Basic-liver, pancreas, and biliary tractRole of farnesoid X receptor in determining hepatic ABC transporter expression and liver injury in bile duct-ligated mice☆
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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.).
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M.W. and P.F. contributed equally to this work.