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Journal of Lipid Research, Vol. 47, 582-592, March 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

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

Hanns-Ulrich Marschall^1,*, Martin Wagner, Karl Bodin, Gernot Zollner, Peter Fickert, Judith Gumhold, Dagmar Silbert, Andrea Fuchsbichler, Jan Sjövall and Michael Trauner

^* Karolinska Institutet, Department of Medicine at Karolinska University Hospital Huddinge, S-14186 Stockholm, Sweden
Laboratory of Experimental and Molecular Hepatology, Department of Internal Medicine, Medical University, A-8036 Graz, Austria
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-17177 Stockholm, Sweden

Published, JLR Papers in Press, December 4, 2005.

¹ To whom correspondence should be addressed. e-mail: hanns-ulrich.marschall{at}medhs.ki.se

Farnesoid X receptor knockout (Fxr^–/–) mice cannot upregulate the bile salt export pump in bile acid loading or cholestatic conditions. To investigate whether Fxr^–/– mice differ in bile acid detoxification compared with 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 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 1ß, 2ß, 4ß, 6, 6ß, 22, or 23 position 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 multidrug resistance-related protein 4 (Mrp4) were increased in kidneys of both genotypes during common bile duct ligation. 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.

Supplementary key words farnesoid X receptor knockout • multidrug resistance-related protein 4 • cytochrome 3a11 • gas chromatography-mass spectrometry • electrospray mass spectrometry

Abbreviations: Asbt, apical sodium-dependent bile acid transporter; Bsep, bile salt export pump; CA, cholic acid; CBDL, common bile duct ligation; DCA, deoxycholic acid; ES-MS, electrospray mass spectrometry; FXR, farnesoid X receptor; LCA, lithocholic acid; MCA, muricholic acid; MeTMS, methyl ester trimethylsilyl ether; Mrp, multidrug resistance-related protein; Oatp1, organic anion-transporting polypeptide 1; PXR, pregnane X receptor; RI, retention index; UDCA, ursodeoxycholic acid

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