title: Human organic anion transporting polypeptide 8 promoter is transactivated by the farnesoid X receptor/bile acid receptor.
abstract: OBJECTIVE
  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.
authors.affiliation: Division of Clinical Pharmacology and Toxicology, University Hospital, Zurich, Switzerland.
authors.forename: Diana
authors.initials: D
authors.lastname: Jung
authors.forename: Michael
authors.initials: M
authors.lastname: Podvinec
authors.forename: Urs A
authors.initials: UA
authors.lastname: Meyer
authors.forename: David J
authors.initials: DJ
authors.lastname: Mangelsdorf
authors.forename: Michael
authors.initials: M
authors.lastname: Fried
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Meier
authors.forename: Gerd A
authors.initials: GA
authors.lastname: Kullak-Ublick
mesh_terms: D000818:Animals; D001483:Base Sequence / Q000235:genetics; D001647:Bile Acids and Salts / Q000494:pharmacology; D001665:Binding Sites / Q000235:genetics; D002635:Chenodeoxycholic Acid / Q000494:pharmacology; D002645:Chickens; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000502:physiology*; D019281:Dimerization; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008969:Molecular Sequence Data; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear; D012091:Repetitive Sequences, Nucleic Acid; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D014157:Transcription Factors / Q000737:chemistry / Q000502:physiology*; D024363:Transcription Initiation Site; D015533:Transcriptional Activation / Q000502:physiology*; D014407:Tumor Cells, Cultured; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D002635:Chenodeoxycholic Acid; D004268:DNA-Binding Proteins; D029362:Organic Anion Transporters, Sodium-Independent; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D000074542:Solute Carrier Organic Anion Transporter Family Member 1B3; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C421209:SLCO1B3 protein, human