TY - JOUR
T1 - Role of farnesoid X receptor in determining hepatic ABC transporter expression and liver injury in bile duct-ligated mice
AU - Wagner, Martin
AU - Fickert, Peter
AU - Zollner, Gernot
AU - Fuchsbichler, Andrea
AU - Silbert, Dagmar
AU - Tsybrovskyy, Oleksiy
AU - Zatloukal, Kurt
AU - Guo, Grace L.
AU - Schuetz, John D.
AU - Gonzalez, Frank J.
AU - Marschall, Hanns Ulrich
AU - Denk, Helmut
AU - Trauner, Michael
N1 - Funding Information:
Supported by Grant P15502 from the Austrian Science Foundation (to M.T.), grant 2002/A1054 from Karolinska Institute and the Swedish Science Council (to H.-U.M.), and National Institutes of Health Grant GM60904 and the St. Jude Charity American Lebanese Syrian Associated Charities (to J.D.).
PY - 2003/9/1
Y1 - 2003/9/1
N2 - 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.
AB - 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.
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U2 - 10.1016/S0016-5085(03)01068-0
DO - 10.1016/S0016-5085(03)01068-0
M3 - Article
C2 - 12949728
AN - SCOPUS:0042825756
SN - 0016-5085
VL - 125
SP - 825
EP - 838
JO - Gastroenterology
JF - Gastroenterology
IS - 3
ER -