PPAR Signaling

The peroxisome proliferator-activated receptor (PPAR) family consists of PPARα, PPARδ, and PPARγ. They act as ligand activated transcriptional regulators. Their ligands include n-3 and n-6 unsaturated fatty acids and their eicosanoid products which makes the PPARs closely linked to intracellular lipid levels. As a consequence they often regulate the expression of genes involved in lipid metabolism.PPARα and -δ are found in a complex with hsp90/hsp90-XAP2 which maintain PPAR in a repressed state. These proteins dissociate upon binding of ligand to receptor. PPARα, -γ and -δ form heterodimeric complexes with the retinoid X receptor (RXR), bind to PPRE and induce genes that affect fatty acid metabolism, peroxisome proliferation,colon and hepatocarcinogenesis.PPAR function is supressed by cytokines, growth factors and insulin. For example, IL-1 and TNF-alpha suppress PPAR-γ function through NF-κB activated by the TAK1/TAB1/NIK cascade. PPARγ can be inhibited via the ERK pathway in response to growth factors. COUP-TF strongly antagonizes the action of PPARα. Thus PPARs regulate metabolic pathways.