Role of farnesoid X receptor in determining hepatic ABC transporter expression and liver injury in bile duct-ligated mice.
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.[1]References
- Role of farnesoid X receptor in determining hepatic ABC transporter expression and liver injury in bile duct-ligated mice. Wagner, M., Fickert, P., Zollner, G., Fuchsbichler, A., Silbert, D., Tsybrovskyy, O., Zatloukal, K., Guo, G.L., Schuetz, J.D., Gonzalez, F.J., Marschall, H.U., Denk, H., Trauner, M. Gastroenterology (2003) [Pubmed]
Annotations and hyperlinks in this abstract are from individual authors of WikiGenes or automatically generated by the WikiGenes Data Mining Engine. The abstract is from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.About WikiGenesOpen Access LicencePrivacy PolicyTerms of Useapsburg
