hai Pan, Department of Gastroenterology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China
Chen-Yan Ding, Department of Emergency Medicine, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, Zhejiang Province, China
Author contributions: Zhou XX designed the experiments; Ren MT, Gu ML, Yu MS, and Pan HH performed the experiments and analyzed the data; Ren MT drafted the manuscript; Zhou XX and Gu ML critically revised the manuscript; Ji F and Ding CY offered help during the experiments; all authors have read and approved the final manuscript.
Supported by the National Nature Science Foundation of China, No. 81600414; the Natural Science Foundation of Zhejiang Province, No. LQ16H030001; and Zhejiang TCM Science and Technology Project, No. 2016ZA123 and No. 2018ZA013.
Institutional review board statement: This study was reviewed and approved by the Institutional Review Board of the First Affiliated Hospital, College of Medicine, Zhejiang University.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Ethics Committee of the First Affiliated Hospital, College of Medicine, Zhejiang University.
Conflict-of-interest statement: No potential conflicts of interest exist.
Data sharing statement: No additional data are available.
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 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/
Corresponding author: Xin-Xin Zhou, MD, Attending Doctor, Department of Gastroenterology, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, Zhejiang Province, China. zhouxinxin@zju.edu.cn
Telephone: +86-571-87236863 Fax: +86-571-87236611
Received: July 16, 2019
Peer-review started: July 16, 2019
First decision: August 2, 2019
Revised: September 11, 2019
Accepted: September 13, 2019
Article in press: September 13, 2019
Published online: October 14, 2019
Abstract
BACKGROUND

Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylase that is involved in various diseases, including cancers, metabolic diseases, and inflammation-associated diseases. However, the role of SIRT1 in ulcerative colitis (UC) is still confusing.

AIM

To investigate the role of SIRT1 in intestinal epithelial cells (IECs) in UC and further explore the underlying mechanisms.

METHODS

We developed a coculture model using macrophages and Caco-2 cells. After treatment with the SIRT1 activator SRT1720 or inhibitor nicotinamide (NAM), the expression of occludin and zona occludens 1 (ZO-1) was assessed by Western blot analysis. Annexin V-APC/7-AAD assays were performed to evaluate Caco-2 apoptosis. Dextran sodium sulfate (DSS)-induced colitis mice were exposed to SRT1720 or NAM for 7 d. Transferase-mediated dUTP nick-end labeling (TUNEL) assays were conducted to assess apoptosis in colon tissues. The expression levels of glucose-regulated protein 78 (GRP78), CCAAT/enhancer-binding protein homologous protein (CHOP), caspase-12, caspase-9, and caspase-3 in Caco-2 cells and the colon tissues of treated mice were examined by quantitative real-time PCR and Western blot.

RESULTS

SRT1720 treatment increased the protein levels of occludin and ZO-1 and inhibited Caco-2 apoptosis, whereas NAM administration caused the opposite effects. DSS-induced colitis mice treated with SRT1720 had a lower disease activity index (P < 0.01), histological score (P < 0.001), inflammatory cytokine levels (P < 0.01), and apoptotic cell rate (P < 0.01), while exposure to NAM caused the opposite effects. Moreover, SIRT1 activation reduced the expression levels of GRP78, CHOP, cleaved caspase-12, cleaved caspase-9, and cleaved caspase-3 in Caco-2 cells and the colon tissues of treated mice.

CONCLUSION

SIRT1 activation reduces apoptosis of IECs via the suppression of endoplasmic reticulum stress-mediated apoptosis-associated molecules CHOP and caspase-12. SIRT1 activation may be a potential therapeutic strategy for UC.

Keywords: Sirtuin 1, Endoplasmic reticulum stress, Apoptosis, Ulcerative colitis, Intestinal barrier

Core tip: The purpose of this article was to investigate the role of sirtuin 1 (SIRT1) in intestinal epithelial cells (IECs) in ulcerative colitis (UC) in a UC coculture model and in mice with dextran sodium sulfate (DSS)-induced colitis. It was found that SIRT1 activation contributes to enhanced intestinal barrier and reduced apoptosis of IECs via the suppression of endoplasmic reticulum stress-mediated apoptosis-associated molecules CCAAT/enhancer-binding protein homologous protein and caspase-12. SIRT1 activation may be a potential therapeutic strategy for UC.