Conjugated secondary 12α-hydroxylated bile acids promote liver fibrogenesis
Guoxiang Xie,
Runqiu Jiang,
Xiaoning Wang,
Ping Liu,
Aihua Zhao,
Yiran Wu,
Fengjie Huang,
Zhipeng Liu,
Cynthia Rajani,
Xiaojiao Zheng,
Jiannan Qiu,
Xiaoling Zhang,
Suwen Zhao,
Hua Bian,
Xin Gao,
Beicheng Sun,
Wei Jia
Affiliations
Guoxiang Xie
Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China; Human Metabolomics Institute, Inc., Shenzhen, Guangdong 518109, China
Runqiu Jiang
Department of Hepatobiliary Surgery, The Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, Jiangsu 210009, China
Xiaoning Wang
E-institute of Shanghai Municipal Education Committee, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
Ping Liu
E-institute of Shanghai Municipal Education Committee, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
Aihua Zhao
Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
Yiran Wu
The iHuman Institute, ShanghaiTech University, Shanghai 201210, China
Fengjie Huang
Human Metabolomics Institute, Inc., Shenzhen, Guangdong 518109, China
Zhipeng Liu
Medical School of Southeast University, Nanjing, Jiangsu 210096, China
Cynthia Rajani
University of Hawaii Cancer Center, Honolulu, HI 96813, USA
Xiaojiao Zheng
Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
Jiannan Qiu
E-institute of Shanghai Municipal Education Committee, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
Xiaoling Zhang
Department of Hygienic Analysis and Detection, Nanjing Medical University, Nanjing, Jiangsu 211166, China
Suwen Zhao
The iHuman Institute, ShanghaiTech University, Shanghai 201210, China
Hua Bian
Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai 200032, China
Xin Gao
Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai 200032, China
Beicheng Sun
Department of Hepatobiliary Surgery, The Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, Jiangsu 210009, China
Wei Jia
Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China; University of Hawaii Cancer Center, Honolulu, HI 96813, USA; Hong Kong Traditional Chinese Medicine Phenome Research Centre, School of Chinese Medicine, Hong Kong Baptist University, Kowloon Tong, Hong Kong 999077, China; Lead contact; Corresponding author.
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 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. Interpretation: 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. Fundings: 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).
