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

Abstract

Problem Maternal 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 study Mouse 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. Results Expression 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. Conclusion Our 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.

SESTRINs: Emerging Dynamic Stress-Sensors in Metabolic and Environmental Health

“…Metabolic dysregulation induces Sestrins as a defense mechanism against obesity and metabolic diseases (Lee et al, 2012;Parmigiani and Budanov, 2016;Dalina et al, 2018). Important key features of cellular function are the regulation of insulin sensitivity, lipid/fatty acid (FA) metabolism, ER stress, and autophagy (Lee et al, 2012(Lee et al, , 2020Park et al, 2014). Glucose starvation, ER stress, amino acid deprivation and mitochondrial dysfunction induces Sestrins as a protective mechanism (Park et al, 2014;Ro et al, 2015;Ye et al, 2015;Ding et al, 2016;Garaeva et al, 2016;Saveljeva et al, 2016).…”

Sestrin2 as a gatekeeper of cellular homeostasis: Physiological effects for the regulation of hypoxia‐related diseases

“…Conversely, overexpressing SESN2 in dendritic cells (DCs) decreased their apoptosis rate and inhibited ER stress‐related protein translation. Consistent with these findings, Lee et al 38 disclosed that SESN2 suppressed impaired trophoblast invasion caused by palmitate and attenuated palmitate‐induced ER stress; conversely, knockdown of SESN2 increased palmitate‐mediated ER stress, inflammatory signalling and apoptosis. Moreover, a recent study proved that glucose starvation caused both energy deficiency and activation of ER stress, in which SESN2 protected cells from glucose starvation‐induced cell death 40 .…”

“…Bruening et al 37 found that the upregulation of SESN2 was associated with the expression of ER stress markers ATF4, ATF3 and C/EBP‐homologous protein (CHOP) in cancer cells. Another study reported that SESN2 inhibited ER stress and inflammation through the AMPK/mTORC1 pathways 38 …”

mTOR-Dependent Role of Sestrin2 in Regulating Tumor Progression of Human Endometrial Cancer

“…Protein levels of SESN2 are induced upon chronic activation of mTORC1, which subsequently inhibit mTORC1 activation [ 12 , 20 , 24 ]. To evaluate the regulatory effect of SESN2 on the mTORC1 pathway, lentiviral vectors expressing short hairpin RNAs (shRNAs) against human SESN2 or control were transduced into HEC-1A and Ishikawa cells.…”

“…Sestrins (SESNs) are a highly conserved protein family comprising SESN1, SESN2, and SESN3 in mammals, and can be induced by various cellular stresses including DNA damage, increased ROS, hypoxia, and ER stress [ 12 , 16 , 17 , 18 ]. SESN2 maintains metabolic homeostasis and prevents age- and obesity-related pathologies by inhibiting ROS accumulation and the mTORC1 pathway [ 12 , 18 , 19 , 20 ]. SESN2 , which is homologous to the SESN1 , is induced by genotoxic and oxidative stresses in a p53-dependent manner [ 19 , 21 ], while SESN2 induction in response to hypoxia and ER stress is p53-independent [ 12 , 22 ].…”