Overview: Peroxisome proliferator-activated receptors (PPARs, nomenclature as agreed by NC-IUPHAR Committee on Nuclear Receptors, see Michalik et al., 2006) 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 (see Michalik et al., 2006), including 15-deoxy-Δ12,14-prostaglandin J2, prostacyclin, many fatty acids and their oxidation products, lysophosphatidic acid (McIntyre et al., 2003), 13-HODE, 15-HETE, Paz-PC, azelaoyl-PAF and leukotriene B4. 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.
| Nomenclature | PPARα | PPARβ | PPARγ |
|---|---|---|---|
| Systematic nomenclature | NR1C1 | NR1C2 | NR1C3 |
| Other names | – | PPARδ, NUC1, FAAR | – |
| Ensembl ID | ENSG00000100406 | ENSG00000112033 | ENSG00000132170 |
| Selective agonists | GW7647, WY14643, clofibrate, fenofibrate, ciprofibrate, gemfibrozil | L165041, GW501516, GW0742 | Rosiglitazone, ciglitazone, troglitazone, pioglitazone, CDDO, GW1929 |
| Selective antagonists | GW6471 (Xu et al., 2002) | GSK0660 (Shearer et al., 2008) | GW9662 (Huang et al., 1999), CDDO-Me (Wang et al., 2000), diclofenac (6.2, Adamson et al., 2002), BADGE (4.0, Wright et al., 2000), T0070907 (Lee et al., 2002) |
As with the oestrogen receptor antagonists, many agents show tissue-selective efficacy (e.g. Bishop-Bailey, 2000; Rocchi et al., 2001; Nakamuta et al., 2002). Agonists with mixed activity at PPARα and PPARγ have recently been described (e.g. Doebber et al., 2004; Guo et al., 2004; Xu et al., 2004).
Glossary
Abbreviations:
- 13-HODE
13-hydroxyoctadecadienoic acid
- 15-HETE
15-hydroxyeicosatetraenoic acid
- azelaoyl-PAF
1-O-hexadecyl-2-O-(9-carboxyoctanoyl)-sn-glyceryl-3-phosphocholine
- BADGE
bisphenol A diglycidyl ether
- CDDO
2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid
- CDDO-Me
2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid methyl ester
- GSK0660
3-([{2-methoxy-4-(phenylamino)phenyl}amino]sulfonyl)-2-thiophenecarboxylic acid methyl ester
- GW1929
(2S)-([2-benzoylphenyl]amino)-3-(4-[2-{methylpyridin-2-ylamino}ethoxy]phenyl)propionic acid
- GW501516
2-methyl-4([{(4-methyl-2-[4-trifluoromethylphenyl]-1,3-thiazol-5-yl)methyl}sulfanyl]phenoxy)acetic acid, GW7647, 2-([4-{2-([{cyclohexylamino}carbonyl][4-cyclohexylbutyl]amino)ethyl}phenyl]thio)-2-methylpropanoic acid
- GW9662
2-chloro-5-nitro-N-phenylbenzamide
- L165041
(4-[3-{4-acetyl-3-hydroxy-2-propylphenoxy}propoxyl]phenoxy)acetic acid
- Paz-PC
1-palmitoyl-2-azelaoyl-sn-glycero-3-phosphocholine
- T0070907
2-chloro-5-nitro-N-(4-pyridyl)benzamide
- WY14643
N-(3-[2-quinolinylmethoxy]phenyl)-trifluoromethanesulphonamide
Further Reading
Brown JD, Plutzky J (2007). Peroxisome proliferator-activated receptors as transcriptional nodal points and therapeutic targets. Circulation115: 518–533.
Chaturvedi RK, Beal MF (2008). PPAR: a therapeutic target in Parkinson's disease. J Neurochem106: 506–518.
Culman J, Zhao Y, Gohlke P, Herdegen T (2007). PPAR-γ: therapeutic target for ischemic stroke. Trends Pharmacol Sci28: 244–249.
Gervois P, Fruchart JC, Staels B (2007). Drug Insight: mechanisms of action and therapeutic applications for agonists of peroxisome proliferator-activated receptors. Nat Clin Pract Endocrinol Metab3: 145–156.
Grimaldi PA (2007). Regulatory functions of PPARβ in metabolism: implications for the treatment of metabolic syndrome. Biochimica et Biophysica Acta-Molecular and Cell Biology of Lipids1771: 983–990.
Heneka MT, Landreth GE, Hull M (2007). Drug insight: effects mediated by peroxisome proliferator-activated receptor-gamma in CNS disorders. Nat Clin Pract Neurol3: 496–504.
Itoh T, Yamamoto K (2008). Peroxisome proliferator activated receptor gamma and oxidized docosahexaenoic acids as new class of ligand. Naunyn Schmiedebergs Arch Pharmacol377: 541–547.
Michalik L, Wahli W (2008). PPARs mediate lipid signaling in inflammation and cancer. PPAR Res2008: 134059.
Michalik L, Auwerx J, Berger JP, Chatterjee VK, Glass CK, Gonzalez FJ et al. (2006). International Union of Pharmacology. LXI. Peroxisome proliferator-activated receptors. Pharmacol Rev58: 726–741.
Reilly SM, Lee CH (2008). PPARδ as a therapeutic target in metabolic disease. FEBS Lett582: 26-31.
Robinson E, Grieve DJ (2009). Significance of peroxisome proliferator-activated receptors in the cardiovascular system in health and disease. Pharmacol Ther122: 246–263.
Rubenstrunk A, Hanf R, Hum DW, Fruchart JC, Staels B (2007). Safety issues and prospects for future generations of PPAR modulators. Biochim Biophys Acta1771: 1065–1081.
Sertznig P, Seifert M, Tilgen W, Reichrath J (2007). Present concepts and future outlook: function of peroxisome proliferator-activated receptors (PPARs) for pathogenesis, progression, and therapy of cancer. J Cell Physiol212: 1–12.
Straus DS, Glass CK (2007). Anti-inflammatory actions of PPAR ligands: new insights on cellular and molecular mechanisms. Trends Immunol28: 551–558.
Szeles L, Torocsik D, Nagy L (2007). PPARγ in immunity and inflammation: cell types and diseases. Biochimica et Biophysica Acta-Molecular and Cell Biology of Lipids1771: 1014–1030.
Villacorta L, Schopfer FJ, Zhang J, Freeman BA, Chen YE (2009). PPARγ and its ligands: therapeutic implications in cardiovascular disease. Clin Sci116: 205–218.
Yu S, Reddy JK (2007). Transcription coactivators for peroxisome proliferator-activated receptors. Biochim Biophys Acta1771: 936–951.
Ziouzenkova O, Plutzky J (2008). Retinoid metabolism and nuclear receptor responses: new insights into coordinated regulation of the PPAR-RXR complex. FEBS Lett582: 32–38.
Zoete V, Grosdidier A, Michielin O (2007). Peroxisome proliferator-activated receptor structures: ligand specificity, molecular switch and interactions with regulators. Biochimica et Biophysica Acta-Molecular and Cell Biology of Lipids1771: 915–925.
References
- Adamson DJ, et al. Mol Pharmacol. 2002;61:7–12. doi: 10.1124/mol.61.1.7. [DOI] [PubMed] [Google Scholar]
- Bishop-Bailey D. Br J Pharmacol. 2000;129:823–833. doi: 10.1038/sj.bjp.0703149. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Doebber TW, et al. Biochem Biophys Res Commun. 2004;318:323–328. doi: 10.1016/j.bbrc.2004.04.032. [DOI] [PubMed] [Google Scholar]
- Guo Q, et al. Endocrinology. 2004;145:1640–1648. doi: 10.1210/en.2003-1270. [DOI] [PubMed] [Google Scholar]
- Huang JT, et al. Nature. 1999;400:378–382. doi: 10.1038/22572. [DOI] [PubMed] [Google Scholar]
- Lee G, et al. J Biol Chem. 2002;277:19649–19657. doi: 10.1074/jbc.M200743200. [DOI] [PubMed] [Google Scholar]
- McIntyre TM, et al. Proc Natl Acad Sci USA. 2003;100:131–136. doi: 10.1073/pnas.0135855100. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nakamuta M, et al. Cell Biol Int. 2002;26:235–241. doi: 10.1006/cbir.2001.0838. [DOI] [PubMed] [Google Scholar]
- Rocchi S, et al. Mol Cell. 2001;8:737–747. doi: 10.1016/s1097-2765(01)00353-7. [DOI] [PubMed] [Google Scholar]
- Shearer BG, et al. Mol Endocrinol. 2008;22:523–529. doi: 10.1210/me.2007-0190. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wang Y, et al. Mol Endocrinol. 2000;14:1550–1556. doi: 10.1210/mend.14.10.0545. [DOI] [PubMed] [Google Scholar]
- Wright HM, et al. J Biol Chem. 2000;275:1873–1877. doi: 10.1074/jbc.275.3.1873. [DOI] [PubMed] [Google Scholar]
- Xu HE, et al. Nature. 2002;415:813–817. doi: 10.1038/415813a. [DOI] [PubMed] [Google Scholar]
- Xu Y, et al. J Med Chem. 2004;47:2422–2425. doi: 10.1021/jm0342616. [DOI] [PubMed] [Google Scholar]