Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Frankfurt 60438, Germany.
Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Frankfurt 60438, Germany; Structural Genomics Consortium, BMLS, Goethe University Frankfurt, Frankfurt 60438, Germany.
Cell Chem Biol. 2021 Oct 21;28(10):1489-1500.e8. doi: 10.1016/j.chembiol.2021.04.019. Epub 2021 May 13.
Vitamin E exhibits pharmacological effects beyond established antioxidant activity suggesting involvement of unidentified mechanisms. Here, we characterize endogenously formed tocopherol carboxylates and the vitamin E mimetic garcinoic acid (GA) as activators of the peroxisome proliferator-activated receptor gamma (PPARγ). Co-stimulation of PPARγ with GA and the orthosteric agonist pioglitazone resulted in additive transcriptional activity. In line with this, the PPARγ-GA complex adopted a fully active conformation and interestingly contained two bound GA molecules with one at an allosteric site. A co-regulator interaction scan demonstrated an unanticipated co-factor recruitment profile for GA-bound PPARγ compared with canonical PPARγ agonists and gene expression analysis revealed different effects of GA and pioglitazone on PPAR signaling in hepatocytes. These observations reveal allosteric mechanisms of PPARγ modulation as an alternative avenue to PPARγ targeting and suggest contributions of PPARγ activation by α-13-tocopherolcarboxylate to the pharmacological effects of vitamin E.
维生素 E 表现出超越既定抗氧化活性的药理学效应，表明存在未被识别的机制。在这里，我们将内源性形成的生育酚羧酸酯和维生素 E 类似物 Garcinoic 酸 (GA) 表征为过氧化物酶体增殖物激活受体 γ (PPARγ) 的激活剂。GA 和正构激动剂吡格列酮共同刺激 PPARγ 导致转录活性的加性。与此一致，PPARγ-GA 复合物采用了完全活性的构象，有趣的是包含两个结合的 GA 分子，其中一个位于别构部位。共调节剂相互作用扫描显示，与典型的 PPARγ 激动剂相比，GA 结合的 PPARγ 具有出乎意料的共因子募集谱，基因表达分析显示 GA 和吡格列酮对肝细胞中 PPAR 信号的不同影响。这些观察结果揭示了 PPARγ 调节的变构机制，作为针对 PPARγ 的替代途径，并表明α-13-生育酚羧酸酯对 PPARγ 激活的贡献可能是维生素 E 药理学效应的基础。
