PPARα blocks glucocorticoid receptor α-mediated transactivation but cooperates with the activated glucocorticoid receptor α for transrepression on NF-κB

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.