Elevated Levels of Follicular Fatty Acids Induce Ovarian Inflammation via ERK1/2 and Inflammasome Activation in PCOS
Elevated Levels of Follicular Fatty Acids Induce Ovarian Inflammation via ERK1/2 and Inflammasome Activation in PCOS
复制标题
PCOS 中卵泡脂肪酸水平升高通过 ERK1/2 和炎症小体激活诱导卵巢炎症
DOI：
10.1210/clinem/dgac281
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发表时间：
2022-05-17
影响因子：
5.8
通讯作者：
Qiao, Jie
中科院分区：
文献类型：
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作者：
Lai, Yuchen;Ye, Zhenhong;Qiao, Jie
多囊卵巢综合征（PCOS）伴有慢性炎症和代谢紊乱。代谢异常是否影响PCOS患者的炎症，其机制尚不清楚。目的探讨多囊卵巢综合征（PCOS）患者卵泡生态位脂肪酸的变化及其对炎症反应的影响。方法本研究招募50例PCOS患者和50例年龄匹配的对照组，收集卵泡液和卵巢壁颗粒细胞。采用人卵巢颗粒细胞系KGN评价油酸刺激对卵巢颗粒细胞的影响。采用液相色谱-串联质谱法测定卵泡脂肪酸水平。用电化学发光法和酶联免疫吸附法检测炎症细胞因子浓度。通过定量聚合酶链反应和免疫印迹法证实OA刺激后炎症相关基因的调控作用。结果PCOS患者卵泡液中3种饱和脂肪酸和8种不饱和脂肪酸含量明显高于对照组。卵泡白细胞介素(IL)-6、IL-8和成熟IL-18浓度在PCOS组显著升高，且与脂肪酸水平呈正相关。此外，OA刺激通过细胞外调节的激酶1/2信号通路上调了KGN细胞中IL-6和IL-8的转录水平。此外，OA处理诱导活性氧产生和炎性体活化，表现为caspase-1活性和成熟IL-18蛋白水平的增强。结论多囊卵巢综合征患者卵泡生态位脂肪酸代谢明显改变。脂肪酸水平升高可在转录水平和翻译后加工中诱导卵巢炎症。
Context Polycystic ovary syndrome (PCOS) is accompanied by chronic inflammation and metabolic disorders. Whether metabolic abnormalities affect inflammation in PCOS or not, the underlying mechanism remains to be clarified. Objective We aimed to investigate changes in fatty acids and their effects on inflammatory response in the follicular niche of PCOS patients. Methods This study recruited 50 PCOS patients and 50 age-matched controls for follicular fluids and ovarian mural granulosa cells collection. The human ovarian granulosa cell line KGN was used for evaluating the effect of oleic acid (OA) stimulation. The levels of follicular fatty acids were measured by liquid chromatography-tandem mass spectrometry. The concentrations of inflammatory cytokines were detected by electrochemiluminescence and enzyme-linked immunosorbent assays. The regulation of inflammation-related genes was confirmed by quantitative polymerase chain reaction and Western blotting after OA stimuli. Results Three saturated fatty acids and 8 unsaturated fatty acids were significantly elevated in follicular fluids of PCOS patients compared to those in controls. The concentrations of follicular interleukin (IL)-6, IL-8, and mature IL-18 were significantly higher in the PCOS group and were positively correlated with the levels of fatty acids. Moreover, OA stimulation upregulated the transcription levels of IL-6 and IL-8 via extracellularly regulated kinase 1/2 signaling pathways in KGN cells. Furthermore, OA treatment induced reactive oxygen species production and inflammasome activation, which is manifested by enhanced caspase-1 activity and mature IL-18 protein level. Conclusion Fatty acid metabolism was significantly altered in the follicular niche of PCOS patients. Elevated levels of fatty acids could induce ovarian inflammation both at the transcriptional level and in posttranslational processing.