PPARβ/δ activation protects against corticosterone-induced ER stress in astrocytes by inhibiting the CpG hypermethylation of microRNA-181a
PPARβ/δ activation protects against corticosterone-induced ER stress in astrocytes by inhibiting the CpG hypermethylation of microRNA-181a
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DOI：
10.1016/j.neuropharm.2016.10.022
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发表时间：
2017-02
影响因子：
4.7
通讯作者：
J. Ji;Xiao-ning Zeng;Lu-Lu Cao-Lu;Ling Zhang;Zhan Zhao;Dan-dan Yang;Xiulan Sun
中科院分区：
文献类型：
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作者：
J. Ji;Xiao-ning Zeng;Lu-Lu Cao-Lu;Ling Zhang;Zhan Zhao;Dan-dan Yang;Xiulan Sun
越来越多的证据表明过氧化物酶体增殖物激活受体（PPARs）在体内和体外的各种神经退行性疾病模型中发挥神经保护作用。然而，其潜在机制仍不清楚。星形胶质细胞的增殖是神经发育的关键过程，在穿透伤后神经组织的再生中起着重要作用。皮质酮可显著降低体外培养的大鼠海马星形胶质细胞胶质细胞酸性蛋白（GFAP）的表达，导致星形胶质细胞功能障碍。我们的研究发现皮质酮处理导致星形胶质细胞损伤并降低了PPARβ/δ的表达。GW 0742是一种选择性和高亲和力的PPARβ/δ激动剂，可减轻皮质酮诱导的星形胶质细胞损伤，但也可显著逆转内质网（ER）应激中两种主要蛋白GRP 78和CHOP表达的增加。此外，GW 0742降低caspase-12和切割caspase-3的水平，从而保护星形胶质细胞免受皮质酮诱导的星形胶质细胞凋亡。我们随后证实GRP 78是microRNA-181 a的靶基因，并发现PPARβ/δ激活可增加microRNA-181 a水平。最后，我们证明了GW 0742激活的PPARβ/δ显著抑制了星形胶质细胞中DNA甲基转移酶的活性和表达，并减少了皮质酮诱导的microRNA-181 a1的CpG岛超甲基化。因此，本研究首次揭示了PPARβ/δ激活抑制CpG岛高甲基化相关的microRNA-181 a沉默，从而保护星形胶质细胞免受ER应激诱导的损伤。我们的研究结果表明，星形胶质细胞中的PPARβ/δ活化可能是调节ER应激诱导的星形胶质细胞损伤的一个有希望的靶点。
Increasing evidence indicates that peroxisome proliferator-activated receptors (PPARs) play neuroprotective roles in various neurodegenerative disease modelsin vivoandin vitro. However, the underlying mechanisms remain unclear. Astrocyte proliferation is a key process in neural development and plays significant roles in the regeneration of neural tissue after a penetrating injury. Corticosterone can significantly reduce the expression of glial fibrillary acid protein (GFAP) in cultured rat hippocampal astrocytesin vitro, and induce astrocytic dysfunction. Our research found that corticosterone treatment resulted in astrocyte damage and reduced the expression of PPARβ/δ. GW0742, a selective and high-affinity PPARβ/δ agonist, attenuated the corticosterone-induced astrocyte damage, but also significantly reversed the increase in the expression of GRP78 and CHOP, the two predominant proteins in endoplasmic reticulum (ER) stress. Moreover, GW0742 decreased the levels of caspase-12 and cleaved caspase-3, thereby protecting astrocytes against corticosterone-induced astrocyte apoptosis. We then confirmed that GRP78 was a target gene of microRNA-181a and found that PPARβ/δ activation increased microRNA-181a levels. Finally, we demonstrated that PPARβ/δ activation by GW0742 noticeably inhibited the activities and expression of DNA methyltransferases, and reduced the corticosterone-induced CpG island hypermethylation of microRNA-181a1 in astrocytes. Therefore, the present study is the first to reveal that PPARβ/δ activation suppresses CpG island hypermethylation-associated silencing of microRNA-181a and thereby protects against ER stress-induced damage in astrocytes. Our findings suggest that PPARβ/δ activation in astrocytes might be a promising target for regulating ER stress-induced astrocytic injury.