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

doi:10.1194/jlr.m500427-jlr200

Hanns-Ulrich Marschall, Martin Wagner + Show 8 more

Open Access

https://doi.org/10.1194/jlr.m500427-jlr200

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Abstract

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 1beta, 2beta, 4beta, 6alpha, 6beta, 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.

Highlights

Farnesoid X receptor knockout (Fxr2/2) mice cannot upregulate the bile salt export pump in bile acid loading or cholestatic conditions
When studying the adaptive response of hepatic ABC transport proteins, we found that common bile duct ligation (CBDL) induced the expression of multidrug resistance-related protein 3 (Mrp3) and multidrug resistance-related protein 4 (Mrp4) in wild-type mice and even more in Fxr2/2 mice, whereas Mrp2 expression remained unchanged [7]
This study presents detailed analyses of bile acids in liver, serum, bile, and urine of cholestatic Fxr2/2 mice and parallel measurements of the expression of major renal bile acid transporters

Summary

Introduction

Farnesoid X receptor knockout (Fxr2/2) mice cannot upregulate the bile salt export pump in bile acid loading or cholestatic conditions. 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 Fxr2/2 mice, in particular hydroxylations of cholic acid in the 1b, 2b, 4b, 6a, 6b, 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 Fxr2/2 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. Fxr2/2 mice detoxify accumulating bile acids in the liver by enhanced hydroxylation reactions probably catalyzed by Cyp3a11. Fxr2/2 mice adapt to biliary obstruction by enhanced phase I detoxification and renal elimination of bile acids.

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