TY - JOUR
T1 - Conjugated secondary 12α-hydroxylated bile acids promote liver fibrogenesis
AU - Xie, Guoxiang
AU - Jiang, Runqiu
AU - Wang, Xiaoning
AU - Liu, Ping
AU - Zhao, Aihua
AU - Wu, Yiran
AU - Huang, Fengjie
AU - Liu, Zhipeng
AU - Rajani, Cynthia
AU - Zheng, Xiaojiao
AU - Qiu, Jiannan
AU - Zhang, Xiaoling
AU - Zhao, Suwen
AU - Bian, Hua
AU - Gao, Xin
AU - Sun, Beicheng
AU - Jia, Wei
N1 - Funding Information:
This study was financially 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). The Funders did not have any role in study design, data collection, data analyses, interpretation, or writing of this manuscript.
Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.
PY - 2021/4/1
Y1 - 2021/4/1
N2 - 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).
AB - 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).
KW - 12α-hydroxylated bile acids
KW - ERK1/2
KW - G protein-coupled bile acid receptor
KW - Hepatic stellate cell
KW - Liver fibrosis
KW - p38MAPK
KW - TGR5
UR - http://www.scopus.com/inward/record.url?scp=85102883530&partnerID=8YFLogxK
U2 - 10.1016/j.ebiom.2021.103290
DO - 10.1016/j.ebiom.2021.103290
M3 - Journal article
C2 - 33752128
AN - SCOPUS:85102883530
SN - 2352-3964
VL - 66
JO - EBioMedicine
JF - EBioMedicine
M1 - 103290
ER -
