Peroxisome Proliferator-Activated Receptors and the Control of Inflammation

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Abstract:

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors which form a subfamily of the nuclear receptor gene family. This subfamily consists of three isotypes, α (NR1C1), γ (NR1C3), and β / δ (NRC1C2) with a differential tissue distribution. PPARα is expressed primarily in tissues with a high level of fatty acid catabolism such as liver, brown fat, kidney, heart and skeletal muscle. PPARβis ubiquitously expressed, and PPARγ has a restricted pattern of expression, mainly in white and brown adipose tissues, whereas other tissues such as skeletal muscle and heart contain limited amounts. Furthermore, PPARα and g isotypes are expressed in vascular cells including endothelial and smooth muscle cells and macrophages / foam cells. PPARs are activated by ligands, such as naturally occurring fatty acids, which are activators of all three PPAR isotypes. In addition to fatty acids, several synthetic compounds, such as fibrates and thiazolidinediones, bind and activate PPARαand PPARg, respectively. In order to be transcriptionally active, PPARs need to heterodimerize with the retinoid-X-receptor (RXR). Upon activation, PPAR-RXR heterodimers bind to DNA specific sequences called peroxisome proliferator-response elements (PPRE) and stimulate transcription of target genes. PPARs play a critical role in lipid and glucose homeostasis, but lately they have been implicated as regulators of inflammatory responses. The first evidence of the involvement of PPARs in the control of inflammation came from the PPARa null mice, which showed a prolonged inflammatory response. PPARa activation results in the repression of NF-κB signaling and inflammatory cytokine production in different cell-types. A role for PPARγin inflammation has also been reported in monocyte / macrophages, where ligands of this receptor inhibited the activation of macrophages and the production of inflammatory cytokines (TNFα, interleukin 6 and 1β), although part of the anti-inflammatory effects of these ligands seems to be mediated by a mechanism not involving PPARγ. All these findings suggest a role of PPARs in the control of the inflammatory response with potential therapeutic applications in inflammation-related diseases

Keywords: AP-1; Cytokines; Inflammation; PPAR

Document Type: Review Article

DOI: http://dx.doi.org/10.2174/1568010023344616

Publication date: September 1, 2002

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