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LIVER AND BILIARY TRACT

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

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 and retinoid X receptor-:retinoic acid receptor- 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, 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, HNF-4 cotransfection led to a robust 20-fold activation. Deletion analysis of mouse and rat Ntcp promoters mapped a conserved HNF-4 consensus site at –345/–326 and –335/–316 bp, respectively. p-475bpmNtcpLUC is not transactivated by HNF-1 but shows a 50-fold enhanced activity upon cotransfection with HNF-4. Gel mobility shift assays demonstrated a complex of the HNF-4-element formed with liver nuclear extracts that was blocked by an HNF-4 specific antibody. HNF-4 binding was confirmed by chromatin immunoprecipitation. Using Hepa 1–6 cells, HNF-4-knockdown resulted in a significant 95% reduction in NTCP mRNA. In conclusion, mouse Ntcp is regulated by HNF-4 via a conserved distal cis-element independently of HNF-1.

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

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