1C. Peroxisome proliferator-activated receptors
More information on this family may be found on the IUPHAR-DB family and introduction pages.
Peroxisome proliferator-activated receptors (PPARs, nomenclature as agreed by NC-IUPHAR Committee on Nuclear Receptors, [20]) are nuclear hormone receptors of the NR1C family, with diverse roles regulating lipid homeostasis, cellular differentiation, proliferation and the immune response. PPARs have many potential endogenous agonists [5,20], including 15-deoxy-Δ12,14-PGJ2, prostacyclin (PGI2), many fatty acids and their oxidation products, lysophosphatidic acid (LPA) [19], 13-HODE, 15S-HETE, Paz-PC, azelaoyl-PAF and leukotriene B4 (LTB4). These receptors also bind hypolipidaemic drugs (PPARα) and anti-diabetic thiazolidinediones (PPARγ), as well as many non-steroidal anti-inflammatory drugs, such as sulindac and indomethacin. Once activated by a ligand, the receptor forms a heterodimer with members of the retinoid X receptor family and can act as a transcription factor. Although radioligand binding assays have been described for all three receptors, the radioligands are not commercially available. Commonly, receptor occupancy studies are conducted using fluorescent ligands and truncated forms of the receptor limited to the ligand binding domain.
Unless otherwise stated all data refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
Receptors 
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Peroxisome proliferator-activated receptor-γ Show »« Hide
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Belvisi, MG; Mitchell, JA. (2009) Targeting PPAR receptors in the airway for the treatment of inflammatory lung disease. Br. J. Pharmacol., 158 (4): 994-1003. [PMID:19703165]
Chaturvedi, RK; Beal, MF. (2008) PPAR: a therapeutic target in Parkinson's disease. J. Neurochem., 106 (2): 506-18. [PMID:18384649]
Christodoulides, C; Vidal-Puig, A. (2010) PPARs and adipocyte function. Mol. Cell. Endocrinol., 318 (1-2): 61-8. [PMID:19772894]
Ehrenborg, E; Krook, A. (2009) Regulation of skeletal muscle physiology and metabolism by peroxisome proliferator-activated receptor delta. Pharmacol. Rev., 61 (3): 373-93. [PMID:19805479]
Hiukka, A; Maranghi, M; Matikainen, N; Taskinen, MR. (2010) PPARalpha: an emerging therapeutic target in diabetic microvascular damage. Nat Rev Endocrinol, 6 (8): 454-63. [PMID:20567246]
Itoh, T; Yamamoto, K. (2008) Peroxisome proliferator activated receptor gamma and oxidized docosahexaenoic acids as new class of ligand. Naunyn Schmiedebergs Arch. Pharmacol., 377 (4-6): 541-7. [PMID:18193404]
Kawai, M; Rosen, CJ. (2010) PPARγ: a circadian transcription factor in adipogenesis and osteogenesis. Nat Rev Endocrinol, 6 (11): 629-36. [PMID:20820194]
Kawai, M; Sousa, KM; MacDougald, OA; Rosen, CJ. (2010) The many facets of PPARgamma: novel insights for the skeleton. Am. J. Physiol. Endocrinol. Metab., 299 (1): E3-9. [PMID:20407009]
Lockyer, P; Schisler, JC; Patterson, C; Willis, MS. (2010) Minireview: Won't get fooled again: the nonmetabolic roles of peroxisome proliferator-activated receptors (PPARs) in the heart. Mol. Endocrinol., 24 (6): 1111-9. [PMID:20016041]
Michalik, L; Auwerx, J; Berger, JP; Chatterjee, VK; Glass, CK; Gonzalez, FJ; Grimaldi, PA; Kadowaki, T; Lazar, MA; O'Rahilly, S; Palmer, CN; Plutzky, J; Reddy, JK; Spiegelman, BM; Staels, B; Wahli, W. (2006) International Union of Pharmacology. LXI. Peroxisome proliferator-activated receptors. Pharmacol. Rev., 58 (4): 726-41. [PMID:17132851]
Michalik, L; Wahli, W. (2008) PPARs Mediate Lipid Signaling in Inflammation and Cancer. PPAR Res, 2008: 134059. [PMID:19125181]
Reilly, SM; Lee, CH. (2008) PPAR delta as a therapeutic target in metabolic disease. FEBS Lett., 582 (1): 26-31. [PMID:18036566]
Robinson, E; Grieve, DJ. (2009) Significance of peroxisome proliferator-activated receptors in the cardiovascular system in health and disease. Pharmacol. Ther., 122 (3): 246-63. [PMID:19318113]
Varga, T; Czimmerer, Z; Nagy, L. (2011) PPARs are a unique set of fatty acid regulated transcription factors controlling both lipid metabolism and inflammation. Biochim. Biophys. Acta, 1812 (8): 1007-22. [PMID:21382489]
Villacorta, L; Schopfer, FJ; Zhang, J; Freeman, BA; Chen, YE. (2009) PPARgamma and its ligands: therapeutic implications in cardiovascular disease. Clin. Sci., 116 (3): 205-18. [PMID:19118492]
Wan, Y. (2010) PPARγ in bone homeostasis. Trends Endocrinol. Metab., 21 (12): 722-8. [PMID:20863714]
Wang, N; Yin, R; Liu, Y; Mao, G; Xi, F. (2011) Role of peroxisome proliferator-activated receptor-γ in atherosclerosis: an update. Circ. J., 75 (3): 528-35. [PMID:21325726]
Youssef, J; Badr, M. (2011) Peroxisome proliferator-activated receptors and cancer: challenges and opportunities. Br. J. Pharmacol., 164 (1): 68-82. [PMID:21449912]
Yu, S; Reddy, JK. (2007) Transcription coactivators for peroxisome proliferator-activated receptors. Biochim. Biophys. Acta, 1771 (8): 936-51. [PMID:17306620]
Ziouzenkova, O; Plutzky, J. (2008) Retinoid metabolism and nuclear receptor responses: New insights into coordinated regulation of the PPAR-RXR complex. FEBS Lett., 582 (1): 32-8. [PMID:18068127]
1. Adamson, DJ; Frew, D; Tatoud, R; Wolf, CR; Palmer, CN. (2002) Diclofenac antagonizes peroxisome proliferator-activated receptor-gamma signaling. Mol. Pharmacol., 61 (1): 7-12. [PMID:11752200]
2. Berger, J; Bailey, P; Biswas, C; Cullinan, CA; Doebber, TW; Hayes, NS; Saperstein, R; Smith, RG; Leibowitz, MD. (1996) Thiazolidinediones produce a conformational change in peroxisomal proliferator-activated receptor-gamma: binding and activation correlate with antidiabetic actions in db/db mice. Endocrinology, 137 (10): 4189-95. [PMID:8828476]
3. Berger, J; Leibowitz, MD; Doebber, TW; Elbrecht, A; Zhang, B; Zhou, G; Biswas, C; Cullinan, CA; Hayes, NS; Li, Y; Tanen, M; Ventre, J; Wu, MS; Berger, GD; Mosley, R; Marquis, R; Santini, C; Sahoo, SP; Tolman, RL; Smith, RG; Moller, DE. (1999) Novel peroxisome proliferator-activated receptor (PPAR) gamma and PPARdelta ligands produce distinct biological effects. J. Biol. Chem., 274 (10): 6718-25. [PMID:10037770]
4. Bishop-Bailey, D; Hla, T; Warner, TD. (2000) Bisphenol A diglycidyl ether (BADGE) is a PPARgamma agonist in an ECV304 cell line. Br. J. Pharmacol., 131 (4): 651-4. [PMID:11030710]
5. Bishop-Bailey, D; Wray, J. (2003) Peroxisome proliferator-activated receptors: a critical review on endogenous pathways for ligand generation. Prostaglandins Other Lipid Mediat., 71 (1-2): 1-22. [PMID:12749590]
6. Brown, KK; Henke, BR; Blanchard, SG; Cobb, JE; Mook, R; Kaldor, I; Kliewer, SA; Lehmann, JM; Lenhard, JM; Harrington, WW; Novak, PJ; Faison, W; Binz, JG; Hashim, MA; Oliver, WO; Brown, HR; Parks, DJ; Plunket, KD; Tong, WQ; Menius, JA; Adkison, K; Noble, SA; Willson, TM. (1999) A novel N-aryl tyrosine activator of peroxisome proliferator-activated receptor-gamma reverses the diabetic phenotype of the Zucker diabetic fatty rat. Diabetes, 48 (7): 1415-24. [PMID:10389847]
7. Brown, PJ; Stuart, LW; Hurley, KP; Lewis, MC; Winegar, DA; Wilson, JG; Wilkison, WO; Ittoop, OR; Willson, TM. (2001) Identification of a subtype selective human PPARalpha agonist through parallel-array synthesis. Bioorg. Med. Chem. Lett., 11 (9): 1225-7. [PMID:11354382]
8. Doebber, TW; Kelly, LJ; Zhou, G; Meurer, R; Biswas, C; Li, Y; Wu, MS; Ippolito, MC; Chao, YS; Wang, PR; Wright, SD; Moller, DE; Berger, JP. (2004) MK-0767, a novel dual PPARalpha/gamma agonist, displays robust antihyperglycemic and hypolipidemic activities. Biochem. Biophys. Res. Commun., 318 (2): 323-8. [PMID:15120604]
9. Forman, BM; Chen, J; Evans, RM. (1997) Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta. Proc. Natl. Acad. Sci. U.S.A., 94 (9): 4312-7. [PMID:9113986]
10. Graham, TL; Mookherjee, C; Suckling, KE; Palmer, CN; Patel, L. (2005) The PPARdelta agonist GW0742X reduces atherosclerosis in LDLR(-/-) mice. Atherosclerosis, 181 (1): 29-37. [PMID:15939051]
11. Guo, Q; Sahoo, SP; Wang, PR; Milot, DP; Ippolito, MC; Wu, MS; Baffic, J; Biswas, C; Hernandez, M; Lam, MH; Sharma, N; Han, W; Kelly, LJ; MacNaul, KL; Zhou, G; Desai, R; Heck, JV; Doebber, TW; Berger, JP; Moller, DE; Sparrow, CP; Chao, YS; Wright, SD. (2004) A novel peroxisome proliferator-activated receptor alpha/gamma dual agonist demonstrates favorable effects on lipid homeostasis. Endocrinology, 145 (4): 1640-8. [PMID:14701675]
12. Henke, BR. (2004) Peroxisome proliferator-activated receptor alpha/gamma dual agonists for the treatment of type 2 diabetes. J. Med. Chem., 47 (17): 4118-27. [PMID:15293980]
13. Henke, BR; Blanchard, SG; Brackeen, MF; Brown, KK; Cobb, JE; Collins, JL; Harrington, WW; Hashim, MA; Hull-Ryde, EA; Kaldor, I; Kliewer, SA; Lake, DH; Leesnitzer, LM; Lehmann, JM; Lenhard, JM; Orband-Miller, LA; Miller, JF; Mook, RA; Noble, SA; Oliver, W; Parks, DJ; Plunket, KD; Szewczyk, JR; Willson, TM. (1998) N-(2-Benzoylphenyl)-L-tyrosine PPARgamma agonists. 1. Discovery of a novel series of potent antihyperglycemic and antihyperlipidemic agents. J. Med. Chem., 41 (25): 5020-36. [PMID:9836620]
14. Huang, JT; Welch, JS; Ricote, M; Binder, CJ; Willson, TM; Kelly, C; Witztum, JL; Funk, CD; Conrad, D; Glass, CK. (1999) Interleukin-4-dependent production of PPAR-gamma ligands in macrophages by 12/15-lipoxygenase. Nature, 400 (6742): 378-82. [PMID:10432118]
15. Inoue, I; Itoh, F; Aoyagi, S; Tazawa, S; Kusama, H; Akahane, M; Mastunaga, T; Hayashi, K; Awata, T; Komoda, T; Katayama, S. (2002) Fibrate and statin synergistically increase the transcriptional activities of PPARalpha/RXRalpha and decrease the transactivation of NFkappaB. Biochem. Biophys. Res. Commun., 290 (1): 131-9. [PMID:11779144]
16. Lee, G; Elwood, F; McNally, J; Weiszmann, J; Lindstrom, M; Amaral, K; Nakamura, M; Miao, S; Cao, P; Learned, RM; et al.. (2002) T0070907, a selective ligand for peroxisome proliferator-activated receptor gamma, functions as an antagonist of biochemical and cellular activities. J. Biol. Chem., 277 (22): 19649-57. [PMID:11877444]
17. Lehmann, JM; Lenhard, JM; Oliver, BB; Ringold, GM; Kliewer, SA. (1997) Peroxisome proliferator-activated receptors alpha and gamma are activated by indomethacin and other non-steroidal anti-inflammatory drugs. J. Biol. Chem., 272 (6): 3406-10. [PMID:9013583]
18. Liu, K; Xu, L; Berger, JP; Macnaul, KL; Zhou, G; Doebber, TW; Forrest, MJ; Moller, DE; Jones, AB. (2005) Discovery of a novel series of peroxisome proliferator-activated receptor alpha/gamma dual agonists for the treatment of type 2 diabetes and dyslipidemia. J. Med. Chem., 48 (7): 2262-5. [PMID:15801817]
19. McIntyre, TM; Pontsler, AV; Silva, AR; St Hilaire, A; Xu, Y; Hinshaw, JC; Zimmerman, GA; Hama, K; Aoki, J; Arai, H; et al.. (2003) Identification of an intracellular receptor for lysophosphatidic acid (LPA): LPA is a transcellular PPARgamma agonist. Proc. Natl. Acad. Sci. U.S.A., 100 (1): 131-6. [PMID:12502787]
20. Michalik, L; Auwerx, J; Berger, JP; Chatterjee, VK; Glass, CK; Gonzalez, FJ; Grimaldi, PA; Kadowaki, T; Lazar, MA; O'Rahilly, S; Palmer, CN; Plutzky, J; Reddy, JK; Spiegelman, BM; Staels, B; Wahli, W. (2006) International Union of Pharmacology. LXI. Peroxisome proliferator-activated receptors. Pharmacol. Rev., 58 (4): 726-41. [PMID:17132851]
21. Nakamuta, M; Enjoji, M; Uchimura, K; Ohta, S; Sugimoto, R; Kotoh, K; Kato, M; Irie, T; Muta, T; Nawata, H. (2002) Bisphenol a diglycidyl ether (BADGE) suppresses tumor necrosis factor-alpha production as a PPARgamma agonist in the murine macrophage-like cell line, RAW 264.7. Cell Biol. Int., 26 (3): 235-41. [PMID:11991651]
22. Oliver, WR; Shenk, JL; Snaith, MR; Russell, CS; Plunket, KD; Bodkin, NL; Lewis, MC; Winegar, DA; Sznaidman, ML; Lambert, MH; Xu, HE; Sternbach, DD; Kliewer, SA; Hansen, BC; Willson, TM. (2001) A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport. Proc. Natl. Acad. Sci. U.S.A., 98 (9): 5306-11. [PMID:11309497]
23. Rocchi, S; Picard, F; Vamecq, J; Gelman, L; Potier, N; Zeyer, D; Dubuquoy, L; Bac, P; Champy, MF; Plunket, KD; Leesnitzer, LM; Blanchard, SG; Desreumaux, P; Moras, D; Renaud, JP; Auwerx, J. (2001) A unique PPARgamma ligand with potent insulin-sensitizing yet weak adipogenic activity. Mol. Cell, 8 (4): 737-47. [PMID:11684010]
24. Sakamoto, J; Kimura, H; Moriyama, S; Odaka, H; Momose, Y; Sugiyama, Y; Sawada, H. (2000) Activation of human peroxisome proliferator-activated receptor (PPAR) subtypes by pioglitazone. Biochem. Biophys. Res. Commun., 278 (3): 704-11. [PMID:11095972]
25. Shearer, BG; Steger, DJ; Way, JM; Stanley, TB; Lobe, DC; Grillot, DA; Iannone, MA; Lazar, MA; Willson, TM; Billin, AN. (2008) Identification and characterization of a selective peroxisome proliferator-activated receptor beta/delta (NR1C2) antagonist. Mol. Endocrinol., 22 (2): 523-9. [PMID:17975020]
26. Sznaidman, ML; Haffner, CD; Maloney, PR; Fivush, A; Chao, E; Goreham, D; Sierra, ML; LeGrumelec, C; Xu, HE; Montana, VG; Lambert, MH; Willson, TM; Oliver, WR; Sternbach, DD. (2003) Novel selective small molecule agonists for peroxisome proliferator-activated receptor delta (PPARdelta)--synthesis and biological activity. Bioorg. Med. Chem. Lett., 13 (9): 1517-21. [PMID:12699745]
27. Wang, Y; Porter, WW; Suh, N; Honda, T; Gribble, GW; Leesnitzer, LM; Plunket, KD; Mangelsdorf, DJ; Blanchard, SG; Willson, TM; Sporn, MB. (2000) A synthetic triterpenoid, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), is a ligand for the peroxisome proliferator-activated receptor gamma. Mol. Endocrinol., 14 (10): 1550-6. [PMID:11043571]
28. Willson, TM; Brown, PJ; Sternbach, DD; Henke, BR. (2000) The PPARs: from orphan receptors to drug discovery. J. Med. Chem., 43 (4): 527-50. [PMID:10691680]
29. Wright, HM; Clish, CB; Mikami, T; Hauser, S; Yanagi, K; Hiramatsu, R; Serhan, CN; Spiegelman, BM. (2000) A synthetic antagonist for the peroxisome proliferator-activated receptor gamma inhibits adipocyte differentiation. J. Biol. Chem., 275 (3): 1873-7. [PMID:10636887]
30. Xu, HE; Stanley, TB; Montana, VG; Lambert, MH; Shearer, BG; Cobb, JE; McKee, DD; Galardi, CM; Plunket, KD; Nolte, RT; et al.. (2002) Structural basis for antagonist-mediated recruitment of nuclear co-repressors by PPARalpha. Nature, 415 (6873): 813-7. [PMID:11845213]
31. Xu, Y; Rito, CJ; Etgen, GJ; Ardecky, RJ; Bean, JS; Bensch, WR; Bosley, JR; Broderick, CL; Brooks, DA; Dominianni, SJ; Hahn, PJ; Liu, S; Mais, DE; Montrose-Rafizadeh, C; Ogilvie, KM; Oldham, BA; Peters, M; Rungta, DK; Shuker, AJ; Stephenson, GA; Tripp, AE; Wilson, SB; Winneroski, LL; Zink, R; Kauffman, RF; McCarthy, JR. (2004) Design and synthesis of alpha-aryloxy-alpha-methylhydrocinnamic acids: a novel class of dual peroxisome proliferator-activated receptor alpha/gamma agonists. J. Med. Chem., 47 (10): 2422-5. [PMID:15115385]
32. Young, PW; Buckle, DR; Cantello, BC; Chapman, H; Clapham, JC; Coyle, PJ; Haigh, D; Hindley, RM; Holder, JC; Kallender, H; Latter, AJ; Lawrie, KW; Mossakowska, D; Murphy, GJ; Roxbee Cox, L; Smith, SA. (1998) Identification of high-affinity binding sites for the insulin sensitizer rosiglitazone (BRL-49653) in rodent and human adipocytes using a radioiodinated ligand for peroxisomal proliferator-activated receptor gamma. J. Pharmacol. Exp. Ther., 284 (2): 751-9. [PMID:9454824]
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As with the estrogen receptor antagonists, many agents show tissue-selective efficacy (e.g. [4,21,23]). Agonists with mixed activity at PPARα and PPARγ have also been described (e.g [8,11,31]).