Transcription PPAR Pathway
PPAR Pathway
Peroxisome Proliferator-Activated Receptors (PPAR ) are ligand-inducibletranscription factors that belong to the nuclear hormone receptor superfamily. ThePPAR group consists of three types: PPAR-alpha, PPAR-beta(delta)and PPAR-gamma. They have some differences in tissue distribution, ligand andtarget specificity, as well as in mechanisms controlling their activity, and in processescontrolled 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 threetypes of PPARs [3]. A lot of Long chain fatty acids activatePPAR-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) [11], [9], [10].Components of oxidized low-density lipoprotein 15-HETE (15-hydroxyeicosatetraenoicacid) and 13-HODE (13-hydroxyoctadecadienoic acid) also enable the activation ofPPAR-gamma. [12], [13], [14], [10]. PPAR-beta(delta) is activated by prostacyclin, which issynthesized from arachidonic acid by Prostaglandin-endoperoxide synthase 2 ( COX-2) and Prostaglandin I2 synthase ( PTGIS ) [15]. Moreover, manyartificial PPAR ligands have been identified (for example, Fibrates for PPAR-alphaand Thiazolidinediones for PPAR-gamma ) [3], [16], [17], [11].
PPAR activity depends on many pathways, which is why these transcriptionalfactors are found on the crossroads of major regulatory networks. Activation of a numberof growth factor receptors (for example, Platelet-derived growth factor receptor (PDGF receptor ) [18]) by the specific growth factors, oractivation of Insulin receptor by insulin lead to recruitment of adaptors, such asSHC transforming protein ( Shc ), Growth factor receptor-bound protein 2 (GRB2 ) and Son of sevenless protein homologs 1 and 2 ( SOS ) that in turnactivate 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 atarget of action of hormones that bind to G protein-coupled receptors and activate GNAScomplex locus ( G-protein alpha-s )-dependent Adenylate cyclase [19], [18] p38alpha -catalyzing phosphorilation ofPPAR-alpha occurs as a result of MAPK cascade activity [18],[20]. Activation of p38 by Mitogen-activated protein kinase kinasekinase 7 ( TAK1 )/Mitogen-activated protein kinase kinase 3 and 6 ( MKK3 andMKK6 ) cascade is followed by up-regulation of PPAR-gamma [21].Also, it is demonstrated that the activity of PPAR-beta(delta) andPPAR-gamma is stimulated by V-akt murine thymoma viral oncogene homolog 1 (AKT(PKB) ) regulatory pathway [18], [22], wherePhosphatidylinositol 3-kinase ( PI3K ), activated by H-Ras catalyzes theconversion of Phosphatidylinositol 4,5-biphosphate ( PtdIns(4,5)P2 ) toPhosphatidylinositol 3,4,5-triphosphate ( PtdIns(3,4,5)P3 ), which then activatesAKT.
To regulate gene expression, PPAR forms a heterodimer with Retinoid X receptoralpha ( RXRA ) and this complex binds with specific DNA response element termedPeroxisome Proliferator Response Element (PPRE) [2], [3],[4]. PPARs are able to bind a number of corepressors and coactivatorproteins. 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 Nuclearreceptor subfamily 0 group B member 2 ( SHP ) [23]. Basic factorsthat suppress the activity of all three PPAR s 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 acidoxidation (liver, heart, muscle, kidney and arterial wall cells) [3], [8]. It is involved in fatty acid metabolism (see Map 'PPAR regulation of lipidmetabolism'), lipid homeostasis, and peroxisome proliferation [3], [4], [6], [25], [20]. There are studies alsodescribing 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 andinsuline homeostasis, macrophage function and inflammation [3], [4], [28], [11], [25], [29], [30], [31],[9]. Findings involving PPAR-gamma havebeen useful for treatment of diseases, such as atherosclerosis and diabetes [2], [32], [33], [11], [34].PPAR-beta(delta) is found in many tissues [3], however, itsphyisiological function still remains unclear [3], [17], [8]. This factor effects expression of some genes involved in fatty acidmetabolism, lipid homeostasis, skin proliferation and inflammation [35],[36], [10]
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