Conjugated secondary 12α-hydroxylated bile acids promote liver fibrogenesis

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.

Automated summary

Elevated levels of conjugated 12 alpha-hydroxylated bile acids, such as TDCA and GDCA, significantly contribute to liver fibrosis by promoting HSC proliferation and expression of fibrosis-related markers. The fibrotic effects of 12 alpha-OH bile acids are mediated through TGR5-dependent p38 MAPK and ERK1/2 signaling pathways.