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Research ArticleArticle

CYP4F3B Expression Is Associated with Differentiation of HepaRG Human Hepatocytes and Unaffected by Fatty Acid Overload

Stéphanie Madec, Virginie Cerec, Emmanuelle Plée-Gautier, Joseph Antoun, Denise Glaise, Jean-Pierre Salaun, Christiane Guguen-Guillouzo and Anne Corlu
Drug Metabolism and Disposition October 2011, 39 (10) 1987-1996; DOI: https://doi.org/10.1124/dmd.110.036848
Stéphanie Madec
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Virginie Cerec
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Emmanuelle Plée-Gautier
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Joseph Antoun
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Denise Glaise
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Jean-Pierre Salaun
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Christiane Guguen-Guillouzo
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Anne Corlu
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Abstract

Fatty acid microsomal ω-oxidation involves cytochrome P450 enzymes. Some of them belonging to the CYP4F3 family are mainly expressed in the liver, making this organ a major player in energy homeostasis and lipid metabolism. To study this important regulation pathway, we used HepaRG cells, which gradually undergo a complete differentiation process. Even at the early stage of the differentiation process, CYP4F3B generated by alternative splicing of the CYP4F3 gene represented the prevalent isoform in HepaRG cells as in the liver. Its increasing expression associated with hepatocyte differentiation status suggested a hepatic-specific control of this isoform. As in liver microsomes, the catalytic hydroxylation of the CYP4F3B substrate [1-14C]Z9(10)-epoxystearic acid led to major production of 18-hydroxy-9(10)-epoxystearic acid. When treated with saturated, monounsaturated, or polyunsaturated fatty acids, CYP4F3B and CYP4A11 expression remained unchanged whereas CYP4F2 and CYP4F12 expression was transiently up-regulated. A 24-h exposure of differentiated HepaRG cells to various polyunsaturated fatty acids and derivatives induced microvesicular steatosis; down-regulation of lipid metabolism gene regulators such as sterol regulatory element-binding protein-1c, fatty acid synthase, peroxisome proliferator-activated receptor γ (PPARγ), PPARα, and decreased expression of glucose-dependent metabolism genes, which could limit de novo lipogenesis. Docosahexaenoic acid seemed to be the most effective compound. These results suggest that a PPARα-independent pathway could participate to limit lipogenesis and emphasize the role of hepatocytes in the fatty acid ω-hydroxylation pathway. They also give insights on the use of HepaRG hepatocytes to open new avenues of investigations on factors mediating the lipid metabolic pathway and finding new hypolipidemic molecules.

Footnotes

  • This work was supported by l'Agence Nationale de la Recherche [Grant PCV07_184566, μHepaReTox project]; le Conseil Régional de Bretagne [Grants PRIR-A3CBL9, 560408]; and the European Community 6th Framework Program [Grant COMICS, project 037575]. This research was also supported in part by Institut National de la Santé et Recherche Médicale and Centre National de Recherche Scientifique et Technique. S.M. was a recipient of Agence National de la Recherche Technique (ANRT) fellowship, and V.C. was a recipient of ANRT and BIOPREDIC International Company fellowship.

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

    doi:10.1124/dmd.110.036848.

  • ABBREVIATIONS:

    FA
    fatty acid
    Z(10)-EpSTA
    Z9(10)-epoxystearic acid
    Z9(10)-EpSTA
    [1-14C]Z9(10)-epoxystearic acid
    AA
    arachidonic acid
    C/EBPα
    CCAAT/enhancer binding protein α
    DHA
    docosahexaenoic acid
    DMSO
    dimethyl sulfoxide
    EPA
    eicosapentaenoic acid
    FAS
    fatty acid synthase
    GAPDH
    glyceraldehydes-3-phosphate dehydrogenase
    GC-MS
    gas chromatography-mass spectrometry
    MUFA
    monounsaturated acid
    PBS
    phosphate-buffered saline
    PEPCK-1
    phosphoenolpyruvate carboxykinase 1
    PPAR
    peroxisome proliferator-activated receptor
    PUFA
    polyunsaturated fatty acid
    RP-HPLC
    reverse-phase high-performance liquid chromatography
    SREBP-1c
    sterol regulatory element-binding protein-1
    P450
    cytochrome P450
    HNF4α
    hepatocyte nuclear factor 4α
    RT
    reverse transcription
    PCR
    polymerase chain reaction
    qPCR
    quantitative PCR
    Ct
    cycle threshold.

  • Received October 28, 2010.
  • Accepted July 21, 2011.
  • Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 39 (10)
Drug Metabolism and Disposition
Vol. 39, Issue 10
1 Oct 2011
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Research ArticleArticle

CYP4F3B AND ω-HYDROXYLATION OF FATTY ACIDS IN HepaRG CELLS

Stéphanie Madec, Virginie Cerec, Emmanuelle Plée-Gautier, Joseph Antoun, Denise Glaise, Jean-Pierre Salaun, Christiane Guguen-Guillouzo and Anne Corlu
Drug Metabolism and Disposition October 1, 2011, 39 (10) 1987-1996; DOI: https://doi.org/10.1124/dmd.110.036848

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Research ArticleArticle

CYP4F3B AND ω-HYDROXYLATION OF FATTY ACIDS IN HepaRG CELLS

Stéphanie Madec, Virginie Cerec, Emmanuelle Plée-Gautier, Joseph Antoun, Denise Glaise, Jean-Pierre Salaun, Christiane Guguen-Guillouzo and Anne Corlu
Drug Metabolism and Disposition October 1, 2011, 39 (10) 1987-1996; DOI: https://doi.org/10.1124/dmd.110.036848
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