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Research ArticleArticle

Opposite Regulation of the Human Paraoxonase-1 Gene PON-1 by Fenofibrate and Statins

Cédric Gouédard, Nadine Koum-Besson, Robert Barouki and Yannick Morel
Molecular Pharmacology April 2003, 63 (4) 945-956; DOI: https://doi.org/10.1124/mol.63.4.945
Cédric Gouédard
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Nadine Koum-Besson
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Robert Barouki
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Yannick Morel
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Abstract

The human paraoxonase-1 (PON-1) is a serum high-density lipoprotein-associated phosphotriesterase secreted mainly by the liver. This enzyme is able to hydrolyze toxic organophosphate xenobiotics, endogenous oxidized phospholipids, and homocysteine thiolactone. Physiologically, it is thought to protect against cardiovascular diseases. The level of PON-1 gene expression is a major determinant of paraoxonase-1 status but little is known regarding the regulation of this gene. We identified several transcription start sites and characterized the regulation of its promoter by fibrates and statins. In HuH7 human hepatoma cells, the PON-1 secreted enzymatic activity and mRNA levels were increased by fenofibric acid (approximately 70%) and decreased by several statins (approximately 50%). Transient and stable transfection assays in HuH7 cells indicated that the modulation of the mRNA and enzymatic activity levels could be accounted for by the regulation of the PON-1 gene promoter activity by these drugs. These effects are probably not mediated by the PPARα because over-expression of this receptor decreased the fibrate effect and did not modify statins activity. The repressive effect of statins is reversed by mevalonate and 22(R)-hydroxycholesterol, suggesting the involvement of the liver X receptor in the mechanism. The opposite effects of fenofibrate and statins could be consistent with clinical data on homocysteine levels after hypolipidemic drug treatment. Regarding the toxicological aspects, the induction achieved with fenofibric acid, although limited, could increase organophosphate metabolism and may be relevant in certain conditions for protective treatments.

Footnotes

  • This work was supported by the Délégation Générale pour l'Armement (DGA/STTC contract 99 CO 099), Université René Descartes, and Région Ile de France. C.G. has a Délégation Générale pour l'Armement–Centre National de la Recherche Scientifique grant.

  • Abbreviations:
    HDL
    high-density lipoprotein
    OP
    organophosphate
    LDL
    low-density lipoprotein
    OD
    optical density
    FCS
    fetal calf serum
    RT-PCR
    reverse transcriptase-mediated polymerase chain reaction
    G3PDH
    glucose-3-phosphate deshydrogenase
    PPRE
    peroxisome proliferator responsive element
    PPAR
    peroxisome proliferator-activated receptor
    CMV
    cytomegalovirus
    kb
    kilobase(s)
    WY-14643
    (4-chloro-6-[(2,3-dimethylphenyl)amino]-2-pyrimidinyl)thioacetic acid
    HMG
    3-hydroxy-3-methylglutaryl
    LXR
    liver X receptor
    LXRE
    liver X receptor response element
    Hcy
    homocysteine
    DMSO
    dimethyl sulfoxide
    DR
    direct repeat
    Apo
    apolipoprotein
    • Received June 3, 2002.
    • Accepted January 15, 2003.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 63 (4)
Molecular Pharmacology
Vol. 63, Issue 4
1 Apr 2003
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Research ArticleArticle

Opposite Regulation of the Human Paraoxonase-1 Gene PON-1 by Fenofibrate and Statins

Cédric Gouédard, Nadine Koum-Besson, Robert Barouki and Yannick Morel
Molecular Pharmacology April 1, 2003, 63 (4) 945-956; DOI: https://doi.org/10.1124/mol.63.4.945

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Research ArticleArticle

Opposite Regulation of the Human Paraoxonase-1 Gene PON-1 by Fenofibrate and Statins

Cédric Gouédard, Nadine Koum-Besson, Robert Barouki and Yannick Morel
Molecular Pharmacology April 1, 2003, 63 (4) 945-956; DOI: https://doi.org/10.1124/mol.63.4.945
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