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Research ArticleSpecial Issue IUPHAR Compendium of the Pharmacology and Classification of the Nuclear Receptor Superfamily 2006

International Union of Pharmacology. LXI. Peroxisome Proliferator-Activated Receptors

Liliane Michalik, Johan Auwerx, Joel P. Berger, V. Krishna Chatterjee, Christopher K. Glass, Frank J. Gonzalez, Paul A. Grimaldi, Takashi Kadowaki, Mitchell A. Lazar, Stephen O'Rahilly, Colin N. A. Palmer, Jorge Plutzky, Janardan K. Reddy, Bruce M. Spiegelman, Bart Staels and Walter Wahli
Pharmacological Reviews December 2006, 58 (4) 726-741; DOI: https://doi.org/10.1124/pr.58.4.5

Article Figures & Data

Figures

  • Fig. 1.
    Fig. 1.

    Endogenous pathways for PPAR ligand production. Unsaturated fatty acids can act both as ligands and as substrates for ligand-generating enzymes, such as the 8/12/15- and 5-lipoxygenases (LOs), the cyclooxygenases (COX-1 and COX-2), the cytochrome (CYP)/epoxygenases, or the lipoprotein and endothelial lipases. In addition, ligands can be generated by nonspecific/nonenzymatic pathways. The levels of substrates available depend on physiological and pathophysiological conditions.

Tables

  • TABLE 1

    PPARα

    Receptor nomenclature NR1C1
    Receptor code 4.10.1:FA:1:C1
    Molecular information Hs: 468aa, Q07869, chr. 22q13.311
    Rn: 468aa, P37230, chr. 7q342
    Mm: 468aa, P23204, chr. 15 E23
    DNA binding
       Structure Heterodimer, RXR partner
       HRE core sequence AACTAGGNCA A AGGTCA (DR-1, DR-2)
    Partners RXR (physical, functional) DNA binding4
    Agonists GW409544 (8.7), LY-518674 (7.6), LY-510929 (7.55), TZD18 (7.55), LTB4 (7), oleylethanolamide (6.92), LY-465608 (6.8), pirinixic acid (6.22), fatty acids (6), ragaglitazar (6), AD-5061 (5.55), fenofibric acid (4.46) [pIC50]5–22; GW7647 (8.22), GW9578 (7.3), TAK-559 (7.17), KRP-297/MK-0767 (6.8), eicosatetraenoic acid (6.7), farglitazar (6.35), reglitazar (5.72), DRF 2519 (∼5), pristanic acid (4.4), bezafibrate (4.3), clofibrate (4.25) [pEC50]6,13,14,18,23–33; KRP-297/MK-0767 (7.64), 8S-HETE (7), GW2331 (6.8), NS-220* (6.73), [3H]AD-5061* (5.5) [pKd]9,17,18,34–38; pterostilbene, tetradecylglycidic acid, ortylthiopropionic acid39,40
    Antagonists MK886 (4.6) [pIC50]41
    Coactivators PPARBP, NCOA6, BFE, CREBBP, CITED2, NCOA1, NCOA3, SWI2/SNF2, PGC-1α, PPARGC1B42–52
    Corepressors NRIP1, NCOR139,53–57
    Biologically important isoforms PPARα {Hs, Mm, Rn}: encoded by eight exons1–3, 58; PPARαtr (truncated) {Hs}: lacks exon 6, truncated protein lacking part of hinge region and LBD, dominant-negative, 20–50% of total PPARα mRNA, not detected in rodents59
    Tissue distribution Very active peroxisomal β-oxidation tissues; liver, brown fat, kidney, heart, skeletal muscle, large intestine {Hs, Mm, Rn} [Northern blot, Q-PCR, in situ hybridization, immunohistology]39
    Main target genes Activated: liver fatty acid binding protein39,60, Acyl-CoA oxidase {Rn}61,62, bifunctional enzyme {Rn}61, CPTI {Hs}63–65, MCAD {Rn}66, FIAF {Mm}67, FATP {Mm}68, apolipoprotein A-II {Mm}69, G0/G1 switch gene 2 (G0S2) {Mm}70
    Mutant phenotype Hypothermia and hypoglycemia upon fasting, reduced insulin resistance, prolonged inflammatory reaction, transient delay in skin healing, resistance to fibrate-induced cancer {Mm} [knockout]7,71–76; overexpression in the heart leads to cardiac insulin resistance associated with defects in insulin signaling and STAT3 activity, reduced heart function {Mm} [transgenesis]77,78; overexpression in muscle leads to the development of glucose intolerance, increased fatty acid oxidation rates, reduced AMP-activated protein kinase activity, reduced insulin-stimulated glucose uptake, repression of GLUT4 gene {Mm} [transgenesis]79; PPARαΔ13: dominant-negative mutant results in transient-impaired wound-healing and impaired inflammatory phase {Mm} [transgenesis]80
    Human disease Arteriosclerosis81,82

    • aa, amino acids; chr., chromosome; HRE, hormone response element; HETE, hydroxyeicosatetraenoic acid; Q-PCR, quantitative polymerase chain reaction; FIAF, fasting-induced adipose factor; BFE, bifunctional enzyme; CREBBP, cAMP response element binding protein binding protein; CPTI, carnitine palmitoyl transferase; MCAD, medium-chain acyl-CoA dehydrogenase; FATP, fatty acid transport protein

    • ↵* Radioligand

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  • TABLE 2

    PPARβ

    Receptor nomenclature NR1C2
    Receptor code 4.10.1:FA:1:C2
    Other names PPARβ, PPARδ, NUC1, FAAR
    Molecular information Hs: 441aa, Q03181, chr. 6p21.2–p21.11
    Rn: 440aa, Q62879, chr. 20p122
    Mm: 440aa, P35396, chr. 17 A3.33
    DNA binding
       Structure Heterodimer, RXR partner
       HRE core sequence AACTAGGNCA A AGGTCA (DR-1)
    Partners RXR (physical, functional) DNA binding4
    Agonists GW0742X (7.52), GW2433 (6.57), GW9578 (5.9) [pEC50]5–8; GW0742 (9), fatty acids (5.2) [pIC50]9,10; L-783483* (9), GW501516 (8.96), retinoic acid (7.77) [pKd]9,11–13; L-796449 (8.7), L-165461 (8.52), L-165041 (8.22) [pKi]8,11,14
    Coactivators NCOA1, NCOA3, NCOA6, PGC-1α15–18
    Corepressors NCOR1, NCOR219–22
    Biologically important isoforms PPARβ {Hs, Mm, Rn}: partial organization of the gene with six exons in Xenopus related so far1–3,23
    Tissue distribution Ubiquitous {Hs} [Northern blot, Q-PCR]24
    Functional assays Adipogenesis assay using 3T3-C2 fibroblasts {Mm}25
    Main target genes Activated: ILK {Mm}26, PDK1 {Mm}26, DFF45 {Mm}27, FIAF {Hs}28; repressed: PTEN {Mm}26
    Mutant phenotype Overexpression in C2C12 myoblasts participates in their transdifferentiation into adipocytes {Mm} [retroviral infection]29; overexpression of constitutively active PPARβ-VP16 fusion protein in white adipose tissue triggers fatty acid mobilization and oxidation leading to mass reduction {Mm} [transgenesis]19; overexpression in skeletal muscle provokes a shift toward more oxidative fibers and general decrease of body fat content {Mm} [transgenesis]30; knockout mice exhibit decreased amount of brown and white adipose tissues, enhanced sensitivity to skin carcinogenesis, exacerbated epithelial proliferation, delayed wound repair, enhanced colon carcinogenesis, and LDL hypertriglyceridemia {Mm} [knockout]31–36; heterozygous knockout mice exhibit delayed wound closure {Mm}[knockout]35,37,38
    Human disease Atherosclerosis (controversial): deletion of PPARβ/δ from foam cells increases the availability of inflammatory suppressors, which in turn reduces atherosclerotic lesion formation7,39–41

    • aa, amino acids; chr., chromosome; HRE, hormone response element; Q-PCR, quantitative polymerase chain reaction; FIAF, fasting-induced adipose factor; FAAR, fatty acid-activated receptor; PTEN, phosphatase and tensing homolog deleted on chromosome 10; LDL, low-density lipoprotein

    • ↵* Radioligand

    • ↵1. Schmidt A, Endo N, Rutledge SJ, Vogel R, Shinar D, and Rodan GA (1992) Identification of a new member of the steroid hormone receptor superfamily that is activated by a peroxisome proliferator and fatty acids. Mol Endocrinol 6: 1634-1641

    • ↵2. Xing G, Zhang L, Heynen T, Yoshikawa T, Smith M, Weiss S, and Detera-Wadleigh S (1995) Rat PPAR delta contains a CGG triplet repeat and is prominently expressed in the thalamic nuclei. Biochem Biophys Res Commun 217: 1015-1025

    • ↵3. Kliewer SA, Forman BM, Blumberg B, Ong ES, Borgmeyer U, Mangelsdorf DJ, Umesono K, and Evans RM (1994) Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. Proc Natl Acad Sci USA 91: 7355-7359

    • ↵4. Kliewer SA, Umesono K, Noonan DJ, Heyman RA, and Evans RM (1992) Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors. Nature (Lond) 358: 771-774

    • ↵5. Brown PJ, Smith-Oliver TA, Charifson PS, Tomkinson NC, Fivush AM, Sternbach DD, Wade LE, Orband-Miller L, Parks DJ, Blanchard SG, et al. (1997) Identification of peroxisome proliferator-activated receptor ligands from a biased chemical library. Chem Biol 4: 909-918

    • ↵6. Brown PJ, Stuart LW, Hurley KP, Lewis MC, Winegar DA, Wilson JG, Wilkison WO, Ittoop OR, and Willson TM (2001) Identification of a subtype selective human PPARalpha agonist through parallel-array synthesis. Bioorg Med Chem Lett 11: 1225-1227

    • ↵7. Graham TL, Mookherjee C, Suckling KE, Palmer CN, and Patel L (2005) The PPARdelta agonist GW0742X reduces atherosclerosis in LDLR(–/–) mice. Atherosclerosis 181: 29-37

    • ↵8. Willson TM, Brown PJ, Sternbach DD, and Henke BR (2000) The PPARs: from orphan receptors to drug discovery. J Med Chem 43: 527-550

    • ↵9. Sznaidman ML, Haffner CD, Maloney PR, Fivush A, Chao E, Goreham D, Sierra ML, LeGrumelec C, Xu HE, Montana VG, et al. (2003) Novel selective small molecule agonists for peroxisome proliferator-activated receptor delta (PPARdelta)—synthesis and biological activity. Bioorg Med Chem Lett 13: 1517-1521

    • ↵10. Xu HE, Lambert MH, Montana VG, Parks DJ, Blanchard SG, Brown PJ, Sternbach DD, Lehmann JM, Wisely GB, Willson TM, et al. (1999) Molecular recognition of fatty acids by peroxisome proliferator-activated receptors. Mol Cell 3: 397-403

    • ↵11. Berger J, Leibowitz MD, Doebber TW, Elbrecht A, Zhang B, Zhou G, Biswas C, Cullinan CA, Hayes NS, Li Y, et al. (1999) Novel peroxisome proliferator-activated receptor (PPAR) gamma and PPARdelta ligands produce distinct biological effects. J Biol Chem 274: 6718-6725

    • ↵12. Oliver WR Jr, Shenk JL, Snaith MR, Russell CS, Plunket KD, Bodkin NL, Lewis MC, Winegar DA, Sznaidman ML, Lambert MH, et al. (2001) A selective peroxisome proliferator-activated receptor delta agonist promotes reverse cholesterol transport. Proc Natl Acad Sci USA 98: 5306-5311

    • ↵13. Shaw N, Elholm M, and Noy N (2003) Retinoic acid is a high affinity selective ligand for the peroxisome proliferator-activated receptor beta/delta. J Biol Chem 278: 41589-41592

    • ↵14. Henke BR (2004) Peroxisome proliferator-activated receptor alpha/gamma dual agonists for the treatment of type 2 diabetes. J Med Chem 47: 4118-4127

    • ↵15. Caira F, Antonson P, Pelto-Huikko M, Treuter E, and Gustafsson JA (2000) Cloning and characterization of RAP250, a novel nuclear receptor coactivator. J Biol Chem 275: 5308-5317

    • ↵16. Molnar F, Matilainen M, and Carlberg C (2005) Structural determinants of the agonist-independent association of human peroxisome proliferator-activated receptors with coactivators. J Biol Chem 280: 26543-26556

    • ↵17. Qi C, Zhu Y, and Reddy JK (2000) Peroxisome proliferator-activated receptors, coactivators, and downstream targets. Cell Biochem Biophys 32: 187-204

    • ↵18. Wang YX, Lee CH, Tiep S, Yu RT, Ham J, Kang H, and Evans RM (2003) Peroxisome-proliferator-activated receptor delta activates fat metabolism to prevent obesity. Cell 113: 159-170

    • ↵19. Jackson TA, Richer JK, Bain DL, Takimoto GS, Tung L, and Horwitz KB (1997) The partial agonist activity of antagonist-occupied steroid receptors is controlled by a novel hinge domain-binding coactivator L7/SPA and the corepressors N-CoR or SMRT. Mol Endocrinol 11: 693-705

    • ↵20. Krogsdam AM, Nielsen CA, Neve S, Holst D, Helledie T, Thomsen B, Bendixen C, Mandrup S, and Kristiansen K (2002) Nuclear receptor corepressor-dependent repression of peroxisome-proliferator-activated receptor delta-mediated transactivation. Biochem J 363: 157-165

    • ↵21. Yu C, Markan K, Temple KA, Deplewski D, Brady MJ, and Cohen RN (2005) The nuclear receptor corepressors NCoR and SMART decrease peroxisome proliferator-activated receptor gamma transcriptional activity and repress 3T3-L1 adipogenesis. J Biol Chem 280: 13600-13605

    • ↵22. Zamir I, Harding HP, Atkins GB, Horlein A, Glass CK, Rosenfeld MG, and Lazar MA (1996) A nuclear hormone receptor corepressor mediates transcriptional silencing by receptors with distinct repression domains. Mol Cell Biol 16: 5458-5465

    • ↵23. Krey G, Keller H, Mahfoudi A, Medin J, Ozato K, Dreyer C, and Wahli W (1993) Xenopus peroxisome proliferator activated receptors: genomic organization, response element recognition, heterodimer formation with retinoid X receptor and activation by fatty acids. J Steroid Biochem Mol Biol 47: 65-73

    • ↵24. Desvergne B and Wahli W (1999) Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr Rev 20: 649-688

    • ↵25. Bastie C, Holst D, Gaillard D, Jehl-Pietri C, and Grimaldi PA (1999) Expression of peroxisome proliferator-activated receptor PPARdelta promotes induction of PPARgamma and adipocyte differentiation in 3T3C2 fibroblasts. J Biol Chem 274: 21920-21925

    • ↵26. Di-Poi N, Tan NS, Michalik L, Wahli W, and Desvergne B (2002) Antiapoptotic role of PPARbeta in keratinocytes via transcriptional control of the Akt1 signaling pathway. Mol Cell 10: 721-733

    • ↵27. Di-Poi N, Michalik L, Tan NS, Desvergne B, and Wahli W (2003) The anti-apoptotic role of PPARbeta contributes to efficient skin wound healing. J Steroid Biochem Mol Biol 82: 257-265

    • ↵28. Mandard S, Zandbergen F, Tan NS, Escher P, Patsouris D, Koenig W, Kleemann R, Bakker A, Veenman F, Wahli W, et al. (2004) The direct peroxisome proliferator-activated receptor target fasting-induced adipose factor (FIAF/PGAR/ANGPTL4) is present in blood plasma as a truncated protein that is increased by fenofibrate treatment. J Biol Chem 279: 34411-34420

    • ↵29. Holst D, Luquet S, Kristiansen K, and Grimaldi PA (2003) Roles of peroxisome proliferator-activated receptors delta and gamma in myoblast transdifferentiation. Exp Cell Res 288: 168-176

    • ↵30. Luquet S, Lopez-Soriano J, Holst D, Fredenrich A, Melki J, Rassoulzadegan M, and Grimaldi PA (2003) Peroxisome proliferator-activated receptor delta controls muscle development and oxidative capability. FASEB J 17: 2299-2301

    • ↵31. Akiyama TE, Lambert G, Nicol CJ, Matsusue K, Peters JM, Brewer HB Jr, and Gonzalez FJ (2004) Peroxisome proliferator-activated receptor beta/delta regulates very low density lipoprotein production and catabolism in mice on a Western diet. J Biol Chem 279: 20874-20881

    • ↵32. Barak Y, Liao D, He W, Ong ES, Nelson MC, Olefsky JM, Boland R, and Evans RM (2002) Effects of peroxisome proliferator-activated receptor delta on placentation, adiposity, and colorectal cancer. Proc Natl Acad Sci USA 99: 303-308

    • ↵33. Harman FS, Nicol CJ, Marin HE, Ward JM, Gonzalez FJ, and Peters JM (2004) Peroxisome proliferator-activated receptor-delta attenuates colon carcinogenesis. Nat Med 10: 481-483

    • ↵34. Kim DJ, Bility MT, Billin AN, Willson TM, Gonzalez FJ, and Peters JM (2006) PPARbeta/delta selectively induces differentiation and inhibits cell proliferation. Cell Death Diff 13: 53-60

    • ↵35. Michalik L, Desvergne B, Tan NS, Basu-Modak S, Escher P, Rieusset J, Peters JM, Kaya G, Gonzalez FJ, Zakany J, et al. (2001) Impaired skin wound healing in peroxisome proliferator-activated receptor (PPAR)alpha and PPARbeta mutant mice. J Cell Biol 154: 799-814

    • ↵36. Peters JM, Lee SS, Li W, Ward JM, Gavrilova O, Everett C, Reitman ML, Hudson LD, and Gonzalez FJ (2000) Growth, adipose, brain, and skin alterations resulting from targeted disruption of the mouse peroxisome proliferator-activated receptor beta(delta). Mol Cell Biol 20: 5119-5128

    • ↵37. Michalik L, Desvergne B, Basu-Modak S, Tan NS, and Wahli W (2000) Nuclear hormone receptors and mouse skin homeostasis: implication of PPARbeta. Horm Res 54: 263-268

    • ↵38. Tan NS, Michalik L, Desvergne B, and Wahli W (2003) Peroxisome proliferator-activated receptor (PPAR)-beta as a target for wound healing drugs: what is possible? Am J Clin Dermatol 4: 523-530

    • ↵39. Desvergne B, Michalik L, and Wahli W (2004) Be fit or be sick: peroxisome proliferator-activated receptors are down the road. Mol Endocrinol 18: 1321-1332

    • ↵40. Lee CH, Chawla A, Urbiztondo N, Liao D, Boisvert WA, Evans RM, and Curtiss LK (2003) Transcriptional repression of atherogenic inflammation: modulation by PPARdelta. Science 302: 453-457

    • ↵41. Li AC, Binder CJ, Gutierrez A, Brown KK, Plotkin CR, Pattison JW, Valledor AF, Davis RA, Willson TM, Witztum JL, et al. (2004) Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPARalpha, beta/delta, and gamma. J Clin Investig 114: 1564-1576

  • TABLE 3

    PPARγ

    Receptor nomenclature NR1C3
    Receptor code 4.10.1:FA:1:C3
    Molecular information Hs: 478aa, P37231, chr. 3p251–3
    Rn: 505aa, O88275, chr. 4q424
    Mm: 475aa, P37238, chr. 6 E3-F15
    DNA binding
       Structure Heterodimer, RXR partner
       HRE core sequence AACTAGGNCA A AGGTCA (DR-1)
    Partners RXR (physical, functional) DNA binding6
    Agonists SB-219994 (8.68), LY-510929 (8), AD-5061 (7.7), TZD18 (7.24), L-764406 (7.15), ragaglitazar (7.03), GW0072 (6.96), nTzDpa (6.5), troglitazone (6.27), LY-465608 (6.26), pioglitazone (6.23), fatty acids (6), SB-219993 (5.5), 5-ASA (1.82) [pIC50]7–26. GW1929 (8.84), L-796449 (8.7), GW7845 (8.43), CDDO (8), L-783483 (7.85), L-165461 (7.8), AD5075 (7.66), [3H]AD5075* (7.66), FMOC-l-leucine (∼6), CS-045 (5.8) [pKi]27–32. [3H]AD-5061* (8), farglitazar (7.47), indomethacin (7.38), rosiglitazone* (7.37), [125I]SB-236636* (7.1), [3H]GW2331* (6.52), GW2331 (6.52), KRP-297/MK-0767 (6.49), PAT5A (6.35), MCC555 (∼6.3), Iinoleic acid (5.3), BADGE (4) [pKd]13,15, 34,21,22 ,26,33–43. GW409544 (9.55), GW9578 (6) BVT0.13 (7.52), TAK-559 (7.5), reglitazar (7.08), GW9578 (6), ciglitazone (4.64), KRP-297/MK-0767 (7) [pEC50]13,22,44–49; DRF2519, LG10074, ibuprofen, diclofenac, COOH50–56
    Antagonists GW9662 (8.48), PD068235 (6.1), BADGE (5), SR-202 (3.85) [pIC50]57–59, 42; CDDO-Me (8), LG100641 (6.36) [pKi]32,60; diclofenac55
    Coactivators PGC-2, ARA-70, PGC-1α, PPARGC1B, CREBBP, p300, CITED2, ERAP140, PPARBP, PRMT-2, PIMT, NCOA1, NCOA2, NCOA3, NCOA6, SWI/SNF, PDIP61–76,80–88,137
    Corepressors NRIP1, SAF-B, TAZ, NCOR1, NCOR268,89–94
    Biologically important isoforms PPARγ1 {Hs, Mm}: encoded by eight exons (two of them PPARγ1-specific)2,95,96; PPARγ2 {Hs, Mm, Rn}: N terminus carries 30 additional amino acids encoded by exon B PPARγ2-specific, encoded by seven exons2,95; PPARγ3 {Hs}: gives rise to a protein indistinguishable from PPARγ1 from a distinct promoter—expression restricted to the colon and adipose tissue97; γORF4 {Hs}: read-through in intron 4, encoded protein lacks the LBD, dominant-negative vs. PPARγ, expressed in tumor cell lines and tissues3
    Tissue distribution Adipose tissues, lymphoid tissues, colon, liver, and heart {Hs, Mm, Rn} [Northern blot, Western blot, immunohistology]90
    Functional assays BADGE adipogenesis assay using 3T3-L1 and 3T3-F442A cells {Mm}42; induction of apoptotic cell death by measuring lipogenesis in C6 glioma cells {Rn}98; measurement of lipogenesis in C3H10T1/2 cells to determine adipocyte differentiation {Hs}29,35
    Main target genes Activated: FATP {Mm}99, acyl CoA-synthetase {Mm}100,101, aP2 adipocyte lipid-binding protein {Mm}102, Lpl {Mm}103, UCP-1 {Mm}104,105, PEPCK {Mm}106, Apoa2 {Mm}107
    Mutant phenotype Forced expression in hepatocytes induced the classic pattern of PPARγ-mediated gene activation and resulted in steatosis {Mm} [retroviral infection]108; disrupted expression in macrophages {Mm} [transgenesis]109; knockout not viable due to defects in placenta formation {Mm} [knockout]110; conditional knockout in adipocytes causes white and brown adipocytes to be replaced with newly formed PPARγ-positive adipocytes {Mm} [conditional knockout]111; conditional knockout in adipocytes results in lipodystrophy (hypocellularity and hypertrophy), elevated plasma FFAs and TGs, decreased plasma leptin and adiponectin, and insuline resistance in fat and liver {Mm} [conditional knockout]112; conditional knockout in white adipocytes results in retarded growth, severe lipodystrophy (hypocellularity and hypertrophy) and hyperlipidemia {Mm} [conditional knockout]113; conditional knockout in muscle causes progressive insulin resistance combined with increased adipose tissue mass {Mm} [conditional knockout]114,115; conditional knockout in pancreatic β-cells results in significant islet hyperplasia on chow diet, blunted expansion of β-cell mass {Mm} [conditional knockout]116; L466A dominant-negative knockin mutant {Mm} [knockin]117; heterozygous mice have reduced body size and weight, reduced insulin resistance, smaller adipocytes and fat depots {Mm} [knockout]54,118,119
    Human disease Obesity and insulin resistance: associated with a mutation in the ligand-independent activation domain of PPARγ2—increased PPARγ2 mRNA found in obese subjects120–124; insulin resistance, type II diabetes mellitus and hypertension: associated with a mutation of the LBD—improved insulin sensitivity associated with polymorphism (Pro12Ala) in PPARγ246,121,123,125,126; syndrome X or metabolic syndrome: associated with dominant-negative PPARγ mutations125–127; atherosclerosis: increased receptor expression in atherosclerotic lesions, macrophages, and monocytic cell lines123,128; colon cancer: associated with loss-of-function mutations in PPARγ LBD—potential antitumor efficacy of combining RXR and PPARγ agonist129–132; prostate cancer: PPARγ expressed in human prostate adenocarcinomas and cell lines derived from human prostate tumors133; thyroid tumors: the PAX8-PPARγ fusion protein promotes differentiated follicular thyroid neoplasia134–136

    • aa, amino acids; chr., chromosome; HRE, hormone response element; CDDO, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid; BADGE, bisphenol A diglycidyl ether; ASA, aminosalicylic acid; FMOC, fluorenylmethoxycarbonyl; CREBB, cAMP response element binding protein binding protein; PIMT, peroxisome proliferator-activated receptor-interacting protein with methyltransferase domain; SWI/SNF, mating-type switching/sucrose nonfermenting; PDIP, PPARγ-DNA-binding domain-interacting protein; SAF-B, scaffold attachment factor B; TAZ, transcriptional coactivator with postsynaptic density 95/disc-large/zona occludens-binding motif; FATP, fatty acid transport protein; PEPCK, phosphoenolpyruvate carboxykinase; FFA, free fatty acid; TG, triglyceride

    • ↵* Radioligand

    • ↵1. Beamer BA, Negri C, Yen CJ, Gavrilova O, Rumberger JM, Durcan MJ, Yarnall DP, Hawkins AL, Griffin CA, Burns DK, et al. (1997) Chromosomal localization and partial genomic structure of the human peroxisome proliferator activated receptor-gamma (hPPAR gamma) gene. Biochem Biophys Res Commun 233: 756-759

    • ↵2. Greene ME, Blumberg B, McBride OW, Yi HF, Kronquist K, Kwan K, Hsieh L, Greene G, and Nimer SD (1995) Isolation of the human peroxisome proliferator activated receptor gamma cDNA: expression in hematopoietic cells and chromosomal mapping. Gene Expr 4: 281-299

    • ↵3. Sabatino L, Casamassimi A, Peluso G, Barone MV, Capaccio D, Migliore C, Bonelli P, Pedicini A, Febbraro A, Ciccodicola A, et al. (2005) A novel peroxisome proliferator-activated receptor gamma isoform with dominant negative activity generated by alternative splicing. J Biol Chem 280: 26517-26525

    • ↵4. Guardiola-Diaz HM, Rehnmark S, Usuda N, Albrektsen T, Feltkamp D, Gustafsson JA, and Alexson SE (1999) Rat peroxisome proliferator-activated receptors and brown adipose tissue function during cold acclimatization. J Biol Chem 274: 23368-23377

    • ↵5. Zhu Y, Alvares K, Huang Q, Rao MS, and Reddy JK (1993) Cloning of a new member of the peroxisome proliferator-activated receptor gene family from mouse liver. J Biol Chem 268: 26817-26820

    • ↵6. Kliewer SA, Umesono K, Noonan DJ, Heyman RA, and Evans RM (1992) Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors. Nature (Lond) 358: 771-774

    • ↵7. Berger JP, Petro AE, Macnaul KL, Kelly LJ, Zhang BB, Richards K, Elbrecht A, Johnson BA, Zhou G, Doebber TW, et al. (2003) Distinct properties and advantages of a novel peroxisome proliferator-activated protein [gamma] selective modulator. Mol Endocrinol 17: 662-676

    • ↵8. Brooks DA, Etgen GJ, Rito CJ, Shuker AJ, Dominianni SJ, Warshawsky AM, Ardecky R, Paterniti JR, Tyhonas J, Karanewsky DS, et al. (2001) Design and synthesis of 2-methyl-2-[4-(2-[5-methyl-2-aryloxazol-4-yl]ethoxy)phenoxy]propionic acids: a new class of dual PPARalpha/gamma agonists. J Med Chem 44: 2061-2064

    • ↵9. Chakrabarti R, Vikramadithyan RK, Misra P, Hiriyan J, Raichur S, Damarla RK, Gershome C, Suresh J, and Rajagopalan R (2003) Ragaglitazar: a novel PPAR alpha PPAR gamma agonist with potent lipid-lowering and insulin-sensitizing efficacy in animal models. Br J Pharmacol 140: 527-537

    • ↵10. Ebdrup S, Pettersson I, Rasmussen HB, Deussen HJ, Frost Jensen A, Mortensen SB, Fleckner J, Pridal L, Nygaard L, and Sauerberg P (2003) Synthesis and biological and structural characterization of the dual-acting peroxisome proliferator-activated receptor alpha/gamma agonist ragaglitazar. J Med Chem 46: 1306-1317

    • ↵11. Elbrecht A, Chen Y, Adams A, Berger J, Griffin P, Klatt T, Zhang B, Menke J, Zhou G, Smith RG, et al. (1999) L-764406 is a partial agonist of human peroxisome proliferator-activated receptor gamma. The role of Cys313 in ligand binding. J Biol Chem 274: 7913-7922

    • ↵12. Guo Q, Sahoo SP, Wang PR, Milot DP, Ippolito MC, Wu MS, Baffic J, Biswas C, Hernandez M, Lam MH, et al. (2004) A novel peroxisome proliferator-activated receptor alpha/gamma dual agonist demonstrates favorable effects on lipid homeostasis. Endocrinology 145: 1640-1648

    • ↵13. Henke BR, Blanchard SG, Brackeen MF, Brown KK, Cobb JE, Collins JL, Harrington WW Jr, Hashim MA, Hull-Ryde EA, Kaldor I, et al. (1998) N-(2-benzoylphenyl)-L-tyrosine PPARgamma agonists. 1. Discovery of a novel series of potent antihyperglycemic and antihyperlipidemic agents. J Med Chem 41: 5020-5036

    • ↵14. Kliewer SA, Lenhard JM, Willson TM, Patel I, Morris DC, and Lehmann JM (1995) A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor gamma and promotes adipocyte differentiation. Cell 83: 813-819

    • ↵15. Kliewer SA, Sundseth SS, Jones SA, Brown PJ, Wisely GB, Koble CS, Devchand P, Wahli W, Willson TM, Lenhard JM, et al. (1997) Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. Proc Natl Acad Sci USA 94: 4318-4323

    • ↵16. Nichols JS, Parks DJ, Consler TG, and Blanchard SG (1998) Development of a scintillation proximity assay for peroxisome proliferator-activated receptor gamma ligand binding domain. Anal Biochem 257: 112-119

    • ↵17. Nosjean O and Boutin JA (2002) Natural ligands of PPARgamma: are prostaglandin J(2) derivatives really playing the part? Cell Signal 14: 573-583

    • ↵18. Oberfield JL, Collins JL, Holmes CP, Goreham DM, Cooper JP, Cobb JE, Lenhard JM, Hull-Ryde EA, Mohr CP, Blanchard SG, et al. (1999) A peroxisome proliferator-activated receptor gamma ligand inhibits adipocyte differentiation. Proc Natl Acad Sci USA 96: 6102-6106

    • ↵19. Pickavance LC, Brand CL, Wassermann K, and Wilding JP (2005) The dual PPARalpha/gamma agonist, ragaglitazar, improves insulin sensitivity and metabolic profile equally with pioglitazone in diabetic and dietary obese ZDF rats. Br J Pharmacol 144: 308-316

    • ↵20. Rousseaux C, Lefebvre B, Dubuquoy L, Lefebvre P, Romano O, Auwerx J, Metzger D, Wahli W, Desvergne B, Naccari GC, et al. (2005) Intestinal antiinflammatory effect of 5-aminosalicylic acid is dependent on peroxisome proliferator-activated receptor-gamma. J Exp Med 201: 1205-1215

    • ↵21. Sakamoto J, Kimura, H, Moriyama S, Odaka H, Momose Y, Sugiyama Y, and Sawada H (2000) Activation of human peroxisome proliferator-activated receptor (PPAR) subtypes by pioglitazone. Biochem Biophys Res Commun 278: 704-711

    • ↵22. Sakamoto J, Kimura H, Moriyama S, Imoto H, Momose Y, Odaka H, and Sawada H (2004) A novel oxyiminoalkanoic acid derivative, TAK-559, activates human peroxisome proliferator-activated receptor subtypes. Eur J Pharmacol 495: 17-26

    • ↵23. Soares AF, Nosjean O, Cozzone D, D'Orazio D, Becchi M, Guichardant M, Ferry G, Boutin JA, Lagarde M, and Geloen A (2005) Covalent binding of 15-deoxydelta(12,14)-prostaglandin J(2) to PPARgamma. Biochem Biophys Res Commun 337: 521-525

    • ↵24. Xu HE, Lambert MH, Montana VG, Parks DJ, Blanchard SG, Brown PJ, Sternbach DD, Lehmann JM, Wisely GB, Willson TM, et al. (1999) Molecular recognition of fatty acids by peroxisome proliferator-activated receptors. Mol Cell 3: 397-403

    • ↵25. Xu Y, Rito CJ, Etgen GJ, Ardecky RJ, Bean JS, Bensch WR, Bosley JR, Broderick CL, Brooks DA, Dominianni SJ, et al. (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: 2422-2425

    • ↵26. Young PW, Buckle DR, Cantello BC, Chapman H, Clapham JC, Coyle PJ, Haigh D, Hindley RM, Holder JC, Kallender H, et al. (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: 751-759

    • ↵27. Berger J, Bailey P, Biswas C, Cullinan CA, Doebber TW, Hayes NS, Saperstein R, Smith RG, and 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: 4189-4195

    • ↵28. Berger J, Leibowitz MD, Doebber TW, Elbrecht A, Zhang B, Zhou G, Biswas C, Cullinan CA, Hayes NS, Li Y, et al. (1999) Novel peroxisome proliferator-activated receptor (PPAR) gamma and PPARdelta ligands produce distinct biological effects. J Biol Chem 274: 6718-6725

    • ↵29. Brown KK, Henke BR, Blanchard SG, Cobb JE, Mook R, Kaldor I, Kliewer SA, Lehmann JM, Lenhard JM, Harrington WW, et al. (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: 1415-1424

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Research ArticleSpecial Issue IUPHAR Compendium of the Pharmacology and Classification of the Nuclear Receptor Superfamily 2006

International Union of Pharmacology. LXI. Peroxisome Proliferator-Activated Receptors

Liliane Michalik, Johan Auwerx, Joel P. Berger, V. Krishna Chatterjee, Christopher K. Glass, Frank J. Gonzalez, Paul A. Grimaldi, Takashi Kadowaki, Mitchell A. Lazar, Stephen O'Rahilly, Colin N. A. Palmer, Jorge Plutzky, Janardan K. Reddy, Bruce M. Spiegelman, Bart Staels and Walter Wahli
Pharmacological Reviews December 1, 2006, 58 (4) 726-741; DOI: https://doi.org/10.1124/pr.58.4.5
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