Overexpression of Lnk in the Ovaries Is Involved in Insulin Resistance in Women With Polycystic Ovary Syndrome
Overexpression of Lnk in the Ovaries Is Involved in Insulin Resistance in Women With Polycystic Ovary Syndrome
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卵巢中 Lnk 的过度表达与多囊卵巢综合征女性的胰岛素抵抗有关
DOI：
10.1210/en.2016-1234
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发表时间：
2016-10-01
期刊：
影响因子：
4.8
通讯作者：
Zhao, Xiaomiao
中科院分区：
文献类型：
--
作者：
Hao, Meihua;Yuan, Feng;Zhao, Xiaomiao
多囊卵巢综合征（PCOS）的进展涉及异常的胰岛素信号传导。含SH 2结构域的衔接蛋白（Lnk）可能是胰岛素信号通路的重要调节因子。我们研究了Lnk是否参与胰岛素抵抗（IR）。从2011年6月至2012年2月，37名女性接受腹腔镜手术，从中山大学孙逸仙纪念医院妇科纳入。采用免疫组织化学方法检测多囊卵巢和正常卵巢组织标本。卵巢细胞系进行胰岛素刺激和Lnk过表达。表达的Lnk与绿色荧光蛋白标记的胰岛素受体和Histagged insulin receptor substrate 1（IRS 1）进行免疫共沉淀试验，并检测它们在HEK 293 T细胞中的共定位。PCOS伴IR患者的卵巢组织中Lnk的表达高于正常对照组和PCOS不伴IR患者，主要表达于卵泡颗粒细胞、次级卵泡的卵泡液和卵母细胞的血浆以及闭锁卵泡中。Lnk与胰岛素受体和IRS 1共免疫沉淀。Lnk和胰岛素受体/IRS 1的位置在核周围重叠。IR、蛋白激酶B（Akt）和ERK 1/2活性被Lnk过表达抑制，并在胰岛素刺激后进一步抑制，而IRS 1丝氨酸活性增加。胰岛素受体（Tyr 1150/1151）、Akt（Thr 308）和ERK 1/2（Thr 202/Tyr 204）磷酸化降低，而IRS 1（Ser 307）磷酸化随着Lnk过表达而增加。总之，Lnk抑制胰岛素对磷脂酰肌醇3激酶-AKT和MAPK-ERK信号通路的应答。Lnk在PCOS中的高表达提示Lnk可能参与了IR的发生发展。
Polycystic ovary syndrome (PCOS) progression involves abnormal insulin signaling. SH2 domain-containing adaptor protein (Lnk) may be an important regulator of the insulin signaling pathway. We investigated whether Lnk was involved in insulin resistance (IR). Thirty-seven women due to receive laparoscopic surgery from June 2011 to February 2012 were included from the gynecologic department of the Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University. Samples of polycystic and normal ovary tissues were examined by immunohistochemistry. Ovarian cell lines underwent insulin stimulation and Lnk overexpression. Expressed Lnk underwent coimmunoprecipitation tests with green fluorescent protein-labeled insulin receptor and Histagged insulin receptor substrate 1 (IRS1), and their colocalization in HEK293T cells was examined. Ovarian tissues from PCOS patients with IR exhibited higher expression of Lnk than ovaries from normal control subjects and PCOS patients without IR; mainly in follicular granulosa cells, the follicular fluid and plasma of oocytes in secondary follicles, and atretic follicles. Lnk was coimmunoprecipitated with insulin receptor and IRS1. Lnk and insulin receptor/IRS1 locations overlapped around the nucleus. IR, protein kinase B (Akt), and ERK1/2 activities were inhibited by Lnk overexpression and inhibited further after insulin stimulation, whereas IRS1 serine activity was increased. Insulin receptor (Tyr1150/1151), Akt (Thr308), and ERK1/2 (Thr202/Tyr204) phosphorylation was decreased, whereas IRS1 (Ser307) phosphorylation was increased with Lnk overexpression. In conclusion, Lnk inhibits the phosphatidylinositol 3 kinase-AKT and MAPK-ERK signaling response to insulin. Higher expression of Lnk in PCOS suggests that Lnk probably plays a role in the development of IR.