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Molecular Pharmacology

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Research ArticleArticle

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

Kerstin Klein, Christoph Jüngst, Jessica Mwinyi, Bruno Stieger, Franz Krempler, Wolfgang Patsch, Jyrki J. Eloranta and Gerd A. Kullak-Ublick
Molecular Pharmacology December 2010, 78 (6) 1079-1087; DOI: https://doi.org/10.1124/mol.110.065201
Kerstin Klein
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Christoph Jüngst
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Jessica Mwinyi
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Bruno Stieger
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Franz Krempler
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Wolfgang Patsch
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Jyrki J. Eloranta
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Gerd A. Kullak-Ublick
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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.

Footnotes

  • This study was supported by the Swiss National Science Foundation [Grant 320030_120463/1]; the Novartis Foundation for Biomedical Research, the Center of Clinical Research at the University Hospital Zurich; the Austrian Science Fund (Fonds zur Förderung der wissenschaftlichen Forschung) [Grant P19893-B05]; the Land Salzburg; and the Verein für Medizinische Forschung Salzburg.

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.110.065201.

  • ABBREVIATIONS:

    TMD
    transmembrane domain
    OAT
    organic anion transporter
    SLC
    solute carrier
    HNF
    hepatocyte nuclear factor
    EMSA
    electromobility shift assay
    ChIP
    chromatin immunoprecipitation
    siRNA
    small interfering RNA
    PCR
    polymerase chain reaction
    PBS-T
    phosphate-buffered saline–Tween 20
    bp
    base pair(s).

  • Received March 31, 2010.
  • Accepted September 9, 2010.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 78 (6)
Molecular Pharmacology
Vol. 78, Issue 6
1 Dec 2010
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Research ArticleArticle

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

Kerstin Klein, Christoph Jüngst, Jessica Mwinyi, Bruno Stieger, Franz Krempler, Wolfgang Patsch, Jyrki J. Eloranta and Gerd A. Kullak-Ublick
Molecular Pharmacology December 1, 2010, 78 (6) 1079-1087; DOI: https://doi.org/10.1124/mol.110.065201

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Research ArticleArticle

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

Kerstin Klein, Christoph Jüngst, Jessica Mwinyi, Bruno Stieger, Franz Krempler, Wolfgang Patsch, Jyrki J. Eloranta and Gerd A. Kullak-Ublick
Molecular Pharmacology December 1, 2010, 78 (6) 1079-1087; DOI: https://doi.org/10.1124/mol.110.065201
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