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 synthetic triterpenoid, 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO), is a ligand for the peroxisome proliferator-activated receptor γ
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DOI：
10.1210/me.14.10.1550
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发表时间：
2000-10-01
影响因子：
--
通讯作者：
Sporn, MB
中科院分区：
文献类型：
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作者：
Wang, YP;Porter, WW;Sporn, MB
一种新型合成三萜类化合物 2-cyano-3,12-dioxooieana-1,9-dien-28-oic 酸 (CDDO) 先前报道具有有效的分化、抗增殖和抗炎活性，现已被鉴定为过氧化物酶体增殖物激活受体 γ (PPAR γ) 的配体。 CDDO 可诱导 3T3-L1 细胞的脂肪细胞分化，尽管它不如 PPAR γ 完全激动剂罗格列酮那么有效。使用闪烁邻近测定法进行 CDDO 与 PPAR gamma 的结合研究得出 K-i 在 10(-8) 至 10(-7) M 之间。在反式激活测定中，CDDO 是 PPAR gamma 的部分激动剂。 CDDO 的甲酯 CDDO-Me 以类似的亲和力与 PPAR gamma 结合，但它是一种拮抗剂。与其他 PPAR γ 配体一样，CDDO 与类视黄醇 X 受体 (RXR) 特异性配体协同作用，诱导 3T3-L1 分化，而 CDDO-Me 是该测定中的拮抗剂。 CDDO的部分激动作用和CDDO-Me的拮抗作用反映了它们招募或取代转录调控辅助因子的能力的差异； CDDO 和罗格列酮均从 PPAR gamma 中释放核受体辅阻遏物 NCoR，而 CDDO-Me 则不会。 CDDO 和罗格列酮分别作为部分或完全激动剂的差异在于 CDDO 将共激活剂 CREB 结合蛋白 CBP 募集到 PPAR γ 的能力较弱。我们的结果确立了三萜 CDDO 是一类新型 PPAR γ 配体的成员。
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.