PPARy: A Prominent Member of the PPAR Family in the Ageing Lung

PPARy expression and function appear to have a pivotal role in all molecular and cellular events associated with pulmonary senescence. PPARa, PPARp, and PPARy all show a common structure consisting of 4 domains: a variable amino terminal activation function-1 domain (AF-1), a DNA binding domain, a hinge region, and a conserved activation function-2 domain (AF-2). Domain AF-2 enables PPARs to bind structurally diverse natural and synthetic ligands [43]. In addition, AF-2 associates with co-regulators affecting receptor activity, receptor dimerization and nuclear translocation [44]. PPARs function as hetero-dimers with retinoid X receptors (RXR) . Hetero-dimerization of PPAR with RXR is influenced by competing PPAR isoforms and other nuclear receptors. In their absence PPAR-RXR associates with co-repressor proteins of histone deacetylase activity. Ligands trigger corepressor dissociation, and recruitment of co-activators [45]. Transcriptional activation or suppression may happen after recognition of PPAR response elements (PPRE) in target gene promoters and binding to PPRE consensus sequences [46].

PPARy is a prominent member of the PPAR family and was first described as a regulator of adipocyte differentiation. Activation of PPARy is triggered by a wide variety of natural as well as synthetic ligands. Natural PPARy ligands include polyunsaturated fatty acids (PUFAs), eicosapentaenoic acids, and oxidized lipids [47]. The most studied family of synthetic ligands are the thiazolidinediones (TZDs). TZDs are used in the treatment of type 2 diabetes as they show insulin-sensitizing and hypoglycemic effects via activation of PPARy [48]. Activation of PPARy by TZDs results in the transcription of numerous genes involved in glucose and lipid utilization [49]. Examples for synthetic ligands include rosiglitazone (RGZ), cigli- tazone (CGZ), pioglitazone (PGZ), and troglitazone (TGZ) [50].

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