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peroxisome proliferator-activated receptor gamma; PPAR-gamma; nuclear receptor subfamily 1 group C member 3 (PPARG, NR1C3)

Function: 1) activated by fatty acids & peroxisome proliferators 2) binds to DNA as heterodimer with RXRA 3) regulates transcription of acyl-CoA oxidase thus peroxisomal beta-oxidation pathway of fatty acids 4) regulates transcription of insulin-responsive genes 5) dUTPase prevents PPAR-RXR heterodimerization [4] 6) interacts with FAM120B (putative) 7) interacts with NOCA7 (ligand-inducible) 8) interacts with NCOA1 LXXLL motifs 9) interacts with TGFB1I1 10) interacts with DNTTIP2 Physiologic roles: [4] 1) adipocyte differentiation 2) down-regulation of inflammation 3) increases fat storage in liver 4) decreases volume of brown fat & white fat 5) increases efficiency of energy metabolism 6) improves insulin sensitivity 7) suppresses weight gain induced by high-fat diet 8) physiologic effects of PPAR-gamma2 may depend upon afferent vagal stimulation from liver to CNS [5] Endogenous ligands (activators) 1) monounsaturated fatty acids a) palmitoleic acid [16:1] (2+) b) oleic acid [18:1] (3+) c) elaidic acid [20:1] (+) 3) polyunsaturated fatty acids a) linoleic acid [18:2, n-6] (+) b) alpha-linolenic acid [18:3, n-3] (2+) c) gamma-linolenic acid [18:3, n-6] (2+) d) dihomo-gamma-linolenic acid [20:3, n-6] (3+) e) arachidonic acid [20:4, n-6] (3+) f) eicosapentaenoic acid [22:5, n-3] (3+) g) docosahexaenoic acid [22:6, n-3] (+/-) 4) eicosanoids a) PGA1 (+) b) PGA2 (+) c) PGD1 (2+) d) PGD2 (2+) e) PGJ2 (3+) f) 15-deoxy-delta 12,14-PGJ2 (3+) g) 9-HODE* h) 13-HODE* * HODE = hydroxyoctadecadienoic acid Coactivators: 1) p300/CBP 2) PPAR-binding protein 3) PGC-1* 4) PGC-2* 5) Ara70* 6) steroid coactivator-1 (SRC-1) 7) NCOA6 > PPARBP [4] * uncertain as to identity of these proteins Corepressors: 1) SMRT/TRAC 2) RIP140 Structure: - belongs to the nuclear hormone receptor family, NR1 subfamily - contains 1 nuclear receptor DNA-binding domain Compartment: - nucleus Alternative splicing: -named isoforms=2 Expression: - adipose tissue (4+) > skeletal muscle, spleen (3+), heart & liver > placenta, lung & ovary - intestine (2+), kidney (+/-) Pathology: - defects in PPARG may be associated with a) severe insulin resistance & marked hypertension b) susceptibility to obesity c) colon cancer d) familial partial lipodystrophy Polymorphism: - variation in PPARG a) is associated with carotid intimal medial thickness 1 b) may influence body mass index c) may influence abdominal body fat distribution Pharmacology: - target of thiazolidinediones (glitazones) which are agonists Exogenous agonists: (peroxisome proliferators) [1] 1) hypolipidemic drugs a) WY-14-643 (2+) b) clofibrate (1+) c) ciprofibrate (1+) d) gemfibrozil (1+) e) GW2331 (2+) 2) non-steroidal anti-inflammatory drugs (NSAIDs) a) indomethacin (3+) b) ibuprofen (1+) c) fenoprofen (1+) d) GW0072 (1+) e) L-764406 (3+) f) L-165041 (1+) 3) thiazolidinediones a) BRL-49653 (3+) b) pioglitazone (2+) c) ciglitazone (2+) d) englitazone (1+) e) KRP-297 (2+) f) MCC-555 (2+) 4) other a) monoethylhexyl phthalate (3+) b) trichloroacetic acid (1+) c) eicosatetraynoic acid (ETYA) (3+) d) LTB4 antagonists 1] MK-571 (2+) 2] LY-171883 (2+)

Related

peroxisome proliferator activated receptor gamma (PPARG/PPARG1/PPARG2) gene retinoid X receptor (RXR)

Useful

thiazolidinedione; glitazone; TZD

General

peroxisome proliferator-activated receptor (PPAR)

Properties

SIZE: entity length = 505 aa MW = 58 kD COMPARTMENT: cell nucleus MOTIF: Ser phosphorylation site {S112} DNA-binding motif SITE: 136-210 MOTIF: Zn finger C4-type SITE: 139-159 EFFECTOR-BOUND: Zn+2 Zn finger C4-type SITE: 176-198 EFFECTOR-BOUND: Zn+2 FAM120B interaction {205-280} binding site SITE: 317-505 FOR-BINDING-OF: ligand MOTIF: binding site SITE: 317-317 FOR-BINDING-OF: agonist binding site SITE: 351-351 FOR-BINDING-OF: agonist binding site SITE: 477-477 FOR-BINDING-OF: agonist binding site SITE: 501-501 FOR-BINDING-OF: agonist

Database Correlations

OMIM correlations MORBIDMAP 601487 UniProt P37231 PFAM correlations

References

  1. UniProt :accession P37231
  2. Journal Watch 20(3):25-26, 2000
  3. Barroso et al Nature 402:880, 1999
  4. Corton JC et al, Central role of peroxisome proliferator-activated receptors in the actions of peroxisome proliferators Ann Rev Pharmacol Toxicol 2000; 40:491 PMID: 10836145
  5. Uno K et al, Neuronal pathway from the liver modulates energy expenditure and systemic insulin sensitivity. Science 2006; 312:1656 PMID: 16778057
  6. Wikipedia; peroxisome proliferator-activated receptor entry http://en.wikipedia.org/wiki/peroxisome_proliferator-activated_receptor
  7. GeneReviews https://www.genecards.org/cgi-bin/carddisp.pl?gene=PPARG
  8. SeattleSNPs http://pga.gs.washington.edu/data/pparg/
  9. SHMPD; The Singapore human mutation and polymorphism database http://shmpd.bii.a-star.edu.sg/gene.php?genestart=A&genename=PPARG
  10. UniProt :accession P37231