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

Abstract

Glucocorticoid receptor ␣ (GR␣) and peroxisome proliferatoractivated receptor ␣ (PPAR␣) are transcription factors with clinically important immune-modulating properties. Either receptor can inhibit cytokine gene expression, mainly through interference with nuclear factor B (NF-B)-driven gene expression. The present work aimed to investigate a functional cross-talk between PPAR␣-and GR␣-mediated signaling pathways. Simultaneous activation of PPAR␣ and GR␣ dose-dependently enhances transrepression of NF-B-driven gene expression and additively represses cytokine production. In sharp contrast and quite unexpectedly, PPAR␣ agonists inhibit the expression of classical glucocorticoid response element (GRE)-driven genes in a PPAR␣-dependent manner, as demonstrated by experiments using PPAR␣ wild-type and knockout mice. The underlying mechanism for this transcriptional antagonism relies on a PPAR␣-mediated interference with the recruitment of GR␣, 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␣ agonist fenofibrate prevents glucocorticoid-induced hyperinsulinemia of mice fed a high-fat diet. Taken together, PPAR␣ negatively interferes with GREmediated GR␣ activity while potentiating its antiinflammatory effects, thus providing a rationale for combination therapy in chronic inflammatory disorders.cross-talk ͉ gluconeogenesis ͉ inflammation ͉ hyperinsulinema ͉ side effects G lucocorticoids (GCs) are presently the most potent drugs for the treatment of acute and chronic inflammatory diseases. Nevertheless, side effects such as osteoporosis, muscle wasting, hypertension, behavioral alterations, and disorders of glucose (Glc) and lipid metabolism, burden their therapeutical use. GCs mediate their effect via the glucocorticoid receptor ␣ (GR␣), a member of the nuclear receptor superfamily. After binding of GCs, a conformational change in the receptor is induced, releasing cytosolic chaperoning proteins followed by GR␣ translocation into the nucleus. Activated GR␣ can directly regulate the expression of its target genes through GR␣ binding onto promoter-imbedded GREs. Target genes of GR␣ homodimers include proteins involved in Glc, fat, and protein metabolism. Alternatively, GR␣ can also influence gene expression by interfering with the activity of nuclear factor B (NF-B), a key regulatory proinflammatory transcription factor (1). Peroxisome proliferator-activated receptor ␣ (PPAR␣), a ligand-activated transcription factor, also belonging to the nuclear receptor superfamily, is highly expressed in liver, skeletal and cardiac muscle, kidney, and in cells involved in inflammatory processes. Besides its involvement in lipid and Glc metabolism, PPAR␣ exhibits potent antiinflammatory properties. Recently, a protective role for PPAR␣ has also been demonstrated in obesityinduced hepatic inflammation (2). Fatty acid derivates and hypolipidemic fibrates are natural and synthetic PPAR␣ ligands, respect...

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