详情页 - 广东省中医院知识库

当前位置：首页 > 详情页

Conjugated secondary 12α-hydroxylated bile acids promote liver fibrogenesis.

文献详情

资源类型：

Pubmed体系：

作者：

机构： [a]Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China [b]Human Metabolomics Institute, Inc., Shenzhen, Guangdong 518109, China [c]Department of Hepatobiliary Surgery, The Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, Jiangsu 210009, China [d]E-institute of Shanghai Municipal Education Committee, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China [e]The iHuman Institute, ShanghaiTech University, Shanghai 201210, China [f]Medical School of Southeast University, Nanjing, Jiangsu 210096, China [g]University of Hawaii Cancer Center, Honolulu, HI 96813, USA [h]Department of Hygienic Analysis and Detection, Nanjing Medical University, Nanjing, Jiangsu 211166, China [i]Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai 200032, China [j]Hong Kong Traditional Chinese Medicine Phenome Research Centre, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong 999077, China

出处：

DOI：

摘要：

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. 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. We found that a group of conjugated 12α-hydroxylated (12α-OH) BAs, such as taurodeoxycholate (TDCA) and glycodeoxycholate (GDCA), significantly increased in NASH patients and liver fibrosis mouse models. 12α-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. Increased hepatic concentrations of conjugated 12α-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. This study was supported by the National Institutes of Health/National Cancer Institute Grant 1U01CA188387-01A1, the National Key Research and Development Program of China (2017YFC0906800); the State Key Program of National Natural Science Foundation (81430062); the National Natural Science Foundation of China (81974073, 81774196), China Postdoctoral Science Foundation funded project, China (2016T90381), and E-institutes of Shanghai Municipal Education Commission, China (E03008). Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.

基金：

语种：

PubmedID：

中科院(CAS)分区：

出版当年[2020]版：

大类 | 2 区医学

小类 | 2 区医学：研究与实验

最新[2025]版：

大类 | 1 区

医学

小类 | 1 区医学：研究与实验

第一作者：

第一作者机构： [a]Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China [b]Human Metabolomics Institute, Inc., Shenzhen, Guangdong 518109, China

共同第一作者：

通讯作者：

通讯机构： [a]Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China [g]University of Hawaii Cancer Center, Honolulu, HI 96813, USA [j]Hong Kong Traditional Chinese Medicine Phenome Research Centre, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong 999077, China

推荐引用方式(GB/T 7714)：

APA：

MLA：