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and Suppressed by Bile Acids
Laboratory of Molecular Gastroenterology and Hepatology (K.P., J.J.E., M.S., M.F., G.A.K.-U.) and Division of Clinical Pharmacology and Toxicology (P.J.M., G.A.K.-U.), University Hospital, Zurich, Switzerland
Abstract
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
(HNF-4), 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 in electrophoretic mobility shift assays. A luciferase-linked hOAT2 promoter fragment containing the HNF-4 binding site was transactivated upon cotransfection of an HNF-4 expression vector in Huh7 cells, whereas site-directed mutagenesis of the DR-1 element abolished activation by HNF-4. Short interfering RNAs inhibiting endogenous HNF-4 expression markedly reduced endogenous expression of hOAT2 in Huh7 cells. Because HNF-4 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-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. The FXR-inducible transcriptional repressor small heterodimer partner inhibited transactivation of hOAT2 promoter constructs and of endogenous hOAT2 expression by HNF-4. We conclude that the hOAT2 gene is critically dependent on HNF-4 and that bile acids repress the hOAT2 gene by inhibiting HNF-4. Hepatic uptake of hOAT2 substrates may thus be decreased in disease conditions associated with elevated intracellular levels of bile acids.
Received for publication December 13, 2004.
Accepted for publication February 2, 2005.
Address correspondence to: Dr. Gerd A. Kullak-Ublick, Department of Internal Medicine, University Hospital, CH-8091 Zurich, Switzerland. E-mail: gerd.kullak{at}usz.ch
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