LNK promotes granulosa cell apoptosis in PCOS via negatively regulating insulin-stimulated AKT-FOXO3 pathway.
LNK promotes granulosa cell apoptosis in PCOS via negatively regulating insulin-stimulated AKT-FOXO3 pathway.
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LNK 通过负调节胰岛素刺激的 AKT-FOXO3 通路促进 PCOS 颗粒细胞凋亡
DOI：
10.18632/aging.202421
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发表时间：
2021-01-20
期刊：
影响因子：
--
通讯作者：
Zhao X
中科院分区：
文献类型：
--
作者：
Tan M;Cheng Y;Zhong X;Yang D;Jiang S;Ye Y;Ding M;Guan G;Yang D;Zhao X
背景资料：多囊卵巢综合征（PCOS）常伴有胰岛素抵抗，与卵巢颗粒细胞凋亡增加密切相关。LNK是胰岛素信号通路的重要调节因子。当胰岛素与受体结合时，PI 3 K/AKT/FOXO信号通路被激活，FOXO从细胞核易位到细胞质，从而抑制促凋亡基因的表达。方法：收集多囊卵巢综合征患者的卵泡颗粒细胞，研究LNK、细胞凋亡与胰岛素抵抗的关系。KGN细胞经历LNK过表达/沉默和胰岛素刺激。用免疫印迹和免疫荧光法研究AKT/FOXO 3通路。采用LNK基因敲除小鼠研究LNK在PCOS发病机制中的作用。结果：PCOS组LNK水平高于对照组。LNK与颗粒细胞凋亡和胰岛素抵抗呈正相关，与卵母细胞成熟率呈负相关。KGN细胞中LNK过表达抑制胰岛素诱导的AKT/FOXO 3信号通路，导致FOXO 3核转位，促进颗粒细胞凋亡。LNK基因敲除可部分恢复PCOS小鼠的动情周期并改善糖代谢。结论：LNK通过AKT/FOXO 3途径与胰岛素抵抗和颗粒细胞凋亡密切相关。LNK基因敲除可部分恢复PCOS小鼠的动情周期，改善糖代谢，提示LNK可能成为临床治疗PCOS的潜在生物学靶点。
Background: Polycystic ovary syndrome (PCOS), which is often accompanied by insulin resistance, is closely related to increased apoptosis of ovarian granulosa cells. LNK is an important regulator of the insulin signaling pathway. When insulin binds to the receptor, the PI3K/AKT/FOXO signaling pathway is activated, and FOXO translocates from the nucleus to the cytoplasm, thereby inhibiting the expression of pro-apoptotic genes. Methods: Granulosa cells were collected from PCOS patients to investigate the relationship between LNK, cell apoptosis and insulin resistance. KGN cells underwent LNK overexpression/silence and insulin stimulation. The AKT/FOXO3 pathway was studied by western blot and immunofluorescence. LNK knockout mice were used to investigate the effect of LNK on the pathogenesis of PCOS. Results: The level of LNK was higher in PCOS group than control group. LNK was positively correlated with granulosa cell apoptosis and insulin resistance, and negatively correlated with oocyte maturation rate. LNK overexpression in KGN cells inhibited insulin-induced AKT/FOXO3 signaling pathway, causing nucleus translocation of FOXO3 and promoting granulosa cell apoptosis. LNK knockout partially restored estrous cycle and improved glucose metabolism in PCOS mice. Conclusions: LNK was closely related to insulin resistance and apoptosis of granulosa cells via the AKT/FOXO3 pathway. LNK knockout partially restored estrous cycle and improved glucose metabolism in PCOS mice, suggesting LNK might become a potential biological target for the clinical treatment of PCOS.
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DOI：
10.1016/j.bbrc.2017.05.057
发表时间：
2017-08-19
影响因子：
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30.8
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van Duijn, Cornelia M.
全基因组关联研究确定了多囊卵巢综合征的八个新风险位点
影响因子：
30.8
作者：
Shi, Yongyong;Zhao, Han;Chen, Zi-Jiang
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FOXO的转录因素和长期生活。
影响因子：
--
作者：
Murtaza G;Khan AK;Rashid R;Muneer S;Hasan SMF;Chen J
通讯作者：
Chen J