PPARs as Key Mediators in the Regulation of Metabolism and Inflammation

Abstract

Nuclear receptors (NRs) form a large family of ligand-dependent transcription factors that control the expression of a multitude of genes involved in diverse, vital biological processes. Three of these receptors, the peroxisome proliferator-activated receptors (PPARs), were discovered in the 1990s and play key roles in the regulation of cellular differentiation, embryonic development, cellular and whole-body metabolism, inflammation, and tumorigenesis in higher organisms. PPARs are activated not only by fatty acids and their derivatives, some of which also signal through membrane receptors, but also by many plant- and marine-derived natural ligands. Furthermore, drugs that target PPARs, such as fibrates and thiazolidinediones, have been developed to treat metabolic diseases. The 'classic' molecular mode of action of PPARs in the control of physiological and metabolic processes is via their direct binding, as PPAR:retinoid X receptor (RXR) heterodimers, to peroxisome proliferator response elements (PPREs) in the regulatory regions of target genes. The activity of PPARs can also be modulated by posttranslational modifications and their transcriptional regulatory capacity may present a circadian pattern, depending on their expression and the availability of ligands.