Peroxisome proliferator-activated receptor alpha physically interacts with CCAAT/enhancer binding protein (C/EBPbeta) to inhibit C/EBPbeta-responsive alpha1-acid glycoprotein gene expression.

ABSTRACT

Recently, the role of the peroxisome proliferator-activated receptor alpha (PPARalpha) 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 (PPARalpha agonist) of alpha1-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 PPARalpha inhibits at the transcriptional level the Dex-induced AGP gene expression. PPARalpha exerts this inhibitory effect by antagonizing the CCAAT/enhancer binding protein (C/EBPbeta) transcription factor that is involved in Dex-dependent up-regulation of AGP gene expression. Overexpression of C/EBPbeta alleviates the repressive effect of PPARalpha, 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 PPARalpha and the C-terminal DNA binding region of C/EBPbeta, 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/EBPbeta transcription factor by PPARalpha and reveal the high potency of the latter in controlling inflammation.