Loss of Bile Salt Export Pump (Bsep/Abcb11) Ameliorates Toxin-induced Hepatic Fibrosis via Suppression of Hepatocellular Jun Amino-terminal Kinase Signaling and Hepatic Stellate Cell Activation

Claudia D Fuchs; Emmanuel D Dixon; Philipp Königshofer; Thierry Claudel; Veronika Mlitz; Hubert Scharnagl; Tatjana Stojakovic; Thomas Reiberger; Michael Trauner

doi:10.1016/j.jcmgh.2025.101630

Loss of Bile Salt Export Pump (Bsep/Abcb11) Ameliorates Toxin-induced Hepatic Fibrosis via Suppression of Hepatocellular Jun Amino-terminal Kinase Signaling and Hepatic Stellate Cell Activation

Cell Mol Gastroenterol Hepatol. 2025 Sep 12;20(1):101630. doi: 10.1016/j.jcmgh.2025.101630. Online ahead of print.

Authors

Claudia D Fuchs¹, Emmanuel D Dixon¹, Philipp Königshofer², Thierry Claudel¹, Veronika Mlitz¹, Hubert Scharnagl³, Tatjana Stojakovic⁴, Thomas Reiberger², Michael Trauner⁵

Affiliations

¹ Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria.
² Experimental Hepatic Hemodynamic lab (HEPEX), Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria; Christian Doppler laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria; CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
³ Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria.
⁴ Clinical Institute of Medical and Chemical Laboratory Diagnostics, University Hospital Graz, Graz, Austria.
⁵ Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria. Electronic address: michael.trauner@meduniwien.ac.at.

Abstract

Background & aims: Loss of Bsep/Abcb11 results in a hydrophilic bile acid (BA) pool consisting of tetrahydroxylated BAs (THBAs) reducing cholestasis-induced liver injury. In this study, we investigated whether loss of Bsep may protect mice from development of toxin-induced liver fibrosis by directly impacting on hepatic stellate cell (HSC) activation.

Methods: Wild-type (WT) and Bsep^-/- mice were exposed to carbon tetrachloride (CCl₄) or thioacetamide (TAA) for 4 weeks (3 injections per week) as models of toxin-induced liver fibrosis. In vitro, the human HSC line LX2 and immortalized human hepatocytes (IHHs) were challenged with TGFβ or 12S-HETE (arachonidonic acid derivate) with or without THBA treatment. Liver immunohistochemistry (IHC), immunofluorescence (IF), gene and protein expression, intrahepatic BA profile, luciferase activity, and 12S-HETE assays were performed.

Results: In contrast to WT mice, serum transaminases were not elevated in Bsep^-/- mice after CCl₄ or TAA injection. Accordingly, IHC accompanied by gene expression profiling and measurement of hepatic hydroxyproline levels reduced hepatic inflammation and fibrosis in Bsep^-/- mice challenged with CCl₄ or TAA. Mechanistically, hepatic protein expression of pJNK (a known mediator of CCl₄-induced liver fibrosis) was reduced in Bsep^-/- CCl₄ mice in comparison to CCl₄-exposed WT mice. In vitro, activation of JNK was suppressed by THBA in IHH cells. LX2 cell activation was attenuated by treatment with THBA as reflected by reduced AP1-luciferase activity and by restoring gene expression levels of p62 and Nrf2 as well as by significant reduction of αSma, Tgfβ, and Mcp-1 gene expression.

Conclusions: Loss of Bsep protects mice from toxin-induced liver fibrosis via suppression of hepatocellular pJNK signaling and attenuation of HSC activation.

Keywords: Fibrosis; Hepatic stellate cells; Hydroxylated bile acids.