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

Gastroenterology. 2003 Sep;125(3):825-38. doi: 10.1016/s0016-5085(03)01068-0.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 11
  • 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*


  • ATP Binding Cassette Transporter, Subfamily B, Member 11
  • ATP-Binding Cassette Transporters
  • Abcb11 protein, mouse
  • Abcc4 protein, mouse
  • DNA-Binding Proteins
  • Multidrug Resistance-Associated Proteins
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • Transcription Factors
  • farnesoid X-activated receptor
  • multidrug resistance-associated protein 3