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

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  • ↵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

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  • ↵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

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  • ↵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

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