Gastroenterology

Gastroenterology

Volume 125, Issue 3, September 2003, Pages 825-838
Gastroenterology

Basic-liver, pancreas, and biliary tract
Role of farnesoid X receptor in determining hepatic ABC transporter expression and liver injury in bile duct-ligated mice

https://doi.org/10.1016/S0016-5085(03)01068-0Get rights and content

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.

Section snippets

Animals

C57/BL6 mice with targeted disruption of FXR (FXR−/−)11 and wild-type littermates (FXR+/+) were housed with a 12:12-hour light/dark cycle and permitted ad libitum consumption of water and a standard mouse diet. The experimental protocols were approved by the local Animal Care and Use Committee, according to criteria outlined in the Guide for the Care and Use of Laboratory Animals prepared by the National Academy of Sciences, as published by the National Institutes of Health (Publication No.

Mortality, serum liver enzymes, and bile acid levels

Because FXR−/− have increased liver injury and mortality in response to CA feeding,11, 12 we questioned whether the accumulation of endogenous bile acids in cholestasis (CBDL model) has similar deleterious effects. However, mortality rates did not significantly differ between CBDL FXR−/− and CBDL FXR+/+ (24% vs. 17%, respectively). Moreover, alanine aminotransferase levels as an indicator of hepatocellular injury showed equally increased levels in CBDL FXR−/− and CBDL FXR+/+ (Table 1). Of

Discussion

The aim of this study was to investigate the role of FXR in determining hepatic ABC transporter expression and liver injury in a mouse model of obstructive cholestasis. This was accomplished by comparing alterations in hepatic ABC transporter expression and morphological features of liver injury in CBDL FXR−/− and CBDL FXR+/+. This work provides evidence that FXR-dependent expression of the canalicular Bsep is linked to the phenotype of cholestatic liver injury in response to bile duct

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    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.).

    1

    M.W. and P.F. contributed equally to this work.

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