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Am J Physiol Gastrointest Liver Physiol (July 7, 2005). doi:10.1152/ajpgi.00319.2004
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Submitted on July 19, 2004
Accepted on June 26, 2005

Role of Nuclear Receptors and Hepatocyte-enriched Transcription Factors for Ntcp Repression in Biliary Obstruction in Mouse Liver

Gernot Zollner1, Martin Wagner1, Peter Fickert1, Andreas Geier2, Andrea Fuchsbichler3, Dagmar Silbert1, Judith Gumhold1, Kurt Zatloukal3, Arthur Kaser4, Herbert Tilg4, Helmut Denk3, and Michael Trauner1*

1 Laboratory of Experimental and Molecular Hepatology, DIvision of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University Graz, Graz, Austria
2 Department of Internal Medicine III, University of Technology Aachen, Aachen, Germany
3 Department of Pathology, Medical University Graz, Graz, Austria
4 University Hospital Innsbruck, Austria

* To whom correspondence should be addressed. E-mail: michael.trauner{at}meduni-graz.at.

Background: Expression of the main hepatic bile acid uptake system, Ntcp, is down-regulated during cholestasis. Bile acid-induced, FXR-mediated induction of the nuclear repressor SHP has been proposed as one key mechanism reducing Ntcp expression. However, the role of FXR and SHP or other nuclear receptors and hepatocyte-enriched transcription factors in mediating Ntcp repression in obstructive cholestasis is unclear. Material & Methods: FXR knockout (FXR-/-) and wild-type (FXR+/+) mice were subjected to CBDL. Cholic acid-fed (CA) and lipopolysaccharide (LPS)-treated FXR-/- and FXR+/+ were studied for comparison. mRNA levels of Ntcp, SHP, nuclear protein levels of hepatocyte nuclear factor 1{alpha} (HNF1{alpha}), HNF3{beta}, HNF4{alpha}, RXR{alpha} and RAR{alpha} and their DNA binding were assessed. In addition, hepatic cytokine mRNA levels were measured. Results: CBDL and CA led to Ntcp repression in FXR+/+ but not in FXR-/- whereas LPS reduced Ntcp expression in both genotypes. CBDL and LPS - but not CA - induced cytokine expression and reduced levels of HNF1{alpha}, HNF3{beta}, HNF4{alpha}, RXR{alpha} and RAR{alpha} to similar extents in FXR+/+ and FXR-/-. DNA binding of these transactivators was unaffected by CA in FXR+/+ but markedly reduced in FXR-/-. Conclusion: Ntcp repression by CBDL and CA is mediated by accumulating bile acids via FXR and does not depend on cytokines while Ntcp repression by LPS is FXR-independent. Reduced levels of HNF1{alpha}, RXR{alpha} and RAR{alpha} in CBDL FXR-/- and reduced DNA binding in FXR-/- despite unchanged Ntcp levels indicate, that these factors may be of minor importance for regulation of mouse Ntcp during cholestasis.




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