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

Gastroenterology. 2002 Jun;122(7):1954-66. doi: 10.1053/gast.2002.33583.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Base Sequence / genetics
  • Bile Acids and Salts / pharmacology
  • Binding Sites / genetics
  • Chenodeoxycholic Acid / pharmacology
  • Chickens
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / physiology*
  • Dimerization
  • Gene Expression Regulation / drug effects
  • Humans
  • Molecular Sequence Data
  • Organic Anion Transporters, Sodium-Independent / genetics*
  • Promoter Regions, Genetic / drug effects
  • Promoter Regions, Genetic / genetics
  • Promoter Regions, Genetic / physiology*
  • RNA, Messenger / metabolism
  • Receptors, Cytoplasmic and Nuclear
  • Repetitive Sequences, Nucleic Acid
  • Solute Carrier Organic Anion Transporter Family Member 1B3
  • Transcription Factors / chemistry
  • Transcription Factors / physiology*
  • Transcription Initiation Site
  • Transcriptional Activation / physiology*
  • Tumor Cells, Cultured


  • Bile Acids and Salts
  • DNA-Binding Proteins
  • Organic Anion Transporters, Sodium-Independent
  • RNA, Messenger
  • Receptors, Cytoplasmic and Nuclear
  • SLCO1B3 protein, human
  • Solute Carrier Organic Anion Transporter Family Member 1B3
  • Transcription Factors
  • farnesoid X-activated receptor
  • Chenodeoxycholic Acid