Map Key
Generic Enzyme
Generic kinase
Protein kinase
Lipid kinase
Generic phosphatase
Protein phosphatase
Lipid phosphatase
Generic phospholipase
Generic protease
RAS - superfamily
G beta/gamma
Regulators (GDI, GAP, GEF)
Generic channel
Ligand-gated channel
Voltage-gated channel
Normal process
Pathological process
Positive effect
Negative effect
Unspecified effect
Technical link
Disrupts in disease
Emerges in disease
Enhances in disease
Weakens in disease
Organsim specific interaction

Generic binding protein
Receptor ligand
Cell membrane glycoprotein
Transcription factor
Inorganic ion
Predicted metabolite or user's structure
Generic receptor
Receptors with enzyme activity

Normal process
Pathological process
Covalent modifications
Transcription regulation
MicroRNA binding
Influence on expression
Unspecified interactions
Pharmacological effect
Toxic effect
Group relation
Complex subunit
Similarity reaction
A complex or a group
Organism specific object

Transcription PPAR Pathway

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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]