A synthetic triterpenoid, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), is a ligand for the peroxisome proliferator-activated receptor gamma.
A novel synthetic triterpenoid, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), previously reported to have potent differentiating, antiproliferative, and antiinflammatory activities, has been identified as a ligand for the peroxisome proliferator-activated receptor gamma (PPARgamma). CDDO induces adipocytic differentiation in 3T3-L1 cells, although it is not as potent as the full agonist of PPARgamma, rosiglitazone. Binding studies of CDDO to PPARgamma using a scintillation proximity assay give a Ki between 10(-8) to 10(-7) M. In transactivation assays, CDDO is a partial agonist for PPARgamma. The methyl ester of CDDO, CDDO-Me, binds to PPARgamma with similar affinity, but is an antagonist. Like other PPARgamma ligands, CDDO synergizes with a retinoid X receptor (RXR)-specific ligand to induce 3T3-L1 differentiation, while CDDO-Me is an antagonist in this assay. The partial agonism of CDDO and the antagonism of CDDO-Me reflect the differences in their capacity to recruit or displace cofactors of transcriptional regulation; CDDO and rosiglitazone both release the nuclear receptor corepressor, NCoR, from PPARgamma, while CDDO-Me does not. The differences between CDDO and rosiglitazone as either partial or full agonists, respectively, are seen in the weaker ability of CDDO to recruit the coactivator CREB-binding protein, CBP, to PPARgamma. Our results establish the triterpenoid CDDO as a member of a new class of PPARgamma ligands.
Wang
Y
Y
Department of Pharmacology, Dartmouth Medical School and Dartmouth College, Hanover, New Hampshire 03755, USA.
Porter
W W
WW
Suh
N
N
Honda
T
T
Gribble
G W
GW
Leesnitzer
L M
LM
Plunket
K D
KD
Mangelsdorf
D J
DJ
Blanchard
S G
SG
Willson
T M
TM
Sporn
M B
MB
D016475:3T3 Cells; D017667:Adipocytes / Q000166:cytology; D000818:Animals; D050882:CREB-Binding Protein; D002454:Cell Differentiation / Q000187:drug effects; D004357:Drug Synergism; D008024:Ligands; D008745:Methylation; D051379:Mice; D009539:Nicotinic Acids / Q000494:pharmacology; D009687:Nuclear Proteins / Q000378:metabolism; D056971:Nuclear Receptor Co-Repressor 1; D009828:Oleanolic Acid / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D047488:Retinoid X Receptors; D000077154:Rosiglitazone; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015533:Transcriptional Activation
C116817:2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; D008024:Ligands; C539128:Ncor1 protein, mouse; D009539:Nicotinic Acids; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D047488:Retinoid X Receptors; D013764:Tetrahydronaphthalenes; D013844:Thiazoles; D045162:Thiazolidinediones; D015534:Trans-Activators; D014157:Transcription Factors; D000077154:Rosiglitazone; D009828:Oleanolic Acid; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse; C095104:LG 100268