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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.
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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