Sestrin2 alleviates palmitate‐induced endoplasmic reticulum stress, apoptosis, and defective invasion of human trophoblast cells

AbstractProblemMaternal obesity induces elevated saturated fatty acid palmitate levels in the blood and causes pregnancy complications such as gestational diabetes, preeclampsia, fetal growth abnormalities, and stillbirth. Sestrin2, a highly conserved stress‐inducible protein, is involved in the cellular responses of various stress conditions and homeostatic regulation. However, the effects of Sestrin2 on trophoblast cells have not yet been investigated. Here, we investigated the role of Sestrin2 in palmitate‐induced lipotoxicity and its underlying mechanisms in human first‐trimester trophoblast cells (Sw.71).Method of studyMouse placental tissues were obtained from low‐fat diet‐fed mice (n = 14) and high‐fat diet‐fed mice (n = 14) at gestation day 17.5. Sw.71 cells were treated with palmitate or bovine serum albumin as vehicle controls. The role of Sestrin2 in palmitate‐induced lipotoxicity was examined by immunocytochemistry, immunoblot analysis, quantitative real‐time PCR, and invasion assay.ResultsExpression of placental Sestrin2 was elevated in high‐fat diet‐fed dams compared to that of low‐fat diet‐fed dams. Prolonged treatment of Sw.71 cells with palmitate‐induced endoplasmic reticulum (ER) stress‐dependent expressions of Sestrin2 protein and mRNA, and the treatment also triggered apoptosis. Knockdown of Sestrin2 increased palmitate‐mediated ER stress, inflammatory signaling, and apoptosis. Furthermore, Sestrin2 suppressed impaired trophoblast invasion caused by palmitate and attenuated palmitate‐induced ER stress and inflammation via AMPK/mTORC1 pathways.ConclusionOur study provides the relationship between Sestrin2, AMPK/mTORC1 pathway, and trophoblast function, suggesting that Sestrin2 may be a novel potential therapeutic target for the prevention of pregnancy complications.