Elevated Levels of Follicular Fatty Acids Induce Ovarian Inflammation via ERK1/2 and Inflammasome Activation in PCOS.

Abstract

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. We aimed to investigate changes in fatty acids and their effects on inflammatory response in the follicular niche of PCOS patients. 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. 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. 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.