Role of farnesoid X receptor in determining hepatic ABC transporter expression and liver injury in bile duct-ligated mice

Martin Wagner, Peter Fickert, Gernot Zollner, Andrea Fuchsbichler, Dagmar Silbert, Oleksiy Tsybrovskyy, Kurt Zatloukal, Grace Guo, John D. Schuetz, Frank J. Gonzalez, Hanns Ulrich Marschall, Helmut Denk, Michael Trauner

Research output: Contribution to journalArticlepeer-review

216 Scopus citations

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. Methods: 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 biliary 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.

Original languageEnglish (US)
Pages (from-to)825-838
Number of pages14
JournalGastroenterology
Volume125
Issue number3
DOIs
StatePublished - Sep 1 2003
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Hepatology
  • Gastroenterology

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