血清淀粉样蛋白A1在多囊卵巢综合征颗粒细胞胰岛素抵抗中的作用及其机制研究

Insulin resistance of ovarian granulosa cells is one of the key factors for the development of polycystic ovary syndrome (PCOS). However the pathogenesis of insulin resistance in granulosa cells is not fully elucidated. The chronic inflammation accompanying with the elevating cytokines was associated with the insulin resistance. Till now few studies have demonstrated the cytokine serum amyloid A1 (SAA1) was involved in regulating insulin resistance of adipose cells, but the role of SAA1 in the ovary of PCOS is not ever reported. Our previous studies have demonstrated that the SAA1 level was elevated in PCOS. And we have found the excessive cortisol and IL-1β induced SAA1expression in granulosa cells for the first time. Moreover, the concentration of SAA1 in the follicular fluid was correlated positively with genes pertinent to insulin resistance in granulosa cells, but the molecular mechanisms for regulating insulin resistance of granulosa cells in PCOS still need to be further explored. Thus by adopting clinical samples, granulosa cells in vitro culture model and PCOS animal model in this proposed project, we set out to explore the effects of SAA1 on the expression of genes pertinent to insulin resistance in granulosa cells and the underlying mechanisms to further deciphering the mechanisms of insulin resistance in granulosa cells of PCOS and providing some evidences for the diagnosis and treatment for PCOS.

卵巢颗粒细胞胰岛素抵抗是多囊卵巢综合征(PCOS)发生与进展的重要因素，但PCOS颗粒细胞胰岛素抵抗的发病机制仍未完全阐明。慢性炎症反应及伴随升高的炎症因子与胰岛素抵抗密切相关，鲜有报导炎症因子血清淀粉样蛋白A1(Serum amyloid A1,SAA1)参与调控脂肪细胞胰岛素抵抗，但其在卵巢局部的作用未曾报导。申请人前期研究发现PCOS卵巢局部SAA1水平增加，并首次发现卵巢局部过多的皮质醇及IL-1β均可促进颗粒细胞SAA1分泌，同时也发现SAA1水平与颗粒细胞胰岛素抵抗相关基因表达成正相关，但其调控颗粒细胞胰岛素抵抗的具体作用及机制仍不明确。因此本课题拟利用PCOS和对照卵泡液和颗粒细胞等临床样本、颗粒细胞体外培养模型及PCOS模式动物，研究SAA1对颗粒细胞胰岛素抵抗的调控作用及其机制，从而为进一步完善PCOS颗粒细胞胰岛素抵抗的发生机制提供理论依据和PCOS临床诊疗提供新靶点。

多囊卵巢综合征是育龄期女性最常见的生殖内分泌及代谢异常类疾病，受遗传及环境因素共同调控。PCOS卵巢颗粒细胞存在胰岛素抵抗，进而会导致卵巢激素合成异常及排卵障碍。PCOS是一种慢性轻度炎症反应性疾病，其伴随的炎症因子升高参与调控排卵障碍及代谢异常。血清淀粉样蛋白A1（SAA1）主要由肝脏分泌的急性期反应蛋白，已被证明在肝外组织如卵巢、巨噬细胞等表达，并且可能参与调控机体炎症反应、肥胖及代谢综合征及胰岛素抵抗。因此我们提出假说卵巢局部过多的SAA1可能会导致PCOS颗粒细胞胰岛素抵抗，影响疾病的发生与进展。本项目通过收集PCOS临床样本、体外颗粒细胞培养模型及PCOS模式动物等，深入探索了SAA1在卵巢颗粒细胞胰岛素抵抗中的作用及机制。本研究首次明确卵巢颗粒细胞局部可以合成SAA1，并受炎症因子IL-1β及SAA1本身诱导。SAA1在PCOS合并胰岛素抵抗患者血清及卵巢局部水平均显著升高。同时我们也发现卵巢局部过多的SAA1通过与TLR2/4受体结合激活NF-κB信号通路诱导PTEN的表达抑制胰岛素激发的Akt磷酸化，从而导致GLUT4转位异常，最终导致葡萄糖摄取障碍，导致颗粒细胞的胰岛素抵抗。本研究首次阐明卵巢局部存在SAA1生成的正反馈环路，并深入阐明卵巢局部过多的SAA1会导致PCOS颗粒细胞的胰岛素抵抗的分子机制，为PCOS的诊疗奠定理论基础和提供潜在的治疗靶点。在本项目的资助下，共发表SCI论文2篇，其中影响因子＞5分1篇，作为主要参与人获得上海市医学科技一等奖1项，申请专利1项，协助培养硕士研究生1名。