Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, P.R. China.
Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, P.R.China.
FASEB J. 2020 Jul;34(7):9563-9574. doi: 10.1096/fj.202000605RR. Epub 2020 May 29.
Insulin resistance (IR) disrupts ovarian functions in polycystic ovary syndrome (PCOS). The contributing factors remains elusive. High mobility group box 1 (HMGB1), a damage-associated molecular pattern molecule, has been shown to be related to IR and autophagy, respectively, in peripheral tissues. Here, we investigated whether increased HMGB1 contributes to IR in granulosa cells of PCOS patients via induction of aberrant autophagy. Results showed that HMGB1 abundance in the follicular fluid was significantly increased with enhanced autophagy in granulosa cells in PCOS patients with IR. HMGB1 exacerbated autophagy in granulosa cells as evinced by increased LC3B II/I ratio and ATG7 as well as decreased p62, the markers for autophagy. Concurrently, HMGB1 impaired insulin sensitivities by attenuating the abundance of insulin receptor substrate-1, Akt phosphorylation, GLUT4 translocation, and glucose uptake in granulosa cells, which were reversed by blocking autophagy pathways with siRNA-mediated knockdown of ATG7 or with chloroquine and bafilomycin A1, the lysosome inhibitors. In conclusion, our results indicate that increased HMGB1 contributes to IR development in granulosa cells of PCOS patients, which is associated with exacerbation of autophagy by HMGB1. Control of HMGB1 production may be benefical for the improvement of insulin sensitivity in granulosa cells in PCOS.
胰岛素抵抗（IR）会破坏多囊卵巢综合征（PCOS）患者的卵巢功能。但其致病因素仍不清楚。高迁移率族蛋白 B1（HMGB1）是一种损伤相关分子模式分子，已分别被证明与外周组织中的 IR 和自噬有关。在这里，我们研究了 HMGB1 是否通过诱导异常自噬而导致 PCOS 患者的颗粒细胞中出现 IR。结果表明，IR 的 PCOS 患者卵泡液中 HMGB1 含量明显增加，颗粒细胞中的自噬增强。HMGB1 通过增加 LC3B II/I 比值和 ATG7 以及减少自噬标志物 p62，加剧了颗粒细胞中的自噬。同时，HMGB1 通过减弱胰岛素受体底物-1、Akt 磷酸化、GLUT4 易位和葡萄糖摄取，损害了颗粒细胞的胰岛素敏感性，而用 siRNA 介导的 ATG7 敲低或用溶酶体抑制剂氯喹和巴弗洛霉素 A1 阻断自噬途径可逆转这一现象。总之，我们的结果表明，HMGB1 的增加导致了 PCOS 患者颗粒细胞中 IR 的发展，这与 HMGB1 加剧自噬有关。控制 HMGB1 的产生可能有助于改善 PCOS 患者颗粒细胞的胰岛素敏感性。
