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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
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Autor/innen der Med Uni Graz:
Denk Helmut
Fickert Peter
Silbert-Wagner Dagmar
Trauner Michael
Tsybrovskyy Oleksiy
Wagner Martin
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

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