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TGR5 agonist inhibits intestinal epithelial cell apoptosis via cAMP/PKA/c-FLIP/JNK signaling pathway and ameliorates dextran sulfate sodium-induced ulcerative colitis

文献类型：期刊论文

作者Yang, Wen-ji2,3; Han, Fang-hui3; Gu, Yi-pei3; Qu, Hui3; Liu, Jia1; Shen, Jian-hua2,3; Leng, Ying2,3
刊名ACTA PHARMACOLOGICA SINICA
出版日期2023-08-01
卷号44期号:8页码:1649-1664
关键词TGR5 agonist ulcerative colitis intestinal epithelial cell apoptosis cAMP PKA signaling pathway c-FLIP
DOI10.1038/s41401-023-01081-y
文献子类Article
英文摘要Excessive apoptosis of intestinal epithelial cell (IEC) is a crucial cause of disrupted epithelium homeostasis, leading to the pathogenesis of ulcerative colitis (UC). The regulation of Takeda G protein-coupled receptor-5 (TGR5) in IEC apoptosis and the underlying molecular mechanisms remained unclear, and the direct evidence from selective TGR5 agonists for the treatment of UC is also lacking. Here, we synthesized a potent and selective TGR5 agonist OM8 with high distribution in intestinal tract and investigated its effect on IEC apoptosis and UC treatment. We showed that OM8 potently activated hTGR5 and mTGR5 with EC50 values of 202 +/- 55 nM and 74 +/- 17 nM, respectively. After oral administration, a large amount of OM8 was maintained in intestinal tract with very low absorption into the blood. In DSS-induced colitis mice, oral administration of OM8 alleviated colitis symptoms, pathological changes and impaired tight junction proteins expression. In addition to enhancing intestinal stem cell (ISC) proliferation and differentiation, OM8 administration significantly reduced the rate of apoptotic cells in colonic epithelium in colitis mice. The direct inhibition by OM8 on IEC apoptosis was further demonstrated in HT-29 and Caco-2 cells in vitro. In HT-29 cells, we demonstrated that silencing TGR5, inhibition of adenylate cyclase or protein kinase A (PKA) all blocked the suppression of JNK phosphorylation induced by OM8, thus abolished its antagonizing effect against TNF-alpha induced apoptosis, suggesting that the inhibition by OM8 on IEC apoptosis was mediated via activation of TGR5 and cAMP/PKA signaling pathway. Further studies showed that OM8 upregulated cellular FLICE-inhibitory protein (c-FLIP) expression in a TGR5-dependent manner in HT-29 cells. Knockdown of c-FLIP blocked the inhibition by OM8 on TNF-alpha induced JNK phosphorylation and apoptosis, suggesting that c-FLIP was indispensable for the suppression of OM8 on IEC apoptosis induced by OM8. In conclusion, our study demonstrated a new mechanism of TGR5 agonist on inhibiting IEC apoptosis via cAMP/PKA/c-FLIP/JNK signaling pathway in vitro, and highlighted the value of TGR5 agonist as a novel therapeutic strategy for the treatment of UC.
WOS关键词TUMOR-NECROSIS-FACTOR ; JNK ACTIVATION ; C-FLIP ; PROTECTS ; MICE ; DSS
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
出版者NATURE PUBL GROUP
WOS记录号WOS:000960579200001
源URL[http://119.78.100.183/handle/2S10ELR8/309661]  
专题新药研究国家重点实验室
通讯作者Shen, Jian-hua; Leng, Ying
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China
2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China;
3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China;
推荐引用方式
GB/T 7714		 Yang, Wen-ji,Han, Fang-hui,Gu, Yi-pei,et al. TGR5 agonist inhibits intestinal epithelial cell apoptosis via cAMP/PKA/c-FLIP/JNK signaling pathway and ameliorates dextran sulfate sodium-induced ulcerative colitis[J]. ACTA PHARMACOLOGICA SINICA,2023,44(8):1649-1664.
APA Yang, Wen-ji.,Han, Fang-hui.,Gu, Yi-pei.,Qu, Hui.,Liu, Jia.,...&Leng, Ying.(2023).TGR5 agonist inhibits intestinal epithelial cell apoptosis via cAMP/PKA/c-FLIP/JNK signaling pathway and ameliorates dextran sulfate sodium-induced ulcerative colitis.ACTA PHARMACOLOGICA SINICA,44(8),1649-1664.
MLA Yang, Wen-ji,et al."TGR5 agonist inhibits intestinal epithelial cell apoptosis via cAMP/PKA/c-FLIP/JNK signaling pathway and ameliorates dextran sulfate sodium-induced ulcerative colitis".ACTA PHARMACOLOGICA SINICA 44.8(2023):1649-1664.

入库方式： OAI收割

来源：上海药物研究所

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