Lysophosphatidic acid is associated with oocyte maturation by enhancing autophagy via PI3K-AKT-mTOR signaling pathway in granulosa cells

Abstract

BackgroundFolliculogenesis is a complex network of interacting cellular signals between somatic cells and oocytes. Many components in ovarian follicular fluid (FF) dynamically change during folliculogenesis and play a positive role in oocyte maturation. Previous studies have reported that lysophosphatidic acid (LPA) promotes cumulus cell expansion, oocyte nuclear maturation, and in vitro maturation of oocytes.ResultsInitially, the expression of LPA was raised in matured FF significantly (P < 0.0001). Then, 10 μM LPA treated for 24 h in human granulosa cells (KGNs) aggravated cell proliferation, with increased autophagy, and reduced apoptosis. Meanwhile, we demonstrated that LPA mediated cell function through the PI3K-AKT-mTOR signaling pathway as PI3K inhibitor (LY294002) significantly prevented LPA-induced AKT, mTOR phosphorylation and autophagy activation. Such results were also verified by immunofluorescence staining and flow cytometry. In addition, an autophagy inhibitor 3 methyladenine (3MA) could also alleviate the effects of LPA, by activating apoptosis through PI3K-AKT-mTOR pathways. Finally, we found blockade with Ki16425 or knockdown LPAR1, alleviated LPA mediated autophagy activation in KGNs, suggesting that LPA enhances autophagy through activation of the LPAR1 and PI3K-AKT-mTOR signaling pathways.ConclusionThis study demonstrates that increased LPA activated PI3K-Akt-mTOR pathway through LPAR1 in granulosa cells, suppressing apoptosis by enhancing autophagy, which might play a role in oocyte maturation in vivo.