ShanghaiTech University Knowledge Management System
| Conjugated secondary 12 alpha-hydroxylated bile acids promote liver fibrogenesis | |
| 2021 | |
| 发表期刊 | EBIOMEDICINE (IF:9.7[JCR-2023],9.2[5-Year]) |
| ISSN | 2352-3964 |
| 卷号 | 66 |
| DOI | 10.1016/j.ebiom.2021.103290 |
| 摘要 | Background: Significantly elevated serum and hepatic bile acid (BA) concentrations have been known to occur in patients with liver fibrosis. However, the roles of different BA species in liver fibrogenesis are not fully understood. Methods: We quantitatively measured blood BA concentrations in nonalcoholic steatohepatitis (NASH) patients with liver fibrosis and healthy controls. We characterized BA composition in three mouse models induced by carbon tetrachloride (CCl4), streptozotocin-high fat diet (STZ-HFD), and long term HFD, respectively. The molecular mechanisms underlying the fibrosis-promoting effects of BAs were investigated in cell line models, a 3D co-culture system, and a Tgr5 (HSC-specific) KO mouse model. Findings: We found that a group of conjugated 12 alpha-hydroxylated (12 alpha-OH) BAs, such as taurodeoxycholate (TDCA) and glycodeoxycholate (GDCA), significantly increased in NASH patients and liver fibrosis mouse models. 12 alpha-OH BAs significantly increased HSC proliferation and protein expression of fibrosis-related markers. Administration of TDCA and GDCA directly activated HSCs and promoted liver fibrogenesis in mouse models. Blockade of BA binding to TGR5 or inhibition of ERK1/2 and p38 MAPK signaling both significantly attenuated the BA-induced fibrogenesis. Liver fibrosis was attenuated in mice with Tgr5 depletion. Interpretation: Increased hepatic concentrations of conjugated 12 alpha-OH BAs significantly contributed to liver fibrosis via TGR5 mediated p38MAPK and ERK1/2 signaling. Strategies to antagonize TGR5 or inhibit ERK1/2 and p38 MAPK signaling may effectively prevent or reverse liver fibrosis. (C) 2021 The Authors. Published by Elsevier B.V. |
| 关键词 | Liver fibrosis Hepatic stellate cell 12 alpha-hydroxylated bile acids G protein-coupled bile acid receptor TGR5 p38MAPK ERK1/2 |
| 收录类别 | SCIE |
| 语种 | 英语 |
| WOS研究方向 | General & Internal Medicine ; Research & Experimental Medicine |
| WOS类目 | Medicine, General & Internal ; Medicine, Research & Experimental |
| WOS记录号 | WOS:000647447600008 |
| 出版者 | ELSEVIER |
| 原始文献类型 | Article |
| 引用统计 | |
| 文献类型 | 期刊论文 |
| 条目标识符 | https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/126812 |
| 专题 | iHuman研究所_PI研究组_赵素文组 |
| 通讯作者 | Jia, Wei |
| 作者单位 | 1.Shanghai Jiao Tong Univ, Affiliated Peoples Hosp 6, Ctr Translat Med, Shanghai 200233, Peoples R China; 2.Human Metabol Inst Inc, Shenzhen 518109, Guangdong, Peoples R China; 3.Nanjing Univ, Med Sch, Drum Tower Hosp, Dept Hepatobiliary Surg, Nanjing 210009, Jiangsu, Peoples R China; 4.Shanghai Univ Tradit Chinese Med, Inst Interdisciplinary Integrat Med Res, Inst E, Shanghai Municipal Educ Comm, Shanghai 201203, Peoples R China; 5.ShanghaiTech Univ, iHuman Inst, Shanghai 201210, Peoples R China; 6.Southeast Univ, Med Sch, Nanjing 210096, Jiangsu, Peoples R China; 7.Univ Hawaii, Canc Ctr, Honolulu, HI 96813 USA; 8.Nanjing Med Univ, Dept Hygien Anal & Detect, Nanjing 211166, Jiangsu, Peoples R China; 9.Fudan Univ, Zhongshan Hosp, Dept Endocrinol & Metab, Shanghai 200032, Peoples R China; 10.Hong Kong Baptist Univ, Sch Chinese Med, Hong Kong Tradit Chinese Med Phenome Res Ctr, Kowloon Tong, Hong Kong 999077, Peoples R China |
| 推荐引用方式 GB/T 7714 | Xie, Guoxiang,Jiang, Runqiu,Wang, Xiaoning,et al. Conjugated secondary 12 alpha-hydroxylated bile acids promote liver fibrogenesis[J]. EBIOMEDICINE,2021,66. |
| APA | Xie, Guoxiang.,Jiang, Runqiu.,Wang, Xiaoning.,Liu, Ping.,Zhao, Aihua.,...&Jia, Wei.(2021).Conjugated secondary 12 alpha-hydroxylated bile acids promote liver fibrogenesis.EBIOMEDICINE,66. |
| MLA | Xie, Guoxiang,et al."Conjugated secondary 12 alpha-hydroxylated bile acids promote liver fibrogenesis".EBIOMEDICINE 66(2021). |
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