PPARalpha blocks glucocorticoid receptor alpha-mediated transactivation but cooperates with the activated glucocorticoid receptor alpha for transrepression on NF-kappaB.
Glucocorticoid receptor alpha (GRalpha) and peroxisome proliferator-activated receptor alpha (PPARalpha) are transcription factors with clinically important immune-modulating properties. Either receptor can inhibit cytokine gene expression, mainly through interference with nuclear factor kappaB (NF-kappaB)-driven gene expression. The present work aimed to investigate a functional cross-talk between PPARalpha- and GRalpha-mediated signaling pathways. Simultaneous activation of PPARalpha and GRalpha dose-dependently enhances transrepression of NF-kappaB-driven gene expression and additively represses cytokine production. In sharp contrast and quite unexpectedly, PPARalpha agonists inhibit the expression of classical glucocorticoid response element (GRE)-driven genes in a PPARalpha-dependent manner, as demonstrated by experiments using PPARalpha wild-type and knockout mice. The underlying mechanism for this transcriptional antagonism relies on a PPARalpha-mediated interference with the recruitment of GRalpha, 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 PPARalpha agonist fenofibrate prevents glucocorticoid-induced hyperinsulinemia of mice fed a high-fat diet. Taken together, PPARalpha negatively interferes with GRE-mediated GRalpha activity while potentiating its antiinflammatory effects, thus providing a rationale for combination therapy in chronic inflammatory disorders.
Lab Eukaryotic Gene Expression and Signal Transduction, Department of Physiology, Ghent University, KL Ledeganckstraat 35, 9000 Gent, Belgium.
Nadia
N
Bougarne
Réjane
R
Paumelle
Sandrine
S
Caron
Nathalie
N
Hennuyer
Roxane
R
Mansouri
Philippe
P
Gervois
Bart
B
Staels
Guy
G
Haegeman
Karolien
K
De Bosscher
D000818:Animals; D045744:Cell Line, Tumor; D004041:Dietary Fats / Q000008:administration & dosage; D011345:Fenofibrate / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006946:Hyperinsulinism / Q000139:chemically induced / Q000517:prevention & control; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D047493:PPAR alpha / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011965:Receptors, Glucocorticoid / Q000819:agonists / Q000378:metabolism*; D015533:Transcriptional Activation
D004041:Dietary Fats; D005938:Glucocorticoids; D016328:NF-kappa B; D047493:PPAR alpha; D011965:Receptors, Glucocorticoid; C411470:glucocorticoid receptor alpha; D011345:Fenofibrate