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SIRT1 Stabilizes β-TrCP1 to Inhibit Snail1 Expression in Maintaining Intestinal Epithelial Integrity to Alleviate Colitis
Cellular and Molecular Gastroenterology and Hepatology ( IF 7.1 ) Pub Date : 2024-05-09 , DOI: 10.1016/j.jcmgh.2024.05.002
Liang Wang 1 , Jinsong Li 2 , Mingshan Jiang 3 , Yue Luo 2 , Xiaoke Xu 2 , Juan Li 2 , Yang Pan 2 , Hu Zhang 3 , Zhi-Xiong Jim Xiao 2 , Yang Wang 2
Cellular and Molecular Gastroenterology and Hepatology ( IF 7.1 ) Pub Date : 2024-05-09 , DOI: 10.1016/j.jcmgh.2024.05.002
Liang Wang 1 , Jinsong Li 2 , Mingshan Jiang 3 , Yue Luo 2 , Xiaoke Xu 2 , Juan Li 2 , Yang Pan 2 , Hu Zhang 3 , Zhi-Xiong Jim Xiao 2 , Yang Wang 2
Affiliation
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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. 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. 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. SIRT1 is pivotal in maintaining the intestinal epithelial barrier integrity via modulation of the β-TrCP1-Snail1-E-cadhein/Occludin/Claudin-1 pathway.
中文翻译：
SIRT1 稳定 β-TrCP1 抑制 Snail1 表达，维持肠上皮完整性，缓解结肠炎
由紧密连接和粘附连接组成的连接复合物组成的肠上皮屏障功能障碍导致肠道通透性增加，这是与炎症性肠病（IBD）相关的炎症不受控制的主要原因。 NAD 依赖性脱乙酰酶 SIRT1 与炎症和 IBD 的病理过程有关。我们的目的是阐明 SIRT1 在细胞-细胞连接和肠上皮完整性中的保护作用和潜在机制。通过GEO或免疫组织化学分析来分析SIRT1表达与人类IBD的相关性。 BK5.mSIRT1转基因小鼠和野生型小鼠给予右旋糖酐硫酸钠（DSS），并分析结肠炎相关表型的表现。通过 FITC-葡聚糖测量肠道通透性，并通过定量聚合酶链反应分析细胞因子表达。通过蛋白质印迹法分析 DSS 处理或 SIRT1 敲除 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。 SIRT1 表达减少与人类 IBD 标本相关。 SIRT1 转基因小鼠的 DSS 诱导的结肠炎表现大大减少。烟酰胺单核苷酸激活 SIRT1 可增强小鼠肠上皮屏障功能并改善 DSS 诱导的结肠炎。 从机制上讲，DSS 下调 SiRT1 表达，导致 β-TrCP1 不稳定和 Snail1 上调，同时 E-cadherin、Occludin 和 Claudin-1 表达减少，从而导致上皮通透性增加和炎症。失调的 SIRT1-β-TrCP1-Snail1-Occludin/Claudin-1/E-cadherin 通路与人类 IBD 相关。 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发挥关键作用。
更新日期：2024-05-09
中文翻译：
SIRT1 稳定 β-TrCP1 抑制 Snail1 表达，维持肠上皮完整性，缓解结肠炎
由紧密连接和粘附连接组成的连接复合物组成的肠上皮屏障功能障碍导致肠道通透性增加，这是与炎症性肠病（IBD）相关的炎症不受控制的主要原因。 NAD 依赖性脱乙酰酶 SIRT1 与炎症和 IBD 的病理过程有关。我们的目的是阐明 SIRT1 在细胞-细胞连接和肠上皮完整性中的保护作用和潜在机制。通过GEO或免疫组织化学分析来分析SIRT1表达与人类IBD的相关性。 BK5.mSIRT1转基因小鼠和野生型小鼠给予右旋糖酐硫酸钠（DSS），并分析结肠炎相关表型的表现。通过 FITC-葡聚糖测量肠道通透性，并通过定量聚合酶链反应分析细胞因子表达。通过蛋白质印迹法分析 DSS 处理或 SIRT1 敲除 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。 SIRT1 表达减少与人类 IBD 标本相关。 SIRT1 转基因小鼠的 DSS 诱导的结肠炎表现大大减少。烟酰胺单核苷酸激活 SIRT1 可增强小鼠肠上皮屏障功能并改善 DSS 诱导的结肠炎。 从机制上讲，DSS 下调 SiRT1 表达，导致 β-TrCP1 不稳定和 Snail1 上调，同时 E-cadherin、Occludin 和 Claudin-1 表达减少，从而导致上皮通透性增加和炎症。失调的 SIRT1-β-TrCP1-Snail1-Occludin/Claudin-1/E-cadherin 通路与人类 IBD 相关。 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发挥关键作用。
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