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

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.

• Authors: Martin Wagner, Peter Fickert, Gernot Zollner, Andrea Fuchsbichler, Dagmar Silbert, Oleksiy Tsybrovskyy, Kurt Zatloukal, Grace L Guo, John D Schuetz, Frank J Gonzalez, Hanns-Ulrich Marschall, Helmut Denk, Michael Trauner
• Journal: Gastroenterology (Gastroenterology) Vol. 125 Issue 3 Pg. 825-38 (Sep 2003) ISSN: 0016-5085 [Print] United States
• PMID: 12949728 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 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

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 11
• ATP-Binding Cassette Transporters (genetics)
• Animals
• Apoptosis
• Cell Division
• Cholestasis (metabolism, pathology)
• DNA-Binding Proteins (physiology)
• Ligation
• Liver (metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Multidrug Resistance-Associated Proteins (genetics)
• Necrosis
• RNA, Messenger (analysis)
• Receptors, Cytoplasmic and Nuclear
• Tight Junctions (pathology)
• Transcription Factors (physiology)