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

• Published in: Molecular endocrinology (Baltimore, Md.) Md.), 2005-05, Vol.19 (5), p.1135-1146
• Main Authors: Mouthiers, Audrey, Baillet, Anita, Delomenie, Claudine, Porquet, Dominique, Mejdoubi-Charef, Najet
• Format: Article
• Language: English
• ISSN: 0888-8809
• DOI: 10.1210/me.2004-0188

Recently, the role of the peroxisome proliferator-activated receptor alpha (PPAR alpha ) 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 alpha agonist) of alpha 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 alpha inhibits at the transcriptional level the Dex-induced AGP gene expression. PPAR alpha exerts this inhibitory effect by antagonizing the CCAAT/enhancer binding protein (C/EBP beta ) transcription factor that is involved in Dex-dependent up-regulation of AGP gene expression. Overexpression of C/EBP beta alleviates the repressive effect of PPAR alpha , 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 alpha and the C-terminal DNA binding region of C/EBP beta , 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/EBP beta transcription factor by PPAR alpha and reveal the high potency of the latter in controlling inflammation.