Identification and functional characterization of the promoter region of the human organic anion transporting polypeptide gene.
The organic anion transporting polypeptide ( OATP) of the basolateral hepatocyte membrane mediates multispecific uptake of anionic and other amphipathic substrates from sinusoidal blood plasma. To investigate the mechanisms controlling OATP expression, the 5'-flanking region of the human OATP gene was isolated from a P1-derived artificial chromosome genomic clone. Sequence analysis of the OATP promoter showed a number of consensus binding sites for both ubiquitous and liver-enriched transcription factors. Transfection of HepG2 cells with a series of 5'-deleted promoter-luciferase constructs identified the minimal promoter region within 91 base pairs relative to the transcription initiation site. A putative silencer element was localized in the -662/-440 region. The minimal promoter was also active in Chang liver, Madin-Darby canine kidney, and Chinese hamster ovary cells, indicating that basal promoter function is independent of liver-specific regulatory mechanisms. In transfected HepG2 cells, taurocholate (100 micromol/L) stimulated and triiodothyronine (1 micromol/L) inhibited OATP promoter activity, whereas hydrocortisone, dexamethasone, beta-estradiol, estrone-3-sulfate, and testosterone had no significant effect. Reverse-transcription polymerase chain reaction analysis showed an increase in OATP messenger RNA in the livers of four patients with chronic cholestatic liver disease compared with three noncholestatic controls. The up-regulation of OATP expression by taurocholate could serve to enhance the sinusoidal efflux of toxic intracellular compounds during chronic cholestasis.[1]References
- Identification and functional characterization of the promoter region of the human organic anion transporting polypeptide gene. Kullak-Ublick, G.A., Beuers, U., Fahney, C., Hagenbuch, B., Meier, P.J., Paumgartner, G. Hepatology (1997) [Pubmed]
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