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