PPARs and molecular mechanisms of transrepression

Abstract

In the last few years, PPARs have emerged as key regulators of inflammatory and immune responses. However, the mechanistic basis of the anti-inflammatory effects of Peroxisome Proliferator-activated receptors (PPARs) remains poorly understood. Accumulating evidence suggests that these effects result from inhibition of signal-dependent transcription factors that mediate inflammatory programs of gene activation. Several mechanisms underlying negative regulation of gene expression by PPARs have been described. Recent studies, using siRNA, microarray analysis and macrophage-specific knockout mice, have highlighted PPARs molecular transrepression mechanism in macrophages. Identification of their mechanism of action should help promote the understanding of the physiologic roles that PPARs play in immunity and contribute to the development of new therapeutic agents.

Recent advances in the regulation of milk fat synthesis

“…Kennedy et al (2008) recently reported that trans-10, cis-12 CLA antagonized ligand activation of PPARg in adipocyte cell culture, presumably via extra cellular signalregulated kinases (ERK), specifically ERK-stimulated phosphorylation of PPARg. Ligand-dependent and -independent repressor mechanisms are well described for the PPARs, but they function primarily to reduce inflammatory and immune responses (Ricote and Glass, 2007); indeed a hematopoietic and endothelial cell-specific PPARg knock-out resulted in increased levels of inflammatory molecules in milk (Wan et al, 2007). Lastly, CLA treatment reduced body fat in PPARa knock-out mice, demonstrating a PPARa-independent mechanism for CLA in growing mice (Peters et al, 2001).…”

Oxidized glycerophosphocholines as biologically active mediators for ultraviolet radiation-mediated effects

“…The ability of PPARs to regulate gene transcription is complex, utilizing ligand-dependent transactivation or ligand-independent target gene repression (reviewed in 37 ). In classic ligand-dependent transactivation, ligand binding induces a conformational change in protein structure that stabilizes heterodimerization with the 9-cis retinoic acid receptor (RXR).…”

“…PPARs can also influence the expression of genes lacking a PPRE. In this case, PPARs act through ligand-dependent transrepression to inhibit the functions of other transcription factors, most notably nuclear factor -kB (NF-kB) and activator protein-1 (AP-1) 37 . This occurs through multiple mechanisms, including direct interaction of PPAR with the transcription factor, competition for co-activator recruitment, and regulation of mitogen-activated protein kinase (MAPK) family member activity 37 .…”

“…Finally, it is quite possible that UVB-induced PPARγ activation acts to suppress immune responses independent of COX-2. There is growing evidence that many of the anti-inflammatory actions of PPARγ are dependent on its ability to block expression of a number of proinflammatory cytokines through several ligand-dependent transrepression mechanisms (reviewed in 37,39 ).…”

“…In this scenario, this would simply indicate that UVR-induced PPARγ signaling is likely to have importantant COX-2 independent effects on photobiology. This would not be surprising, given the complexity and diversity of PPARγ-dependent transcriptional regulation 37,39 .…”