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

作者：Claudia Fuchs, Emmanuel D. Dixon, Philipp Königshofer, Thierry Claudel, Veronika Mlitz, Hubert Scharnagl, Tatjana Stojaković, Thomas Reiberger, Michael Trauner · 发表于：Cellular and Molecular Gastroenterology and Hepatology · 年份：2025 · DOI：10.1016/j.jcmgh.2025.101630 · 被引用次数：2 · 研究领域：Liver physiology and pathology、Drug Transport and Resistance Mechanisms、Drug-Induced Hepatotoxicity and Protection

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 (CCl 4 ) 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 CCl 4 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 CCl 4 or TAA. Mechanistically, hepatic protein expression of pJNK (a known mediator of CCl 4 -induced liver fibrosis) was reduced in Bsep -/- CCl 4 mice in comparison to CCl 4 -exposed WT mice. In vitro, activation of JNK was suppressed by THBA in IHH cells. LX2 cell activation was attenuated by treatment with TH...