PMID- 15692145
OWN - NLM
STAT- MEDLINE
DCOM- 20050615
LR  - 20081121
IS  - 0026-895X (Print)
IS  - 0026-895X (Linking)
VI  - 67
IP  - 5
DP  - 2005 May
TI  - The human organic anion transporter 2 gene is transactivated by hepatocyte 
      nuclear factor-4 alpha and suppressed by bile acids.
PG  - 1629-38
AB  - The human organic anion transporter 2 (hOAT2, SLC22A7) mediates the 
      sodium-independent uptake of numerous drugs, including cephalosporins, 
      salicylates, dicarboxylates, and prostaglandins, and is mainly expressed in 
      hepatocytes. Because the regulation of hOAT2 expression is poorly understood, we 
      characterized cis-acting elements in the 5'-flanking region that regulate hOAT2 
      transcription. A consensus binding motif for the hepatocyte nuclear factor-4 
      alpha (HNF-4 alpha), arranged as a direct repeat (DR)-1, is located at 
      nucleotides -329/-317 relative to the transcription initiation site. This element 
      specifically binds HNF-4 alpha in electrophoretic mobility shift assays. A 
      luciferase-linked hOAT2 promoter fragment containing the HNF-4 alpha binding site 
      was transactivated upon cotransfection of an HNF-4 alpha expression vector in 
      Huh7 cells, whereas site-directed mutagenesis of the DR-1 element abolished 
      activation by HNF-4 alpha. Short interfering RNAs inhibiting endogenous HNF-4 
      alpha expression markedly reduced endogenous expression of hOAT2 in Huh7 cells. 
      Because HNF-4 alpha is a known target for bile acid-mediated repression of gene 
      transcription, we studied whether chenodeoxycholic acid (CDCA) suppresses hOAT2 
      gene expression by inhibiting HNF-4 alpha-mediated transactivation. Treatment of 
      Huh7 cells with CDCA or the synthetic farnesoid X receptor (FXR) agonist GW4064 
      decreased mRNA and protein levels and also nuclear binding activity of HNF-4 
      alpha. The FXR-inducible transcriptional repressor small heterodimer partner 
      inhibited transactivation of hOAT2 promoter constructs and of endogenous hOAT2 
      expression by HNF-4 alpha. We conclude that the hOAT2 gene is critically 
      dependent on HNF-4 alpha and that bile acids repress the hOAT2 gene by inhibiting 
      HNF-4 alpha. Hepatic uptake of hOAT2 substrates may thus be decreased in disease 
      conditions associated with elevated intracellular levels of bile acids.
FAU - Popowski, Katrin
AU  - Popowski K
AD  - Laboratory of Molecular Gastroenterology and Hepatology, University Hospital, 
      Zurich, Switzerland.
FAU - Eloranta, Jyrki J
AU  - Eloranta JJ
FAU - Saborowski, Michael
AU  - Saborowski M
FAU - Fried, Michael
AU  - Fried M
FAU - Meier, Peter J
AU  - Meier PJ
FAU - Kullak-Ublick, Gerd A
AU  - Kullak-Ublick GA
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20050203
PL  - United States
TA  - Mol Pharmacol
JT  - Molecular pharmacology
JID - 0035623
RN  - 0 (Bile Acids and Salts)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Hepatocyte Nuclear Factor 4)
RN  - 0 (Organic Anion Transporters, Sodium-Independent)
RN  - 0 (Phosphoproteins)
RN  - 0 (SLC22A7 protein, human)
RN  - 0 (Trans-Activators)
RN  - 0 (Transcription Factors)
SB  - IM
MH  - Base Sequence
MH  - Bile Acids and Salts/genetics/metabolism/*physiology
MH  - Cell Line, Tumor
MH  - DNA-Binding Proteins/genetics/*physiology
MH  - Hepatocyte Nuclear Factor 4
MH  - Humans
MH  - Molecular Sequence Data
MH  - Organic Anion Transporters, Sodium-Independent/genetics/*metabolism
MH  - Phosphoproteins/genetics/*physiology
MH  - Trans-Activators/*physiology
MH  - Transcription Factors/genetics/*physiology
MH  - Transcriptional Activation/*physiology
EDAT- 2005/02/05 09:00
MHDA- 2005/06/16 09:00
CRDT- 2005/02/05 09:00
PHST- 2005/02/05 09:00 [pubmed]
PHST- 2005/06/16 09:00 [medline]
PHST- 2005/02/05 09:00 [entrez]
AID - mol.104.010223 [pii]
AID - 10.1124/mol.104.010223 [doi]
PST - ppublish
SO  - Mol Pharmacol. 2005 May;67(5):1629-38. doi: 10.1124/mol.104.010223. Epub 2005 Feb 
      3.