Peroxisome proliferator-activated receptors (PPARs): Nuclear receptors at the crossroads between lipid metabolism and inflammation

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear receptor family. PPARs function as regulators of lipid and lipoprotein metabolism and glucose homeostasis and influence cellular proliferation, differentiation and apoptosis. PPAR alpha is highly expressed in tissues such as liver, muscle, kidney and heart, where it stimulates the beta -oxidative degradation of fatty acids. PPAR gamma is predominantly expressed in intestine and adipose tissue. PPAR gamma triggers adipocyte differentiation and promotes lipid storage. The hypolipidemic fibrates and the antidiabetic glitazones are synthetic ligands for PPAR alpha and PPAR gamma, respectively. Furthermore, fatty acids and eicosanoids are natural PPAR ligands: PPAR alpha is activated by leukotriene B4, whereas prostaglandin J2 is a PPAR gamma ligand. These observations suggested a potential role for PPARs not only in metabolic but also in inflammation control. The first evidence for a role of PPAR alpha in inflammation control came from the demonstration that PPAR alpha deficient mice display a prolonged response to inflammatory stimuli. It was suggested that PPAR alpha deficiency results in a reduced beta -oxidative degradation of these inflammatory fatty acid derivatives. More recently, PPAR activators were shown to inhibit the activation of inflammatory response genes (such as IL-2, IL-6, IL-8, TNF alpha and metalloproteases) by negatively interfering with the NF-kappaB, STAT and AP-1 signalling pathways. PPAR activators exert these anti-inflammatory activities in different immunological and vascular wall cell types such as monocyte/macrophages, endothelial, epithelial and smooth muscle cells in which PPARs are expressed. These recent findings indicate a modulatory role for PPARs in the control of the inflammatory response with potential therapeutic applications in inflammation-related diseases, such as atherosclerosis and inflammatory bowel disease.