title: The human organic anion transporter genes OAT5 and OAT7 are transactivated by hepatocyte nuclear factor-1α (HNF-1α).
abstract: 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 < 0.05) or OAT7 (r = 0.461, P < 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.
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, Rämistrasse 100, Zurich, Switzerland.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Klein
authors.forename: Christoph
authors.initials: C
authors.lastname: Jüngst
authors.forename: Jessica
authors.initials: J
authors.lastname: Mwinyi
authors.forename: Bruno
authors.initials: B
authors.lastname: Stieger
authors.forename: Franz
authors.initials: F
authors.lastname: Krempler
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Patsch
authors.forename: Jyrki J
authors.initials: JJ
authors.lastname: Eloranta
authors.forename: Gerd A
authors.initials: GA
authors.lastname: Kullak-Ublick
mesh_terms: D055785:Gene Knockdown Techniques; D056945:Hep G2 Cells; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000502:physiology*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D027361:Organic Anion Transporters / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000502:physiology*; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D051538:Hepatocyte Nuclear Factor 1-alpha; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; C427208:SLC22A10 protein, human; C427207:SLC22A11 protein, human; D015534:Trans-Activators