Conjugated secondary 12α-hydroxylated bile acids promote liver fibrogenesis

作者：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 · 发表于：EBioMedicine · 年份：2021 · DOI：10.1016/j.ebiom.2021.103290 · 被引用次数：117 · 研究领域：Drug Transport and Resistance Mechanisms、Liver physiology and pathology、Liver Disease Diagnosis and Treatment

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: ), 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 Institut...