Receptor nomenclature NR1C3
Receptor code 4.10.1:FA:1:C3
Molecular information Hs: 478aa, P37231, chr. 3p2513
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]726. 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]2732. [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 ,26,3343. 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]13,22,4449; DRF2519, LG10074, ibuprofen, diclofenac, COOH5056
Antagonists GW9662 (8.48), PD068235 (6.1), BADGE (5), SR-202 (3.85) [pIC50]5759, 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, PDIP6176,8088,137
Corepressors NRIP1, SAF-B, TAZ, NCOR1, NCOR268,8994
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 subjects120124; 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 mutations125127; 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 agonist129132; 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 neoplasia134136
  • 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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