A synthetic triterpenoid, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), is a ligand for the peroxisome proliferator-activated receptor γ

A novel synthetic triterpenoid, 2-cyano-3,12-dioxooieana-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 (PPAR gamma). CDDO induces adipocytic differentiation in 3T3-L1 cells, although it is not as potent as the full agonist of PPAR gamma, rosiglitazone. Binding studies of CDDO to PPAR gamma using a scintillation proximity assay give a K-i between 10(-8) to 10(-7) M. In transactivation assays, CDDO is a partial agonist for PPAR gamma. The methyl ester of CDDO, CDDO-Me, binds to PPAR gamma with similar affinity, but is an antagonist. Like other PPAR gamma 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 PPAR gamma, 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 PPAR gamma. Our results establish the triterpenoid CDDO as a member of a new class of PPAR gamma ligands.