TY - JOUR
T1 - Human organic anion transporting polypeptide 8 promoter is transactivated by the farnesoid X receptor/bile acid receptor
AU - Jung, Diana
AU - Podvinec, Michael
AU - Meyer, Urs A.
AU - Mangelsdorf, David J.
AU - Fried, Michael
AU - Meier, Peter J.
AU - KullakUblick, Gerd A.
N1 - Funding Information:
Supported by grants 32-59155.99 and 632-062773 from the Swiss National Science Foundation, Bern, Switzerland.
PY - 2002
Y1 - 2002
N2 - 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.
AB - 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.
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U2 - 10.1053/gast.2002.33583
DO - 10.1053/gast.2002.33583
M3 - Article
C2 - 12055601
AN - SCOPUS:0036080163
SN - 0016-5085
VL - 122
SP - 1954
EP - 1966
JO - Gastroenterology
JF - Gastroenterology
IS - 7
ER -