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LIVER AND BILIARY TRACT

Coordinated induction of bile acid detoxification and alternative elimination in mice: role of FXR-regulated organic solute transporter-/ in the adaptive response to bile acids

¹Laboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine, and ²Department of Pathology, Medical University Graz, Graz, Austria; and ³Karolinska University Hospital Huddinge, Stockholm, Sweden.

Submitted 17 October 2005 ; accepted in final form 9 December 2005

The bile acid receptor farnesoid X 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 (FXR^–/–) mice with cholic acid (CA) and ursodeoxycholic acid (UDCA). Bile acid synthesis and hydroxylation were assessed by real-time RT-PCR for cytochrome P-450 (Cyp)7a1, Cyp3a11, and Cyp2b10 and mass spectrometry-gas chromatography for determination of bile acid composition. Expression of the export systems multidrug resistance proteins (Mrp)4–6 in the liver and kidney and the recently identified basoalteral bile acid transporter, organic solute transporter (Ost-/Ost-), in the liver, kidney, and intestine was also investigated. CA and UDCA repressed Cyp7a1 in FXR^+/+ mice and to lesser extents in FXR^–/– mice and induced Cyp3a11 and Cyp2b10 independent of FXR. CA and UDCA were hydroxylated in both genotypes. CA induced Ost-/Ost- in the liver, kidney, and ileum in FXR^+/+ but not FXR^–/– mice, whereas UDCA had only minor effects. Mrp4 induction in the liver and kidney correlated with bile acid levels and was observed in UDCA-fed and CA-fed FXR^–/– animals but not in CA-fed FXR^+/+ animals. Mrp5/6 remained unaffected by bile acid treatment. In conclusion, we identified Ost-/Ost- as a novel FXR target. Absent Ost-/Ost- induction in CA-fed FXR^–/– animals may contribute to increased liver injury in these animals. The 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.

nuclear receptors; cholestrasis; liver; kidney; intestine; farnesoid X receptor; cholic acid; ursodeoxycholic acid

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