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

被引:162
作者
Wang, YP
Porter, WW
Suh, NJ
Honda, T
Gribble, GW
Leesnitzer, LM
Plunket, KD
Mangelsdorf, DJ
Blanchard, SG
Willson, TM
Sporn, MB [1 ]
机构
[1] Dartmouth Med Sch, Dept Pharmacol, Hanover, NH 03755 USA
[2] Dartmouth Med Sch, Dept Chem, Hanover, NH 03755 USA
[3] Dartmouth Coll, Hanover, NH 03755 USA
[4] Univ Texas, SW Med Ctr, Howard Hughes Med Inst, Dallas, TX 75390 USA
[5] Univ Texas, SW Med Ctr, Dept Pharmacol, Dallas, TX 75390 USA
[6] Univ Texas, SW Med Ctr, Dept Biochem, Dallas, TX 75390 USA
[7] Glaxo Wellcome Inc, Res & Dev, Dept Mol Biochem, Res Triangle Pk, NC 27709 USA
[8] Glaxo Wellcome Inc, Res & Dev, Dept Mol Endocrinol, Res Triangle Pk, NC 27709 USA
[9] Glaxo Wellcome Inc, Res & Dev, Dept Med Chem, Res Triangle Pk, NC 27709 USA
关键词
D O I
10.1210/me.14.10.1550
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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.
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收藏
页码:1550 / 1556
页数:7
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