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Am J Physiol Gastrointest Liver Physiol 295: G226-G233, 2008. First published May 15, 2008; doi:10.1152/ajpgi.00012.2008
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LIVER AND BILIARY TRACT

Hepatocyte nuclear factor-4{alpha} is a central transactivator of the mouse Ntcp gene

Andreas Geier,1,2,* Ina V. Martin,1,* Christoph G. Dietrich,1 Natarajan Balasubramaniyan,3 Sonja Strauch,1 Frederick J. Suchy,3 Carsten Gartung,1 Christian Trautwein,1 and Meenakshisundaram Ananthanarayanan3

1Department of Internal Medicine III, Aachen University (RWTH), University Hospital (UKA), Aachen, Germany; 2Department of Internal Medicine, Division of Gastroenterology & Hepatology, University Hospital Zurich (USZ), Zurich, Switzerland; and 3Laboratory of Developmental and Molecular Hepatology, Department of Pediatrics, Mount Sinai Medical Center, New York, New York

Submitted 8 January 2008 ; accepted in final form 14 May 2008

Sodium taurocholate cotransporting polypeptide (Ntcp) is the major uptake system for conjugated bile acids. Deletions of hepatocyte nuclear factor (HNF)-1{alpha} and retinoid X receptor-{alpha}:retinoic acid receptor-{alpha} binding sites in the mouse 5'-flanking region corresponding to putatively central regulatory elements of rat Ntcp do not significantly reduce promoter activity. We hypothesized that HNF-4{alpha}, which is increasingly recognized as a central regulator of hepatocyte function, may directly transactivate mouse (mNtcp). A 1.1-kb 5'-upstream region including the mouse Ntcp promoter was cloned and compared with the rat promoter. In contrast to a moderate 3.5-fold activation of mNtcp by HNF-1{alpha}, HNF-4{alpha} cotransfection led to a robust 20-fold activation. Deletion analysis of mouse and rat Ntcp promoters mapped a conserved HNF-4{alpha} consensus site at –345/–326 and –335/–316 bp, respectively. p-475bpmNtcpLUC is not transactivated by HNF-1{alpha} but shows a 50-fold enhanced activity upon cotransfection with HNF-4{alpha}. Gel mobility shift assays demonstrated a complex of the HNF-4{alpha}-element formed with liver nuclear extracts that was blocked by an HNF-4{alpha} specific antibody. HNF-4{alpha} binding was confirmed by chromatin immunoprecipitation. Using Hepa 1–6 cells, HNF-4{alpha}-knockdown resulted in a significant 95% reduction in NTCP mRNA. In conclusion, mouse Ntcp is regulated by HNF-4{alpha} via a conserved distal cis-element independently of HNF-1{alpha}.

hepatocyte-enriched transcription factors; nuclear hormone receptors; transcriptional coactivator; gene regulation; bile acid transport


Address for reprint requests and other correspondence: A. Geier, Dept. of Internal Medicine, Div. of Gastroenterology & Hepatology, Univ. Hospital Zurich (USZ), Rämistrasse 100, CH-8091 Zurich, Switzerland (e-mail: andreas.geier{at}usz.ch)






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