Natural ligands of PPARgamma: are prostaglandin J(2) derivatives really playing the part?
The peroxisome proliferator-activated receptor (PPAR) family was discovered from an orphan nuclear receptor approach, and thereafter, three subtypes were identified, namely PPARalpha, PPARbeta or PPARgamma and PPARgamma. The two former seem to regulate lipid homeostasis, whereas the latter is involved, among others, in glucose homeostasis and adipocyte differentiation. PPARs were pharmacologically characterised first using peroxisome proliferators such as clofibrates, which demonstrate moderate affinity (efficiency at micromolar concentrations) and low PPARalpha/delta versus PPARgamma specificity. Hence, several laboratories have started the search for potent and subtype-specific natural PPAR activators. In this respect, prostaglandin (PG)-related compounds were identified as good PPARgamma agonists with varying specificity, the most notable PPAR ligand being 15-deoxy-Delta12-14-PGJ2 (15d-PGJ2). Recently, an oxidized phosphatidylcholine was identified as a potent alternative (patho)physiological natural ligand of PPARgamma. In the present review, we discuss the different PPARgamma-dependent and -independent biological effects of the PG PPARgamma ligands and the concern about their low potency in molecular models as compared with thiazolidinediones (TZDs), a family of potent (nanomolar) synthetic PPARgamma ligands. Finally, the oxidized lipids are presented as a novel and interesting alternative for discovering potent PPARgamma activators in order to understand more in details the implications of PPARgamma in various pathophysiological conditions.
Nosjean
Olivier
O
Pharmacologie Moléculaire et Cellulaire, Institut de Recherches Servier, 125 Chemin de Ronde, 78 290 Croissy-sur-Seine, France.
Boutin
Jean A
JA
D017920:Antiporters / Q000378:metabolism; D016718:Arachidonic Acid / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D008024:Ligands; D019787:Linoleic Acid / Q000378:metabolism; D050356:Lipid Metabolism; D008954:Models, Biological; D008956:Models, Chemical; D027361:Organic Anion Transporters; D010084:Oxidation-Reduction; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D015398:Signal Transduction; D013844:Thiazoles / Q000494:pharmacology; D014157:Transcription Factors / Q000819:agonists*
C097240:15-deoxy-delta(12,14)-prostaglandin J2; D017920:Antiporters; D004268:DNA-Binding Proteins; D008024:Ligands; D027361:Organic Anion Transporters; D018160:Receptors, Cytoplasmic and Nuclear; C503526:SLCO2A1 protein, human; D013844:Thiazoles; D014157:Transcription Factors; D016718:Arachidonic Acid; D019787:Linoleic Acid; D015230:Prostaglandin D2