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-dioxooieana-1,9-dien-28-oic ac id (CDDO), previously reported to have potent differentiating, antiprolifer ative, and antiinflammatory activities, has been identified as a ligand for the peroxisome proliferator-activated receptor gamma (PPAR gamma). CDDO in duces adipocytic differentiation in 3T3-L1 cells, although it is not as pot ent as the full agonist of PPAR gamma, rosiglitazone. Binding studies of CD DO to PPAR gamma using a scintillation proximity assay give a K-i between 1 0(-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 si milar affinity, but is an antagonist. Like other PPAR gamma ligands, CDDO s ynergizes 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 t heir capacity to recruit or displace cofactors of transcriptional regulatio n; CDDO and rosiglitazone both release the nuclear receptor corepressor, NC oR, from PPAR gamma, while CDDO-Me does not. The differences between CDDO a nd rosiglitazone as either partial or full agonists, respectively, are seen in the weaker ability of CDDO to recruit the coactivator CREB-binding prot ein, CBP, to PPAR gamma. Our results establish the triterpenoid CDDO as a m ember of a new class of PPAR gamma ligands.