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J. Lipid Res.
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A more recent version of this article appeared on March 1, 2006

Papers In Press, published online ahead of print December 4, 2005
J. Lipid Res., doi:10.1194/jlr.M500427-JLR200
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Submitted on September 27, 2005
Revised on November 16, 2005
Accepted on December 3, 2005

Fxr -/- mice adapt to biliary obstruction by enhanced phase I detoxification and renal elimination of bile acids

Hanns-Ulrich Marschall, Martin Wagner, Karl Bodin, Gernot Zollner, Peter Fickert, Judith Gumhold, Dagmar Silbert, Andrea Fuchsbichler, Jan Sjovall, and Michael Trauner

Department of Medicine - Division of Gastroenterology and Hepatology, Karolinska Institutet, Stockholm 14186

Corresponding Author: hanns-ulrich.marschall{at}medhs.ki.se

Fxr knock-out (Fxr-/-) mice cannot up-regulate the bile salt export pump (Bsep) in bile acid loading or cholestatic conditions. In order to investigate whether Fxr-/- mice differ in bile acid detoxification compared to wild-type mice we performed a comprehensive analysis of bile acids extracted from liver, bile, serum and urine of naive and common bile-duct-ligated (CBDL) wild-type and Fxr-/- mice using electrospray- and gas chromatography-mass spectrometry. In addition, hepatic and renal gene expression levels of Cyp2b10 and Cyp3a11, and protein expression levels of putative renal bile acid transporting proteins were investigated. We found significantly enhanced hepatic bile acid hydroxylation in Fxr-/- mice, in particular hydroxylations of cholic acid in the 1beta , 2beta , 4beta , 6a, 6beta , 22, and 23 positions, and a significantly enhanced excretion of these metabolites in urine. The gene expression level of Cyp3a11 was increased in the liver of Fxr-/- mice whereas the protein expression levels of Mrp4 were increased in kidneys of both genotypes during CBDL. In conclusion, Fxr-/- mice detoxify accumulating bile acids in the liver by enhanced hydroxylation reactions probably catalyzed by Cyp3a11. The metabolites formed were excreted into urine most likely with the participation of Mrp4.


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