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

Andreas Geier | Zendy; Ina V. Martin | Zendy; Christoph G. Dietrich | Zendy; Natarajan Balasubramaniyan | Zendy; Sonja Strauch | Zendy; Frederick J. Suchy | Zendy; Carsten Gartung | Zendy; Christian Trautwein | Zendy; Meenakshisundaram Ananthanarayanan | Zendy

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

Author(s) -

Andreas Geier,

Ina V. Martin,

Christoph G. Dietrich,

Natarajan Balasubramaniyan,

Sonja Strauch,

Frederick J. Suchy,

Carsten Gartung,

Christian Trautwein,

Meenakshisundaram Ananthanarayanan

Publication year - 2008

Publication title -

ajp gastrointestinal and liver physiology

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 1.644

H-Index - 169

eISSN - 1522-1547

pISSN - 0193-1857

DOI - 10.1152/ajpgi.00012.2008

Subject(s) - hepatocyte nuclear factor 4 , chromatin immunoprecipitation , transactivation , microbiology and biotechnology , hepatocyte nuclear factors , promoter , nuclear receptor , transcription factor , biology , gene knockdown , retinoid x receptor , binding site , chemistry , gene , gene expression , biochemistry

Sodium taurocholate cotransporting polypeptide (Ntcp) is the major uptake system for conjugated bile acids. Deletions of hepatocyte nuclear factor (HNF)-1alpha 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-4alpha, 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-1alpha, HNF-4alpha cotransfection led to a robust 20-fold activation. Deletion analysis of mouse and rat Ntcp promoters mapped a conserved HNF-4alpha consensus site at -345/-326 and -335/-316 bp, respectively. p-475bpmNtcpLUC is not transactivated by HNF-1alpha but shows a 50-fold enhanced activity upon cotransfection with HNF-4alpha. Gel mobility shift assays demonstrated a complex of the HNF-4alpha-element formed with liver nuclear extracts that was blocked by an HNF-4alpha specific antibody. HNF-4alpha binding was confirmed by chromatin immunoprecipitation. Using Hepa 1-6 cells, HNF-4alpha-knockdown resulted in a significant 95% reduction in NTCP mRNA. In conclusion, mouse Ntcp is regulated by HNF-4alpha via a conserved distal cis-element independently of HNF-1alpha.

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