RT Journal Article
SR Electronic
T1 The Human Organic Anion Transporter Genes <em>OAT5</em> and <em>OAT7</em> Are Transactivated by Hepatocyte Nuclear Factor-1α (HNF-1α)
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1079
OP 1087
DO 10.1124/mol.110.065201
VO 78
IS 6
A1 Kerstin Klein
A1 Christoph Jüngst
A1 Jessica Mwinyi
A1 Bruno Stieger
A1 Franz Krempler
A1 Wolfgang Patsch
A1 Jyrki J. Eloranta
A1 Gerd A. Kullak-Ublick
YR 2010
UL http://molpharm.aspetjournals.org/content/78/6/1079.abstract
AB Organic anion transporters (OATs) are anion exchangers that transport small hydrophilic anions and diuretics, antibiotics, nonsteroidal anti-inflammatory drugs, antiviral nucleoside analogs, and antitumor drugs across membrane barriers of epithelia of diverse organs. Three OATs are present in human liver: OAT2, OAT5, and OAT7. Given that hepatocyte nuclear factor-1α (HNF-1α) has previously been shown to regulate the expression of several hepatocellular transporter genes, we investigated whether the liver-specific human OAT genes are also regulated by HNF-1α. Short interfering RNAs targeting HNF-1α reduced endogenous expression of OAT5 and OAT7, but not OAT2, in human liver-derived Huh7 cells. Luciferase reporter gene constructs containing the OAT5 (SLC22A10) and OAT7 (SLC22A9) promoter regions were transactivated by HNF-1α in HepG2 cells. Two putative HNF-1α binding elements in the proximal OAT5 promoter, located at nucleotides −68/−56 and −173/−160, and one element in the OAT7 promoter, located at nucleotides −14/−2 relative to the transcription start site, were shown to bind HNF-1α in electromobility shift assays, and these promoter regions also interacted with HNF-1α in chromatin immunoprecipitation assays. A correlation between HNF-1α and OAT5 (r = 0.134, P &lt; 0.05) or OAT7 (r = 0.461, P &lt; 0.001) mRNA expression levels in surgical liver biopsies from 75 patients further supported an important role of HNF-1α in the regulation of OAT gene expression.