SIRT1 Stabilizes β-TrCP1 to Inhibit Snail1 Expression in Maintaining Intestinal Epithelial Integrity to Alleviate Colitis

Liang Wang; Jinsong Li; Mingshan Jiang; Yue Luo; Xiaoke Xu; Juan Li; Yang Pan; Hu Zhang; Zhi-Xiong Jim Xiao; Yang Wang

doi:10.1016/j.jcmgh.2024.05.002

SIRT1 Stabilizes β-TrCP1 to Inhibit Snail1 Expression in Maintaining Intestinal Epithelial Integrity to Alleviate Colitis

Cell Mol Gastroenterol Hepatol. 2024 May 9:S2352-345X(24)00108-5. doi: 10.1016/j.jcmgh.2024.05.002. Online ahead of print.

Authors

Liang Wang¹, Jinsong Li², Mingshan Jiang³, Yue Luo², Xiaoke Xu², Juan Li², Yang Pan², Hu Zhang⁴, Zhi-Xiong Jim Xiao⁵, Yang Wang⁶

Affiliations

¹ Institute of Basic Medicine and Forensic Medicine, North Sichuan Medical College, Nanchong, China; Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China.
² Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China.
³ Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China.
⁴ Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China. Electronic address: tigerwcums03@sina.com.
⁵ Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China. Electronic address: jimzx@scu.edu.cn.
⁶ Center of Growth, Metabolism and Aging, Key Laboratory of Bio-Resource and Eco-Environment, Ministry of Education, College of Life Sciences, Sichuan University, Chengdu, China. Electronic address: wangy90@scu.edu.cn.

PMID: 38729522
DOI: 10.1016/j.jcmgh.2024.05.002

Abstract

Background & aims: Dysfunction of the intestinal epithelial barrier comprising the junctional complex of tight junctions and adherent junctions leads to increased intestinal permeability, which is a major cause of uncontrolled inflammation related to inflammatory bowel disease (IBD). The NAD⁺-dependent deacetylase SIRT1 is implicated in inflammation and the pathologic process of IBD. We aimed to elucidate the protective role and underlying mechanism of SIRT1 in cell-cell junction and intestinal epithelial integrity.

Methods: The correlation of SIRT1 expression and human IBD was analyzed by GEO or immunohistochemical analyses. BK5.mSIRT1 transgenic mice and wild-type mice were given dextran sodium sulfate (DSS) and the manifestation of colitis-related phenotypes was analyzed. Intestinal permeability was measured by FITC-dextran and cytokines expression was analyzed by quantitative polymerase chain reaction. The expression of the cell junction-related proteins in DSS-treated or SIRT1-knockdown Caco2 or HCT116 cells was analyzed by Western blotting. The effects of nicotinamide mononucleotide in DSS-induced mice colitis were investigated. Correlations of the SIRT1-β-TrCP1-Snail1-Occludin/Claudin-1/E-cadherin pathway with human IBD samples were analyzed.

Results: Reduced SIRT1 expression is associated with human IBD specimens. SIRT1 transgenic mice exhibit much-reduced manifestations of DSS-induced colitis. The activation of SIRT1 by nicotinamide mononucleotide bolsters intestinal epithelial barrier function and ameliorates DSS-induced colitis in mice. Mechanistically, DSS downregulates SiRT1 expression, leading to destabilization of β-TrCP1 and upregulation of Snail1, accompanied by reduced expression of E-cadherin, Occludin, and Claudin-1, consequently resulting in increased epithelial permeability and inflammation. The deregulated SIRT1-β-TrCP1-Snail1-Occludin/Claudin-1/E-cadherin pathway correlates with human IBD.

Conclusions: SIRT1 is pivotal in maintaining the intestinal epithelial barrier integrity via modulation of the β-TrCP1-Snail1-E-cadhein/Occludin/Claudin-1 pathway.

Keywords: Inflammatory Bowel Disease; Intestinal Epithelial Integrity; SIRT1; Snail1; β-TrCP1.