Human organic anion transporting polypeptide 8 promoter is transactivated by the farnesoid X receptor/bile acid receptorw

Jung, Diana and Podvinec, Michael and Meyer, Urs A. and Mangelsdorf, David J. and Fried, Michael and Meier, Peter J. and Kullak-Ublick, Gerd A.. (2002) Human organic anion transporting polypeptide 8 promoter is transactivated by the farnesoid X receptor/bile acid receptorw. Gastroenterology, Vol. 122, H. 7. pp. 1954-1966.

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Official URL: http://edoc.unibas.ch/dok/A5261639

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BACKGROUND & AIMS: OATP8 (gene symbol: SLC21A8) is a multispecific uptake system for organic anions, xenobiotics, and peptides expressed at the basolateral (sinusoidal) membrane of human hepatocytes. We investigated whether OATP8 gene expression is regulated by the nuclear receptors farnesoid X receptor/bile acid receptor (FXR/BAR; NR1H4), pregnane X receptor (PXR), or liver X receptor (LXR). METHODS: OATP8 promoter function was studied in reporter assays. OATP8 expression in cells was quantitated by real-time polymerase chain reaction. RESULTS: The bile acid chenodeoxycholic acid (CDCA), a ligand of FXR/BAR, but not clotrimazole or 25-hydroxycholesterol, ligands of PXR or LXR, respectively, induced OATP8 promoter activity. An inverted hexanucleotide repeat motif (IR-1 element) in the promoter sequence was shown by electrophoretic mobility shift assays to bind the FXR (9-cis-retinoic acid receptor [RXRalpha]) heterodimer. Targeted mutagenesis of the IR-1 element abolished inducibility of the OATP8 promoter by CDCA, confirming its role as a bile acid response element. CDCA treatment increased OATP8 messenger RNA levels in human hepatoma cells, suggesting a physiologic role for FXR-mediated OATP8 gene regulation. CONCLUSIONS: OATP8 gene expression is regulated by bile acids via FXR/BAR. Induction of OATP8 could serve to maintain hepatic extraction of xenobiotics and peptides in conditions of increased intracellular bile acids.
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Services Biozentrum > Research IT (Podvinec)
11 Rektorat und Verwaltung > Vizerektorat Forschung
UniBasel Contributors:Podvinec, Michael and Meier-Abt, Peter J.
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:22 Mar 2012 14:21
Deposited On:22 Mar 2012 13:23

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