Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Fuchs, CD; Dixon, ED; Königshofer, P; Claudel, T; Mlitz, V; Scharnagl, H; Stojakovic, T; Reiberger, T; Trauner, M.
Loss of bile salt export pump (Bsep/Abcb11) ameliorates toxin-induced hepatic fibrosis via suppression of hepatocellular JNK signaling and HSC activation.
Cell Mol Gastroenterol Hepatol. 2025; 101630
Doi: 10.1016/j.jcmgh.2025.101630
PubMed
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- Führende Autor*innen der Med Uni Graz
- Trauner Michael
- Co-Autor*innen der Med Uni Graz
- Claudel Thierry
- Scharnagl Hubert
- Stojakovic Tatjana
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- Abstract:
- BACKGROUND AND AIMS: Loss of Bsep/Abcb11 results in a hydrophilic bile acid (BA) pool consisting of tetrahydroxylated BAs (THBA) 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: 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 (IHH) 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 bile acid (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, (Immuno)histochemistry 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. CONCLUSION: Loss of Bsep protects mice from toxin-induced liver fibrosis via suppression of hepatocellular pJNK signaling and attenuation of HSC activation.