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1 Laboratory of Molecular Gastroenterology and Hepatology, Department of Internal Medicine, University Hospital Zurich, Zurich, Switzerland
2 Division of Clinical Pharmacology and Toxicology, Department of Internal Medicine, University Hospital Zurich, Zurich, Switzerland
3 Laboratory of Molecular Gastroenterology and Hepatology, Department of Internal Medicine, University Hospital Zurich, Zurich, Switzerland; Division of Clinical Pharmacology and Toxicology, Department of Internal Medicine, University Hospital Zurich, Zurich, Switzerland
* To whom correspondence should be addressed. E-mail: gerd.kullak{at}usz.ch.
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
HNF1
and HNF4 and the nuclear 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 CEBP-
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 (i) the transcriptional regulation of the conserved NTCP/Ntcp
5'-regulatory region differs considerably between human, mouse and rat, (ii) 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.
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