Comprehensive analysis of PPARγ agonist activities of stereo-, regio-, and enantio-isomers of hydroxyoctadecadienoic acids
Comprehensive analysis of PPARγ agonist activities of stereo-, regio-, and enantio-isomers of hydroxyoctadecadienoic acids
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羟基十八碳二烯酸立体异构体、区域异构体和对映异构体的 PPARγ 激动剂活性综合分析
DOI：
10.1042/bsr20193767
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发表时间：
2020
影响因子：
4
通讯作者：
Yoshida Yasukazu
中科院分区：
文献类型：
--
作者：
Umeno Aya;Sakashita Mami;Sugino Sakiko;Murotomi Kazutoshi;Okuzawa Tsugumi;Morita Naoki;Tomii Kentaro;Tsuchiya Yuko;Yamasaki Kazuhiko;Horie Masanori;Takahara Kentaro;Yoshida Yasukazu
羟基十八碳二烯酸（HODE）是由亚油酸的氧化和还原产生的。HODE存在多种区域和立体异构体，其体内浓度高于其它脂类。虽然构象异构体可能有不同的生物活性，HODE异构体的细胞内功能的比较分析尚未进行。我们评估了糖尿病治疗靶点过氧化物酶体增殖物激活受体γ（PPARγ）的转录活性，并分析了HODE异构体的PPARγ激动剂活性。12种HODE异构体（9-、10-、12-和13-HODE）在模拟HODE与PPARγ配体结合结构域（LBD）对接时的最低得分基本相似。HODE异构体与PPARγ LBD的直接结合通过梯度光谱（WaterLOGSY）NMR实验观察到的水-配体来确定。相比之下，在双荧光素酶报告基因测定中，9-和13-HODE立体异构体以及12-和13-HODE对映异构体之间的PPARγ激动剂活性存在差异。有趣的是，9-HODE的活性低于其他区域异构体，并且9-（E，E）-HODE倾向于在3 T3-L1细胞成熟过程中降低PPARγ靶基因的表达。此外，10-和12-（Z，E）-HODE，我们以前提出作为早期糖尿病的生物标志物，发挥PPARγ激动剂活性。这些结果表明，所有HODE异构体都具有PPARγ结合亲和力;然而，它们具有不同的PPARγ激动剂活性。我们的研究结果可能有助于了解脂质过氧化产物的生物学功能。
Hydroxyoctadecadienoic acids (HODEs) are produced by oxidation and reduction of linoleates. There are several regio- and stereo-isomers of HODE, and their concentrationsin vivoare higher than those of other lipids. Although conformational isomers may have different biological activities, comparative analysis of intracellular function of HODE isomers has not yet been performed. We evaluated the transcriptional activity of peroxisome proliferator-activated receptor γ (PPARγ), a therapeutic target for diabetes, and analyzed PPARγ agonist activity of HODE isomers. The lowest scores for docking poses of 12 types of HODE isomers (9-, 10-, 12-, and 13-HODEs) were almost similar in docking simulation of HODEs into PPARγ ligand-binding domain (LBD). Direct binding of HODE isomers to PPARγ LBD was determined by water-ligand observed via gradient spectroscopy (WaterLOGSY) NMR experiments. In contrast, there were differences in PPARγ agonist activities among 9- and 13-HODE stereo-isomers and 12- and 13-HODE enantio-isomers in a dual-luciferase reporter assay. Interestingly, the activity of 9-HODEs was less than that of other regio-isomers, and 9-(E,E)-HODE tended to decrease PPARγ-target gene expression during the maturation of 3T3-L1 cells. In addition, 10- and 12-(Z,E)-HODEs, which we previously proposed as biomarkers for early-stage diabetes, exerted PPARγ agonist activity. These results indicate that all HODE isomers have PPARγ-binding affinity; however, they have different PPARγ agonist activity. Our findings may help to understand the biological function of lipid peroxidation products.