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

Diana Jung, Michael Podvinec, Urs A. Meyer, David J. Mangelsdorf, Michael Fried, Peter J. Meier, Gerd A. KullakUblick

Research output: Contribution to journalArticle

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Abstract

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 [RXRα]) 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.

Original languageEnglish (US)
Pages (from-to)1954-1966
Number of pages13
JournalGastroenterology
Volume122
Issue number7
StatePublished - 2002

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Bile Acids and Salts
Anions
Chenodeoxycholic Acid
Peptides
Xenobiotics
Ligands
Clotrimazole
Retinoid X Receptors
Gene Expression
Response Elements
Electrophoretic Mobility Shift Assay
Cytoplasmic and Nuclear Receptors
Mutagenesis
Genes
Real-Time Polymerase Chain Reaction
Hepatocytes
Hepatocellular Carcinoma
Messenger RNA
Membranes
Liver

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Jung, D., Podvinec, M., Meyer, U. A., Mangelsdorf, D. J., Fried, M., Meier, P. J., & KullakUblick, G. A. (2002). Human organic anion transporting polypeptide 8 promoter is transactivated by the farnesoid X receptor/bile acid receptor. Gastroenterology, 122(7), 1954-1966.

Human organic anion transporting polypeptide 8 promoter is transactivated by the farnesoid X receptor/bile acid receptor. / Jung, Diana; Podvinec, Michael; Meyer, Urs A.; Mangelsdorf, David J.; Fried, Michael; Meier, Peter J.; KullakUblick, Gerd A.

In: Gastroenterology, Vol. 122, No. 7, 2002, p. 1954-1966.

Research output: Contribution to journalArticle

Jung, D, Podvinec, M, Meyer, UA, Mangelsdorf, DJ, Fried, M, Meier, PJ & KullakUblick, GA 2002, 'Human organic anion transporting polypeptide 8 promoter is transactivated by the farnesoid X receptor/bile acid receptor', Gastroenterology, vol. 122, no. 7, pp. 1954-1966.
Jung, Diana ; Podvinec, Michael ; Meyer, Urs A. ; Mangelsdorf, David J. ; Fried, Michael ; Meier, Peter J. ; KullakUblick, Gerd A. / Human organic anion transporting polypeptide 8 promoter is transactivated by the farnesoid X receptor/bile acid receptor. In: Gastroenterology. 2002 ; Vol. 122, No. 7. pp. 1954-1966.
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