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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

Nadia Bougarne UGent, Rejane Paumelle, Sandrine Caron, Nathalie Hennuyer, Roxane Mansouri, Philippe Gervois, Bart Staels, Guy Haegeman UGent and Karolien De Bosscher UGent (2009) PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. 106(18). p.7397-7402
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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
REPRESSION, CELLS, INVOLVEMENT, TRANSCRIPTION, INSULIN, GENE-EXPRESSION, side effects, hyperinsulinema, inflammation, cross-talk, gluconeogenesis, MICE, AP-1
journal title
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Proc. Natl. Acad. Sci. U. S. A.
volume
106
issue
18
pages
7397 - 7402
publisher
NATL ACAD SCIENCES
place of publication
WASHINGTON, DC 20418 USA
Web of Science type
Article
Web of Science id
000265783600026
JCR category
MULTIDISCIPLINARY SCIENCES
JCR impact factor
9.432 (2009)
JCR rank
3/48 (2009)
JCR quartile
1 (2009)
ISSN
0027-8424
DOI
10.1073/pnas.0806742106
language
English
UGent publication?
yes
classification
A1
additional info
IDS Number: 441QI Reprint Address: De Bosscher, K (reprint author), Univ Ghent, Dept Physiol, LEGEST, KL Ledeganckstr 35, B-9000 Ghent, Belgium Addresses Authors: 1. Univ Ghent, Dept Physiol, LEGEST, B-9000 Ghent, Belgium 2. Univ Lille Nord France, Inst Pasteur Lille, Inst Natl Sante & Rech Med, U545, F-59019 Lille, France 3. Univ Lille Nord France, Fac Pharm & Med, F-59019 Lille, France Reprint Address: De Bosscher, K (reprint author), Univ Ghent, Dept Physiol, LEGEST, KL Ledeganckstr 35, B-9000 Ghent, Belgium E-mail Addresses: karolien.debosscher@ugent.be
id
677023
handle
http://hdl.handle.net/1854/LU-677023
date created
2009-06-04 09:14:34
date last changed
2009-06-04 12:20:30
@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},
  keyword      = {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://dx.doi.org/10.1073/pnas.0806742106},
  volume       = {106},
  year         = {2009},
}

Chicago
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.
APA
Bougarne, N., Paumelle, R., Caron, S., Hennuyer, N., Mansouri, R., Gervois, P., Staels, B., et al. (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.
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. WASHINGTON, DC 20418 USA: NATL ACAD SCIENCES; 2009;106(18):7397–402.
MLA
Bougarne, Nadia, Rejane Paumelle, Sandrine Caron, 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 106.18 (2009): 7397–7402. Print.