| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
LIVER AND BILIARY TRACT
1Laboratory of Molecular Gastroenterology and Hepatology and 2Division of Clinical Pharmacology and Toxicology, Department of Internal Medicine, University Hospital, CH-8091 Zurich, Switzerland
Submitted 23 October 2003 ; accepted in final form 25 December 2003
Hepatic uptake of bile acids is mediated by the Na+-taurocholate cotransporting polypeptide (NTCP; SLC10A1) of the basolateral hepatocyte membrane. Several cis-acting elements in the rat Ntcp gene promoter have been characterized. However, little is known about the mechanisms that control the expression of the human or mouse NTCP/Ntcp. We, therefore, compared the transcriptional regulation of the human and mouse NTCP/Ntcp gene with that of the rat. By computer alignment, a sequence in the 5'-regulatory region that is conserved between species was identified near the transcription start site. Huh7 cells were transfected with luciferase constructs containing the conserved region from each species. The hepatocyte nuclear factors (HNF)1
and -4 and the retinoid X receptor/retinoic acid receptor dimer (RXR/RAR) bound and transactivated the rat but not the human or mouse NTCP/Ntcp promoters. In contrast, activation by the CCAAT/enhancer binding protein-
was specific for human and mouse NTCP/Ntcp. The only consensus motif present in all three species was HNF3. HNF3 formed a specific DNA-protein complex in electrophoretic mobility shift assays and inhibited NTCP/Ntcp promoter activity in cotransfection assays. Finally, a minor repressive effect of bile acids was only found for rat Ntcp. The transcriptional repressor small heterodimer partner (SHP) did not affect NTCP/Ntcp promoter activity. We conclude that 1) the transcriptional regulation of the conserved NTCP/Ntcp 5'-regulatory region differs considerably among human, mouse, and rat; and 2) the conserved NTCP/Ntcp regulatory region is not directly regulated by SHP. Bile acids may regulate NTCP/Ntcp indirectly by modulating the capacity of nuclear factors to activate gene expression.
organic anion transport; bile acids and salts; cholestasis; transcription factors; cytokines; liver receptor homolog; farnesoid X receptor
This article has been cited by other articles:
|
|
 |
|
  J. Le lay and K. H. Kaestner The Fox Genes in the Liver: From Organogenesis to Functional Integration Physiol Rev, January 1, 2010; 90(1): 1 - 22. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. A. Dawson, T. Lan, and A. Rao Bile acid transporters J. Lipid Res., December 1, 2009; 50(12): 2340 - 2357. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y.-J. He, W. Zhang, J.-H. Tu, J. Kirchheiner, Y. Chen, D. Guo, Q. Li, Z.-Y. Li, H. Chen, D.-L. Hu, et al. Hepatic Nuclear Factor 1{alpha} Inhibitor Ursodeoxycholic Acid Influences Pharmacokinetics of the Organic Anion Transporting Polypeptide 1B1 Substrate Rosuvastatin and Bilirubin Drug Metab. Dispos., August 1, 2008; 36(8): 1453 - 1456. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. D. Wederell, M. Bilenky, R. Cullum, N. Thiessen, M. Dagpinar, A. Delaney, R. Varhol, Y. Zhao, T. Zeng, B. Bernier, et al. Global analysis of in vivo Foxa2-binding sites in mouse adult liver using massively parallel sequencing Nucleic Acids Res., August 1, 2008; 36(14): 4549 - 4564. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Geier, I. V. Martin, C. G. Dietrich, N. Balasubramaniyan, S. Strauch, F. J. Suchy, C. Gartung, C. Trautwein, and M. Ananthanarayanan Hepatocyte nuclear factor-4{alpha} is a central transactivator of the mouse Ntcp gene Am J Physiol Gastrointest Liver Physiol, August 1, 2008; 295(2): G226 - G233. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Fouassier, M. Beaussier, E. Schiffer, C. Rey, V. Barbu, M. Mergey, D. Wendum, P. Callard, J.-Y. Scoazec, E. Lasnier, et al. Hypoxia-induced changes in the expression of rat hepatobiliary transporter genes Am J Physiol Gastrointest Liver Physiol, July 1, 2007; 293(1): G25 - G35. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C Thomas, J-F Landrier, D Gaillard, J Grober, M-C Monnot, A Athias, and P Besnard Cholesterol dependent downregulation of mouse and human apical sodium dependent bile acid transporter (ASBT) gene expression: molecular mechanism and physiological consequences Gut, September 1, 2006; 55(9): 1321 - 1331. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Zollner, M. Wagner, P. Fickert, A. Geier, A. Fuchsbichler, D. Silbert, J. Gumhold, K. Zatloukal, A. Kaser, H. Tilg, et al. Role of nuclear receptors and hepatocyte-enriched transcription factors for Ntcp repression in biliary obstruction in mouse liver Am J Physiol Gastrointest Liver Physiol, November 1, 2005; 289(5): G798 - G805. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Geier, C. G. Dietrich, S. Voigt, M. Ananthanarayanan, F. Lammert, A. Schmitz, M. Trauner, H. E. Wasmuth, D. Boraschi, N. Balasubramaniyan, et al. Cytokine-dependent regulation of hepatic organic anion transporter gene transactivators in mouse liver Am J Physiol Gastrointest Liver Physiol, November 1, 2005; 289(5): G831 - G841. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. R. Boutin, A. B. Rogers, Zeli Shen, R. C. Fry, J. A. Love, P. R. Nambiar, S. Suerbaum, and J. G. Fox Hepatic Temporal Gene Expression Profiling in Helicobacter hepaticus-Infected A/JCr Mice Toxicol Pathol, October 1, 2004; 32(6): 678 - 693. [Abstract] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
