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The Human Organic Anion Transporter Genes OAT5 and OAT7 Are Transactivated by Hepatocyte Nuclear Factor-1{alpha} (HNF-1{alpha})


Klein, K; Jungst, C; Mwinyi, J; Stieger, B; Krempler, F; Patsch, W; Eloranta, J J; Kullak-Ublick, G A (2010). The Human Organic Anion Transporter Genes OAT5 and OAT7 Are Transactivated by Hepatocyte Nuclear Factor-1{alpha} (HNF-1{alpha}). Molecular Pharmacology, 78(6):1079-1087.

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.

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Clinical Pharmacology and Toxicology
04 Faculty of Medicine > Center for Integrative Human Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2010
Deposited On:15 Nov 2010 14:30
Last Modified:05 Apr 2016 14:16
Publisher:American Society for Pharmacology and Experimental Therapeutics
ISSN:0026-895X
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:10.1124/mol.110.065201
PubMed ID:20829431
Permanent URL: http://doi.org/10.5167/uzh-36230

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