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LIVER AND BILIARY TRACT

Role of liver-enriched transcription factors and nuclear receptors in regulating the human, mouse, and rat NTCP gene

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

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