Sestrin2 alleviates palmitate-induced endoplasmic reticulum stress, apoptosis, and defective invasion of human trophoblast cells.,American Journal of Reproductive Immunology

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Sestrin2 alleviates palmitate-induced endoplasmic reticulum stress, apoptosis, and defective invasion of human trophoblast cells.
American Journal of Reproductive Immunology ( IF 2.5 ) Pub Date : 2020-02-05 , DOI: 10.1111/aji.13222
Solji Lee ₁ , Jiha Shin ₁ , Yeji Hong ₂ , Seong Min Shin ₁ , Hye Won Shin ₁ , Jongdae Shin _{1,

3} , Sung Ki Lee _{2,

3} , Hwan-Woo Park _{1,

3}

Affiliation

PROBLEM Maternal obesity induces elevated saturated fatty acid palmitate levels in the blood and causes pregnancy complications such as gestational diabetes, preeclampsia, fetal growth abnormalities, and stillbirth. Sestrin2, a highly conserved stress-inducible protein, is involved in the cellular responses of various stress conditions and homeostatic regulation. However, the effects of Sestrin2 on trophoblast cells have not yet been investigated. Here, we investigated the role of Sestrin2 in palmitate-induced lipotoxicity and its underlying mechanisms in human first-trimester trophoblast cells (Sw.71). METHOD OF STUDY Mouse placental tissues were obtained from low-fat diet-fed mice (n = 14) and high-fat diet-fed mice (n = 14) at gestation day 17.5. Sw.71 cells were treated with palmitate or bovine serum albumin as vehicle controls. The role of Sestrin2 in palmitate-induced lipotoxicity was examined by immunocytochemistry, immunoblot analysis, quantitative real-time PCR, and invasion assay. RESULTS Expression of placental Sestrin2 was elevated in high-fat diet-fed dams compared to that of low-fat diet-fed dams. Prolonged treatment of Sw.71 cells with palmitate-induced endoplasmic reticulum (ER) stress-dependent expressions of Sestrin2 protein and mRNA, and the treatment also triggered apoptosis. Knockdown of Sestrin2 increased palmitate-mediated ER stress, inflammatory signaling, and apoptosis. Furthermore, Sestrin2 suppressed impaired trophoblast invasion caused by palmitate and attenuated palmitate-induced ER stress and inflammation via AMPK/mTORC1 pathways. CONCLUSION Our study provides the relationship between Sestrin2, AMPK/mTORC1 pathway, and trophoblast function, suggesting that Sestrin2 may be a novel potential therapeutic target for the prevention of pregnancy complications.

中文翻译：

Sestrin2 可减轻棕榈酸酯诱导的内质网应激、细胞凋亡和人滋养层细胞的侵袭缺陷。

问题母亲肥胖会导致血液中饱和脂肪酸棕榈酸酯水平升高，并导致妊娠并发症，如妊娠糖尿病、先兆子痫、胎儿生长异常和死产。Sestrin2 是一种高度保守的应激诱导蛋白，参与各种应激条件和稳态调节的细胞反应。然而，尚未研究 Sestrin2 对滋养层细胞的影响。在这里，我们研究了 Sestrin2 在棕榈酸酯诱导的脂毒性中的作用及其在人类妊娠早期滋养层细胞 (Sw.71) 中的潜在机制。研究方法小鼠胎盘组织在妊娠第 17.5 天从低脂饮食喂养的小鼠 (n = 14) 和高脂肪饮食喂养的小鼠 (n = 14) 中获得。Sw.71 细胞用棕榈酸酯或牛血清白蛋白作为载体对照处理。通过免疫细胞化学、免疫印迹分析、定量实时 PCR 和侵袭试验检查了 Sestrin2 在棕榈酸酯诱导的脂毒性中的作用。结果与低脂饮食喂养的母鼠相比，高脂饮食喂养的母鼠胎盘 Sestrin2 的表达升高。用棕榈酸盐诱导的内质网 (ER) 应激依赖性表达 Sestrin2 蛋白和 mRNA 对 Sw.71 细胞进行长时间处理，该处理还引发了细胞凋亡。Sestrin2 的敲低增加了棕榈酸酯介导的 ER 应激、炎症信号和细胞凋亡。此外，Sestrin2 通过 AMPK/mTORC1 通路抑制由棕榈酸酯引起的受损滋养层侵袭并减弱棕榈酸酯诱导的 ER 应激和炎症。结论我们的研究提供了 Sestrin2、AMPK/mTORC1 通路和滋养层功能之间的关系，

更新日期：2020-03-30

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