Peroxisome Proliferator-Activated Receptors (PPAR) are ligand-inducible transcription factors that belong to the nuclear hormone receptor superfamily. The PPAR group consists of three types: PPAR-alpha, PPAR-beta(delta) and PPAR-gamma. They have some differences in tissue distribution, ligand and target specificity, as well as in mechanisms controlling their activity, and in processes controlled by them [1], [2], [3], [4], [5].

Most common intracellular ligands for all PPARs are fatty acids and eicosanoids [1], [3]. Arachidonic acid was shown to activate all three types of PPARs [3]. A lot of Long chain fatty acids activate PPAR-alpha and PPAR-beta(delta) [6], [7], [8]. PPAR-gamma is effectively activated by polyunsaturated fatty acids, such as Linolenic acid and (all-Z)-Eicosapentaenoic acid [9], [10]. Another natural PPAR-alpha activator is leukotriene B4 [3]. One of the most important PPAR-gamma ligands is 15d-PGJ2 (15-deoxy-delta prostaglandin J2) [9], [10], [11]. Components of oxidized low-density lipoprotein 15-HETE (15-hydroxyeicosatetraenoic acid) and 13-HODE (13-hydroxyoctadecadienoic acid) also enable the activation of PPAR-gamma. [10], [12], [13], [14]. PPAR-beta(delta) is activated by prostacyclin, which is synthesized from arachidonic acid by Prostaglandin-endoperoxide synthase 2 (COX-2) and Prostaglandin I2 synthase (PTGIS) [15]. Moreover, many artificial PPAR ligands have been identified (for example, Fibrates for PPAR-alpha and Thiazolidinediones for PPAR-gamma) [3], [11], [16], [17].

PPAR activity depends on many pathways, which is why these transcriptional factors are found on the crossroads of major regulatory networks. Activation of a number of growth factor receptors (for example, Platelet-derived growth factor receptor (PDGF receptor) [18]) by the specific growth factors, or activation of Insulin receptor by insulin lead to recruitment of adaptors, such as SHC transforming protein (Shc), Growth factor receptor-bound protein 2 (GRB2) and Son of sevenless protein homologs 1 and 2 (SOS ) that in turn activate transforming protein V-Ha-ras Harvey rat sarcoma viral oncogene homolog (H-Ras) and Proto-oncogene serine/threonine-protein kinase (e.g. Raf-1), followed by phosphorilation of Mitogen activated protein kinases 1 and 3 (ERK) ([2]. The latter kinase inhibits PPAR-alpha and PPAR-gamma [6], [18]. Phosphorilation by cAMP dependent Protein kinase A (PKA), as well as Mitogen activated protein kinases 14 (p38alpha) activates PPAR-alpha. PKA-cat pathway allows PPAR-alpha to be a target of action of hormones that bind to G protein-coupled receptors and activate GNAS complex locus (G-protein alpha-s)-dependent Adenylate cyclase [18], [19] p38alpha-catalyzing phosphorilation of PPAR-alpha occurs as a result of MAPK cascade activity [18], [20]. Activation of p38 by Mitogen-activated protein kinase kinase kinase 7 (TAK1)/Mitogen-activated protein kinase kinase 3 and 6 (MKK3 and MKK6) cascade is followed by up-regulation of PPAR-gamma [21]. Also, it is demonstrated that the activity of PPAR-beta(delta) and PPAR-gamma is stimulated by V-akt murine thymoma viral oncogene homolog 1 (AKT(PKB)) regulatory pathway [18], [22], where Phosphatidylinositol 3-kinase (PI3K), activated by H-Ras catalyzes the conversion of Phosphatidylinositol 4,5-biphosphate (PtdIns(4,5)P2) to Phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3), which then activates AKT.

To regulate gene expression, PPAR forms a heterodimer with Retinoid X receptor alpha (RXRA) and this complex binds with specific DNA response element termed Peroxisome Proliferator Response Element (PPRE) [2], [3], [4]. PPARs are able to bind a number of corepressors and coactivator proteins. mediator complex subunit 1 (TRIP2) and Nuclear receptor coactivator 1 (NCOA1) is shown to activate PPAR-alpha and PPAR-gamma. [2] Activation of PPAR-gamma is carried out also by binding with Nuclear receptor subfamily 0 group B member 2 (SHP) [23]. Basic factors that suppress the activity of all three PPARs are Nuclear receptor co-repressor (N-CoR) [2] and Nuclear receptor corepressors (SMRT) [2], [24].

PPAR-alpha is preferentially expressed in tissues with intensive fatty acid oxidation (liver, heart, muscle, kidney and arterial wall cells) [3], [8]. It is involved in fatty acid metabolism (see Map 'PPAR regulation of lipid metabolism'), lipid homeostasis, and peroxisome proliferation [3], [4], [6], [20], [25]. There are studies also describing the role of PPAR-alpha in hepatocarcinogenesis[26], [27] and other pathological processes [4], [20]. PPAR-gamma demonstrates highest expression levels in adipose tissues [8]. It regulates genes that participate in adipocyte differentiation, glucose and insuline homeostasis, macrophage function and inflammation [3], [4], [9], [11], [25], [28], [29], [30], [31]. Findings involving PPAR-gamma have been useful for treatment of diseases, such as atherosclerosis and diabetes [2], [11], [32], [33], [34]. PPAR-beta(delta) is found in many tissues [3], however, its phyisiological function still remains unclear [3], [8], [17]. This factor effects expression of some genes involved in fatty acid metabolism, lipid homeostasis, skin proliferation and inflammation [10], [35], [36]

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