Pathway Map Details

Transcription_PPAR Pathway

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Troglitazone quinone cytoplasm, PPAR-alpha, PPAR-gamma, H-Ras, Fenofibrate, TRIP2, PPAR-alpha/RXR-alpha, PtdIns(4,5)P2, Prostaglandin I2 cytoplasm,, Erk (MAPK1/3), GRB2, PI3K reg class IA, PKA-reg (cAMP-dependent), Bezafibrate, Prostaglandin H2,, 13-HPODE, TGF-beta receptor type I, COX-2 (PTGS2), MEK3(MAP2K3), SMRT, Arachidonic acid, TAK1(MAP3K7), G-protein alpha-s, p38alpha (MAPK14), RXRA, SOS, Shc, PI3K cat class IA, 15d-PGJ2, ATP cytosol, PPAR-beta(delta), XIAP, PDGF receptor, N-CoR, cAMP, AKT(PKB), Long-chain fatty acid, PTGIS, PtdIns(3,4,5)P3, MEK1(MAP2K1), IRS-1, Clofibrate, c-Raf-1, NCOA1 (SRC1), Leukotriene B4 cytoplasm, SHP, PKA-cat (cAMP-dependent), PPAR-beta(delta)/RXR-alpha, Ciprofibrate, MEK6(MAP2K6), Insulin receptor, p38 MAPK, PPAR-gamma/RXR-alpha, 15-HETE racemic, Adenylate cyclase type I,, Retinoic acid cytosol,, Linoleic acid


PPAR Pathway

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) [11], [9], [10]. Components of oxidized low-density lipoprotein 15-HETE (15-hydroxyeicosatetraenoic acid) and 13-HODE (13-hydroxyoctadecadienoic acid) also enable the activation of PPAR-gamma. [12], [13], [14], [10]. 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], [16], [17], [11].

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 [19], [18] 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 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 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], [25], [20]. 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], [28], [11], [25], [29], [30], [31], [9]. Findings involving PPAR-gamma have been 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, its phyisiological function still remains unclear [3], [17], [8]. This factor effects expression of some genes involved in fatty acid metabolism, lipid homeostasis, skin proliferation and inflammation [35], [36], [10]


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    Role of the peroxisome proliferator-activated receptor (PPAR) in mediating the effects of fibrates and fatty acids on gene expression. Journal of lipid research 1996 May;37(5):907-25
  2. Desvergne B, Wahli W
    Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocrine reviews 1999 Oct;20(5):649-88
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    Peroxisome proliferator-activated receptors: insight into multiple cellular functions. Mutation research 2000 Mar 17;448(2):121-38
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    Advances in understanding the regulation of apoptosis and mitosis by peroxisome-proliferator activated receptors in pre-clinical models: relevance for human health and disease. Comparative hepatology [electronic resource]. 2003 Jan 31;2(1):3
  6. Barger PM, Kelly DP
    PPAR signaling in the control of cardiac energy metabolism. Trends in cardiovascular medicine 2000 Aug;10(6):238-45
  7. Clarke SD
    Polyunsaturated fatty acid regulation of gene transcription: a molecular mechanism to improve the metabolic syndrome. The Journal of nutrition 2001 Apr;131(4):1129-32
  8. Smith SA
    Peroxisome proliferator-activated receptors and the regulation of mammalian lipid metabolism. Biochemical Society transactions 2002 Nov;30(Pt 6):1086-90
  9. Dubuquoy L, Dharancy S, Nutten S, Pettersson S, Auwerx J, Desreumaux P
    Role of peroxisome proliferator-activated receptor gamma and retinoid X receptor heterodimer in hepatogastroenterological diseases. Lancet 2002 Nov 2;360(9343):1410-8
  10. Kota BP, Huang TH, Roufogalis BD
    An overview on biological mechanisms of PPARs. Pharmacological research : the official journal of the Italian Pharmacological Society 2005 Feb;51(2):85-94
  11. Debril MB, Renaud JP, Fajas L, Auwerx J
    The pleiotropic functions of peroxisome proliferator-activated receptor gamma. Journal of molecular medicine (Berlin, Germany) 2001;79(1):30-47
  12. Huang JT, Welch JS, Ricote M, Binder CJ, Willson TM, Kelly C, Witztum JL, Funk CD, Conrad D, Glass CK
    Interleukin-4-dependent production of PPAR-gamma ligands in macrophages by 12/15-lipoxygenase. Nature 1999 Jul 22;400(6742):378-82
  13. Shappell SB, Gupta RA, Manning S, Whitehead R, Boeglin WE, Schneider C, Case T, Price J, Jack GS, Wheeler TM, Matusik RJ, Brash AR, Dubois RN
    15S-Hydroxyeicosatetraenoic acid activates peroxisome proliferator-activated receptor gamma and inhibits proliferation in PC3 prostate carcinoma cells. Cancer research 2001 Jan 15;61(2):497-503
  14. Schild RL, Schaiff WT, Carlson MG, Cronbach EJ, Nelson DM, Sadovsky Y
    The activity of PPAR gamma in primary human trophoblasts is enhanced by oxidized lipids. The Journal of clinical endocrinology and metabolism 2002 Mar;87(3):1105-10
  15. Lim H, Dey SK
    PPAR delta functions as a prostacyclin receptor in blastocyst implantation. Trends in endocrinology and metabolism: TEM 2000 May-Jun;11(4):137-42
  16. Olefsky JM, Saltiel AR
    PPAR gamma and the treatment of insulin resistance. Trends in endocrinology and metabolism: TEM 2000 Nov;11(9):362-8
  17. Kliewer SA, Xu HE, Lambert MH, Willson TM
    Peroxisome proliferator-activated receptors: from genes to physiology. Recent progress in hormone research 2001;56:239-63
  18. Kelly DP
    The pleiotropic nature of the vascular PPAR gene regulatory pathway. Circulation research 2001 Nov 23;89(11):935-7
  19. Lazennec G, Canaple L, Saugy D, Wahli W
    Activation of peroxisome proliferator-activated receptors (PPARs) by their ligands and protein kinase A activators. Molecular endocrinology (Baltimore, Md.) 2000 Dec;14(12):1962-75
  20. Roberts RA, Chevalier S, Hasmall SC, James NH, Cosulich SC, Macdonald N
    PPAR alpha and the regulation of cell division and apoptosis. Toxicology 2002 Dec 27;181-182:167-70
  21. Hata K, Nishimura R, Ikeda F, Yamashita K, Matsubara T, Nokubi T, Yoneda T
    Differential roles of Smad1 and p38 kinase in regulation of peroxisome proliferator-activating receptor gamma during bone morphogenetic protein 2-induced adipogenesis. Molecular biology of the cell 2003 Feb;14(2):545-55
  22. Zhang J, Fu M, Zhu X, Xiao Y, Mou Y, Zheng H, Akinbami MA, Wang Q, Chen YE
    Peroxisome proliferator-activated receptor delta is up-regulated during vascular lesion formation and promotes post-confluent cell proliferation in vascular smooth muscle cells. The Journal of biological chemistry 2002 Mar 29;277(13):11505-12
  23. Nishizawa H, Yamagata K, Shimomura I, Takahashi M, Kuriyama H, Kishida K, Hotta K, Nagaretani H, Maeda N, Matsuda M, Kihara S, Nakamura T, Nishigori H, Tomura H, Moore DD, Takeda J, Funahashi T, Matsuzawa Y
    Small heterodimer partner, an orphan nuclear receptor, augments peroxisome proliferator-activated receptor gamma transactivation. The Journal of biological chemistry 2002 Jan 11;277(2):1586-92
  24. Krogsdam AM, Nielsen CA, Neve S, Holst D, Helledie T, Thomsen B, Bendixen C, Mandrup S, Kristiansen K
    Nuclear receptor corepressor-dependent repression of peroxisome-proliferator-activated receptor delta-mediated transactivation. The Biochemical journal 2002 Apr 1;363(Pt 1):157-65
  25. Libby P
    Current concepts of the pathogenesis of the acute coronary syndromes. Circulation 2001 Jul 17;104(3):365-72
  26. Roberts RA
    Evidence for cross talk between PPARalpha and p38 MAP kinase. Toxicological sciences : an official journal of the Society of Toxicology 2002 Aug;68(2):270-4
  27. Yu S, Rao S, Reddy JK
    Peroxisome proliferator-activated receptors, fatty acid oxidation, steatohepatitis and hepatocarcinogenesis. Current molecular medicine 2003 Sep;3(6):561-72
  28. Buchan KW, Hassall DG
    PPAR agonists as direct modulators of the vessel wall in cardiovascular disease. Medicinal research reviews 2000 Sep;20(5):350-66
  29. Hsueh WA, Law RE
    PPARgamma and atherosclerosis: effects on cell growth and movement. Arteriosclerosis, thrombosis, and vascular biology 2001 Dec;21(12):1891-5
  30. Walczak R, Tontonoz P
    PPARadigms and PPARadoxes: expanding roles for PPARgamma in the control of lipid metabolism. Journal of lipid research 2002 Feb;43(2):177-86
  31. Picard F, Auwerx J
    PPAR(gamma) and glucose homeostasis. Annual review of nutrition 2002;22:167-97
  32. Ricote M, Huang JT, Welch JS, Glass CK
    The peroxisome proliferator-activated receptor(PPARgamma) as a regulator of monocyte/macrophage function. Journal of leukocyte biology 1999 Nov;66(5):733-9
  33. Neve BP, Fruchart JC, Staels B
    Role of the peroxisome proliferator-activated receptors (PPAR) in atherosclerosis. Biochemical pharmacology 2000 Oct 15;60(8):1245-50
  34. Nikolaidis LA, Levine TB
    Peroxisome proliferator activator receptors (PPAR), insulin resistance, and cardiomyopathy: friends or foes for the diabetic patient with heart failure? Cardiology in review 2004 May-Jun;12(3):158-70
  35. Michalik L, Desvergne B, Dreyer C, Gavillet M, Laurini RN, Wahli W
    PPAR expression and function during vertebrate development. The International journal of developmental biology 2002 Jan;46(1):105-14
  36. Di-Poi N, Michalik L, Tan NS, Desvergne B, Wahli W
    The anti-apoptotic role of PPARbeta contributes to efficient skin wound healing. The Journal of steroid biochemistry and molecular biology 2003 Jun;85(2-5):257-65