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 Sjövall; Michael Trauner

Journal of Lipid Research (Mar 2006)

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 Sjövall,
Michael Trauner

Affiliations

Hanns-Ulrich Marschall: 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
Martin Wagner: 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
Karl Bodin: 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
Gernot Zollner: 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
Peter Fickert: 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
Judith Gumhold: 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
Dagmar Silbert: 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
Andrea Fuchsbichler: 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
Jan Sjövall: 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
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

Journal volume & issue: Vol. 47, no. 3
pp. 582 – 592

Abstract

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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 1β, 2β, 4β, 6α, 6β, 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.

Published in Journal of Lipid Research

ISSN: 0022-2275 (Print); 1539-7262 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science: Chemistry: Organic chemistry: Biochemistry
Website: https://www.journals.elsevier.com/journal-of-lipid-research

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