Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Wagner, M; Fickert, P; Zollner, G; Fuchsbichler, A; Silbert, D; Tsybrovskyy, O; Zatloukal, K; Guo, GL; Schuetz, JD; Gonzalez, FJ; Marschall, HU; Denk, H; Trauner, M.
Role of farnesoid X receptor in determining hepatic ABC transporter expression and liver injury in bile duct-ligated mice.
Gastroenterology. 2003; 125(3):825-838
Doi: 10.1016/S0016-5085(03)01068-0
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- Führende Autor*innen der Med Uni Graz
- Trauner Michael
- Wagner Martin
- Co-Autor*innen der Med Uni Graz
- Denk Helmut
- Fickert Peter
- Silbert-Wagner Dagmar
- Tsybrovskyy Oleksiy
- Zatloukal Kurt
- Zollner Gernot
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- Abstract:
- Background & Aims: Cholestasis induces changes in hepatic adenosine triphosphate-binding cassette (ABC) transporter expression. We aimed to investigate the role of the nuclear bile acid receptor (farnesoid X receptor [FXR]) in mediating changes in ABC transporter expression and in determining liver injury. Metho : Hepatic ABC transporter (multidrug resistance-associated proteins [Mrp] 2-4 and bile salt export pump [Bsep]) expression and localization were studied in common bile duct-ligated (CBDL) FXR knockout (FXR-/-), wild-type (FXR+/+), and sham-operated mice. Serum alanine aminotransferase, alkaline phosphatase, bilirubin and bile acid levels, hepatic bile acid composition, and liver histology were investigated. Cholangiomanometry and bile duct morphometry were performed. Results: CBDL induced expression of Mrp 3 and Mrp 4 in FXR+/+ and even more in FXR-/-, whereas Mrp 2 expression remained unchanged. Bsep expression was maintained in CBDL FXR+/+ but remained undetectable in CBDL FXR-/-. Alanine aminotransferase levels and mortality rates did not differ between CBDL FXR+/+ and FXR-/-. CBDL increased billary pressure and induced bile ductular proliferation and bile infarcts in FXR+/+, whereas FXR-/- had lower biliary pressures, less ductular proliferation, and developed disseminated liver cell necroses. Conclusions: Overexpression of Mrp 3 and Mrp 4 in CBDL mice is FXR independent and could play an important role in the adaptive hepatic ABC transporter response to cholestasis. Maintenance of Bsep expression strictly depends on FXR and is a critical determinant of the cholestatic phenotype. Lack of bile infarcts in CBDL FXR-/- suggests that development of bile infarcts is related to bile acid-dependent bile flow and biliary pressure. This information is relevant for the potential use of FXR modulators in the treatment of cholestatic liver diseases.
- Find related publications in this database (using NLM MeSH Indexing)
- ATP-Binding Cassette Transporters - genetics
- Animals -
- Apoptosis -
- Cell Division -
- Cholestasis - metabolism Cholestasis - pathology
- DNA-Binding Proteins - physiology
- Ligation -
- Liver - metabolism Liver - pathology
- Mice -
- Mice, Inbred C57BL -
- Multidrug Resistance-Associated Proteins - genetics
- Necrosis -
- RNA, Messenger - analysis
- Receptors, Cytoplasmic and Nuclear -
- Tight Junctions - pathology
- Transcription Factors - physiology