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PPAR alpha blocks glucocorticoid receptor alpha-mediated transactivation but cooperates with the activated glucocorticoid receptor alpha for transrepression on NF-kappa B

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Abstract
Glucocorticoid receptor alpha (GR alpha) and peroxisome proliferator-activated receptor alpha (PPAR alpha) are transcription factors with clinically important immune-modulating properties. Either receptor can inhibit cytokine gene expression, mainly through interference with nuclear factor kappa B (NF-kappa B)-driven gene expression. The present work aimed to investigate a functional cross-talk between PPAR alpha- and GR alpha-mediated signaling pathways. Simultaneous activation of PPAR alpha- and GR alpha dose-dependently enhances transrepression of NF-kappa B-driven gene expression and additively represses cytokine production. In sharp contrast and quite unexpectedly, PPAR alpha agonists inhibit the expression of classical glucocorticoid response element (GRE)-driven genes in a PPAR alpha-dependent manner, as demonstrated by experiments using PPAR alpha wild-type and knockout mice. The underlying mechanism for this transcriptional antagonism relies on a PPAR alpha-mediated interference with the recruitment of GR alpha, and concomitantly of RNA polymerase II, to GRE-driven gene promoters. Finally, the biological relevance of this phenomenon is underscored by the observation that treatment with the PPAR alpha agonist fenofibrate prevents glucocorticoid-induced hyperinsulinemia of mice fed a high-fat diet. Taken together, PPAR alpha negatively interferes with GRE-mediated GR alpha activity while potentiating its antiinflammatory effects, thus providing a rationale for combination therapy in chronic inflammatory disorders.
Keywords
REPRESSION, CELLS, INVOLVEMENT, TRANSCRIPTION, INSULIN, GENE-EXPRESSION, side effects, hyperinsulinema, inflammation, cross-talk, gluconeogenesis, MICE, AP-1

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MLA
Bougarne, Nadia, et al. “PPAR Alpha Blocks Glucocorticoid Receptor Alpha-Mediated Transactivation but Cooperates with the Activated Glucocorticoid Receptor Alpha for Transrepression on NF-Kappa B.” PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, vol. 106, no. 18, NATL ACAD SCIENCES, 2009, pp. 7397–402, doi:10.1073/pnas.0806742106.
APA
Bougarne, N., Paumelle, R., Caron, S., Hennuyer, N., Mansouri, R., Gervois, P., … De Bosscher, K. (2009). PPAR alpha blocks glucocorticoid receptor alpha-mediated transactivation but cooperates with the activated glucocorticoid receptor alpha for transrepression on NF-kappa B. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 106(18), 7397–7402. https://doi.org/10.1073/pnas.0806742106
Chicago author-date
Bougarne, Nadia, Rejane Paumelle, Sandrine Caron, Nathalie Hennuyer, Roxane Mansouri, Philippe Gervois, Bart Staels, Guy Haegeman, and Karolien De Bosscher. 2009. “PPAR Alpha Blocks Glucocorticoid Receptor Alpha-Mediated Transactivation but Cooperates with the Activated Glucocorticoid Receptor Alpha for Transrepression on NF-Kappa B.” PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 106 (18): 7397–7402. https://doi.org/10.1073/pnas.0806742106.
Chicago author-date (all authors)
Bougarne, Nadia, Rejane Paumelle, Sandrine Caron, Nathalie Hennuyer, Roxane Mansouri, Philippe Gervois, Bart Staels, Guy Haegeman, and Karolien De Bosscher. 2009. “PPAR Alpha Blocks Glucocorticoid Receptor Alpha-Mediated Transactivation but Cooperates with the Activated Glucocorticoid Receptor Alpha for Transrepression on NF-Kappa B.” PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 106 (18): 7397–7402. doi:10.1073/pnas.0806742106.
Vancouver
1.
Bougarne N, Paumelle R, Caron S, Hennuyer N, Mansouri R, Gervois P, et al. PPAR alpha blocks glucocorticoid receptor alpha-mediated transactivation but cooperates with the activated glucocorticoid receptor alpha for transrepression on NF-kappa B. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. 2009;106(18):7397–402.
IEEE
[1]
N. Bougarne et al., “PPAR alpha blocks glucocorticoid receptor alpha-mediated transactivation but cooperates with the activated glucocorticoid receptor alpha for transrepression on NF-kappa B,” PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, vol. 106, no. 18, pp. 7397–7402, 2009.
@article{677023,
  abstract     = {{Glucocorticoid receptor alpha (GR alpha) and peroxisome proliferator-activated receptor alpha (PPAR alpha) are transcription factors with clinically important immune-modulating properties. Either receptor can inhibit cytokine gene expression, mainly through interference with nuclear factor kappa B (NF-kappa B)-driven gene expression. The present work aimed to investigate a functional cross-talk between PPAR alpha- and GR alpha-mediated signaling pathways. Simultaneous activation of PPAR alpha- and GR alpha dose-dependently enhances transrepression of NF-kappa B-driven gene expression and additively represses cytokine production. In sharp contrast and quite unexpectedly, PPAR alpha agonists inhibit the expression of classical glucocorticoid response element (GRE)-driven genes in a PPAR alpha-dependent manner, as demonstrated by experiments using PPAR alpha wild-type and knockout mice. The underlying mechanism for this transcriptional antagonism relies on a PPAR alpha-mediated interference with the recruitment of GR alpha, and concomitantly of RNA polymerase II, to GRE-driven gene promoters. Finally, the biological relevance of this phenomenon is underscored by the observation that treatment with the PPAR alpha agonist fenofibrate prevents glucocorticoid-induced hyperinsulinemia of mice fed a high-fat diet. Taken together, PPAR alpha negatively interferes with GRE-mediated GR alpha activity while potentiating its antiinflammatory effects, thus providing a rationale for combination therapy in chronic inflammatory disorders.}},
  author       = {{Bougarne, Nadia and Paumelle, Rejane and Caron, Sandrine and Hennuyer, Nathalie and Mansouri, Roxane and Gervois, Philippe and Staels, Bart and Haegeman, Guy and De Bosscher, Karolien}},
  issn         = {{0027-8424}},
  journal      = {{PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA}},
  keywords     = {{REPRESSION,CELLS,INVOLVEMENT,TRANSCRIPTION,INSULIN,GENE-EXPRESSION,side effects,hyperinsulinema,inflammation,cross-talk,gluconeogenesis,MICE,AP-1}},
  language     = {{eng}},
  number       = {{18}},
  pages        = {{7397--7402}},
  publisher    = {{NATL ACAD SCIENCES}},
  title        = {{PPAR alpha blocks glucocorticoid receptor alpha-mediated transactivation but cooperates with the activated glucocorticoid receptor alpha for transrepression on NF-kappa B}},
  url          = {{http://doi.org/10.1073/pnas.0806742106}},
  volume       = {{106}},
  year         = {{2009}},
}

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