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

IF 7.1 1区医学 Q1 GASTROENTEROLOGY & HEPATOLOGY Cellular and Molecular Gastroenterology and Hepatology Pub Date : 2024-01-01 DOI:10.1016/j.jcmgh.2024.05.002

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

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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.

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SIRT1 可稳定 β-TrCP1 以抑制 Snail1 的表达，从而维持肠上皮细胞的完整性，缓解结肠炎。

背景和目的：由紧密连接和粘连连接复合体组成的肠上皮屏障功能失调会导致肠道通透性增加，这是导致炎症性肠病（IBD）相关炎症失控的主要原因。依赖 NAD+ 的去乙酰化酶 SIRT1 与炎症和 IBD 的病理过程有关。我们旨在阐明 SIRT1 在细胞-细胞连接和肠上皮完整性中的保护作用及其内在机制：方法：通过 GEO 或免疫组化分析 SIRT1 表达与人类 IBD 的相关性。给 BK5.mSIRT1 转基因小鼠和 WT 小鼠注射右旋糖酐硫酸钠（DSS），分析结肠炎相关表型的表现。用 FITC-Dextran 测量肠道通透性，用 QPCR 分析细胞因子的表达。用 Western 印迹法分析了 DSS 处理或 SIRT1 敲除的 Caco2 或 HCT116 细胞中细胞连接相关蛋白的表达。研究了烟酰胺单核苷酸（NMN）对DSS诱导的小鼠结肠炎的影响。分析了 SIRT1-β-TrCP1-Snail1-Occludin/Claudin-1/E-cadherin 通路与人类 IBD 样本的相关性：结果：SIRT1表达减少与人类IBD样本有关。SIRT1转基因小鼠表现出的DSS诱导的结肠炎症状大大减轻。NMN激活SIRT1可增强肠上皮屏障功能，改善DSS诱导的小鼠结肠炎。从机理上讲，DSS 会下调 SiRT1 的表达，导致 β-TrCP1 失稳和 Snail1 上调，并伴随 E-cadherin、Occludin 和 Claudin-1 的表达减少，从而导致上皮通透性增加和炎症。SIRT1-β-TrCP1-Snail1-Occludin/Claudin-1/E-cadherin 通路的失调与人类 IBD 相关：结论：SIRT1通过调节β-TrCP1-Snail1-E-cadhein/Occludin/Claudin-1通路，在维持肠上皮屏障完整性方面起着关键作用。

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公司名称	产品信息	其他信息	采购帮参考价格
阿拉丁	Dextran sulfate sodium (DSS)

来源期刊

Cellular and Molecular Gastroenterology and Hepatology Medicine-Gastroenterology

CiteScore

13.00

自引率

2.80%

发文量

246

审稿时长

42 days

期刊介绍： "Cell and Molecular Gastroenterology and Hepatology (CMGH)" is a journal dedicated to advancing the understanding of digestive biology through impactful research that spans the spectrum of normal gastrointestinal, hepatic, and pancreatic functions, as well as their pathologies. The journal's mission is to publish high-quality, hypothesis-driven studies that offer mechanistic novelty and are methodologically robust, covering a wide range of themes in gastroenterology, hepatology, and pancreatology. CMGH reports on the latest scientific advances in cell biology, immunology, physiology, microbiology, genetics, and neurobiology related to gastrointestinal, hepatobiliary, and pancreatic health and disease. The research published in CMGH is designed to address significant questions in the field, utilizing a variety of experimental approaches, including in vitro models, patient-derived tissues or cells, and animal models. This multifaceted approach enables the journal to contribute to both fundamental discoveries and their translation into clinical applications, ultimately aiming to improve patient care and treatment outcomes in digestive health.