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in the adaptive response to bile acids
1 Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University Graz, Graz, Austria
2 Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Pathology, Medical University Graz, Graz, Austria
3 Karolinska University Hospital Huddinge, Stockholm, Sweden
* To whom correspondence should be addressed. E-mail: michael.trauner{at}meduni-graz.at.
The bile acid receptor FXR is a key regulator of hepatic defense mechanisms against bile acids. A comprehensive study addressing the role of FXR in the coordinated regulation of adaptive mechanisms including biosynthesis, metabolism and alternative export together with their functional significance is lacking. We therefore fed FXR knockout mice (FXR-/-) with cholic acid (CA) and ursodeoxycholic acid (UDCA). Bile acid synthesis and hydroxylation were assessed by real-time RT-PCR for Cyp7a1, Cyp3a11 and Cyp2b10 and mass spectrometry-gas chromatography for determination of bile acid composition. Expression of the export systems Mrp4-6 in liver and kidney and the recently identified basoalteral bile acid transporter, organic solute transporter (Ost
/Ost
), in liver, kidney and intestine was also investigated. CA and UDCA repressed Cyp7a1 in FXR+/+ and to lesser extents in FXR-/- and induced Cyp3a11 and Cyp2b10 independent of FXR. CA and UDCA were hydroxylated in both genotypes. CA induced Ost/Ost in liver, kidney and ileum in FXR+/+ but not in FXR-/-, while UDCA had only minor effects. Mrp4 induction in liver and kidney correlated with bile acids levels and was observed in UDCA-fed animals and CA-fed FXR-/- but not in CA-fed FXR+/+. Mrp5/6 remained unaffected by bile acid treatment. In conclusion, we have identified Ost/Ost as a novel FXR target. Absent Ost/Ost induction in CA-fed FXR-/- may contribute to increased liver injury in these animals. Induction of bile acid hydroxylation and Mrp4 was independent of FXR but could not counteract liver toxicity sufficiently. Limited effects of UDCA on Ost/Ost may jeopardize its therapeutic efficacy.
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