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Peroxisome Proliferator-Activated Receptor Physically Interacts with CCAAT/Enhancer Binding Protein (C/EBPß) to Inhibit C/EBPß-Responsive 1-Acid Glycoprotein Gene Expression

Laboratoire de Biochimie et de Biologie Cellulaire (A.M., A.B., D.P., N.M.-C.), Equipe d’Accueil de Doctorants 1595, Faculté de Pharmacie, Université Paris XI, France; Plate-forme Transcriptome-Protéome (C.D.), Institut National de la Santé et de la Recherche Médicale, Institut Fédératif de Recherche-75, Faculté de Pharmacie, Université Paris XI, France

Address all correspondence and requests for reprints to: Najet Mejdoubi-Charef, Laboratoire de Biochimie et de Biologie Cellulaire, Equipe d’Accueil de Doctorants 1595, Tour D4 1^erétage, Faculté de Pharmacie, 5 rue J. B. Clément, 92296 Chatenay-Malabry Cedex, France. E-mail: najet.charef{at}cep.u-psud.fr.

Recently, the role of the peroxisome proliferator-activated receptor (PPAR) in the hepatic inflammatory response has been associated to the decrease of acute phase protein transcription, although the molecular mechanisms are still to be elucidated. Here, we were interested in the regulation by Wy-14643 (PPAR agonist) of 1-acid glycoprotein (AGP), a positive acute phase protein, after stimulation by Dexamethasone (Dex), a major modulator of the inflammatory response. In cultured rat hepatocytes, we demonstrate that PPAR inhibits at the transcriptional level the Dex-induced AGP gene expression. PPAR exerts this inhibitory effect by antagonizing the CCAAT/enhancer binding protein (C/EBPß) transcription factor that is involved in Dex-dependent up-regulation of AGP gene expression. Overexpression of C/EBPß alleviates the repressive effect of PPAR, thus restoring the Dex-stimulated AGP promoter activity. Furthermore, glutathione-S-transferase GST pull-down and coimmunoprecipitation experiments evidenced, for the first time, a physical interaction between PPAR and the C-terminal DNA binding region of C/EBPß, thus preventing it from binding to specific sequence elements of the AGP promoter. Altogether, these results provide an additional molecular mechanism of negative regulation of acute phase protein gene expression by sequestration of the C/EBPß transcription factor by PPAR and reveal the high potency of the latter in controlling inflammation.

NURSA Molecule Pages Link:

Nuclear Receptors:   PPARα  |  GR

Coregulators:   GRIP1

Ligands:   Dexamethasone  |  Pirinixic acid

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