Unsaturated fatty acids protect trophoblast cells from saturated fatty acid-induced autophagy defects

Hong, Yeji; Ahn, Hyo-Ju; Shin, Jongdae; Lee, Joon‐Hyung; Kim, Jin‐Hoi; Park, Hwan‐Woo; Lee, Sung Ki

doi:10.1016/j.jri.2017.12.001

Cited by 17 publications

(17 citation statements)

References 44 publications

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“…Invasive ability was reduced in palmitate‐treated Sestrin2‐knockdown cells compared to that of palmitate‐treated control cells, suggesting that a protective role of Sestrin2 in trophoblast invasion. Our previous study indicated that reduced invasive ability of trophoblast cells by palmitate treatment was associated with regulation of MMP‐2 and MMP‐9 . Here, we found that MMP‐2 and MMP‐9 expressions were reduced in palmitate‐treated Sestrin2‐knockdown cells compared to those of palmitate‐treated control cells.…”

Section: Discussionsupporting

confidence: 48%

“…*P < .05 (Student's t test) study indicated that reduced invasive ability of trophoblast cells by palmitate treatment was associated with regulation of MMP-2 and MMP-9. 26 Here, we found that MMP-2 and MMP-9 expressions were reduced in palmitate-treated Sestrin2-knockdown cells compared to those of palmitate-treated control cells. Our data thus implies that Sestrin2 regulates MMPs of trophoblast cells directly or indirectly.…”

Section: Discussionmentioning

confidence: 55%

“…Based on our previous findings which revealed that invasion ability of Sw.71 cells decreased when treated with palmitate, we hypothesized that the protective effect of Sestrin2 was related to the invasive ability of trophoblast cells. To examine the effects of Sestrin2 on the invasive ability of Sw.71 cells in palmitate‐treated conditions, we knocked down the Sestrin2 gene and proceeded with an invasion assay in vitro.…”

Section: Resultsmentioning

confidence: 93%

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

Lee

Shin

Hong

et al. 2020

American J Rep Immunol

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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.

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Section: Discussionsupporting

confidence: 48%

Section: Discussionmentioning

confidence: 55%

Section: Resultsmentioning

confidence: 93%

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

Lee

Shin

Hong

et al. 2020

American J Rep Immunol

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“…As hypoxia-reoxygenation is known to be more harmful than hypoxia alone in cardiac cells 31 , it potentially impedes trophoblast invasion via ER stress-mediated autophagy inhibition. Prior studies reveal that lipid-induced ER stress inhibits autophagosome-lysosomal fusion in hepatocytes 32 , and similarly, saturated fatty acids disrupt autophagy flux, leading to inhibition of trophoblast invasion 33 . While the mechanisms still remain unclear, ER stress and autophagy inhibition cooperatively disrupt homeostasis in trophoblasts via impairment of lysosomes, which might play a central role in placenta-related complications such as PE and FGR.…”

Section: Discussionmentioning

confidence: 99%

Endoplasmic reticulum stress disrupts lysosomal homeostasis and induces blockade of autophagic flux in human trophoblasts

Nakashima

Cheng

Kusabiraki

et al. 2019

Sci Rep

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Pregnancy is a stress factor culminating into mild endoplasmic reticulum (ER) stress, which is necessary for placental development. However, excessive or chronic ER stress in pre-eclamptic placentas leads to placental dysfunction. The precise mechanisms through which excessive ER stress impacts trophoblasts are not well understood. Here, we showed that ER stress reduces the number of lysosomes, resulting in inhibition of autophagic flux in trophoblast cells. ER stress also disrupted the translocation of lysosomes to the surface of trophoblast cells, and inhibited lysosomal exocytosis, whereby the secretion of lysosomal-associated membrane protein 1 (LAMP1) into culture media was significantly attenuated. In addition, we found that serum LAMP1 and beta-galactosidase levels were significantly decreased in pre-eclampsia patients compared to normal pregnant women, potentially indicating lysosomal dysfunction through ER stress in pre-eclamptic placentas. Thus, we demonstrated that excessive ER stress essentially disrupts homeostasis in trophoblasts in conjunction with autophagy inhibition by lysosomal impairment.

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“…However, hypoxia, a known inducer of autophagy, 106e108 was increased in placentas of patients with obesity and was accompanied by a concomitant increase in placental markers of autophagy in Gohir et al, 56 albeit by messenger RNA (mRNA) expression and not protein expression as reported in the study by Cohen, et al 105 The genes used as autophagy markers were also different between the 2 studies, with Vsp15 and Vps34 used in the study by Gohir et al 56 and LC3B and p62 in the study by Cohen et al, 105 which may account for differences between the 2 studies. Furthering the case for obesity-inducing defects in autophagy, Hong et al 109 found that the addition of palmitate to human extravillous trophoblasts induced protein aggregates, increased the association of p62 with these protein aggregates, and increased LC3B levels in the cell. 109 However, palmitate decreased the ability of autophagosomes to fuse with lysosomes by examining co-localization of the autophagosome marker LC3B with the lysosome marker LAMP1, 109 suggesting that increases in autophagy-related proteins does not necessarily correspond to increased autophagy function.…”

Section: Autophagymentioning

confidence: 99%

The Influence of Obesity and Associated Fatty Acids on Placental Inflammation

Eastman

Moore

Townsend

et al. 2021

Clinical Therapeutics

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Purpose: Maternal obesity, affecting nearly 1 in 4 pregnancies, is associated with increased circulating saturated fatty acids, such as palmitate. These fatty acids are implicated in placental inflammation, which may in turn exacerbate both maternalefetal tolerance and responses to pathogens, such as group B Streptococcus. In this review, we address the question, "How do obesity and associated fatty acids influence placental inflammation?" Methods: In this narrative review, we searched PubMed and Google Scholar using combinations of the key words placental inflammation or pregnancy and lipids, fatty acids, obesity, palmitate, or other closely related search terms. We also used references found within these articles that may have been absent from our original search queries. We analyzed methods and key results of these articles to compare and contrast their findings, which were occasionally at odds with each other.Findings: Although obesity can be studied as a whole, complex phenomena with in vivo mouse models and human samples from patients with obesity, in vitro modeling often relies on the treatment of cells or tissues with 1 fatty acids and occasionally other compounds (eg, glucose and insulin). We found that palmitate, most commonly used in vitro to recreate hallmarks of obesity, induces apoptosis, oxidative stress, mitochondrial dysfunction, autophagy defects, and inflammasome activation in many placental cell types. We compare this to in vivo models of obesity wherever possible.We found that obesity as a whole may have more complex regulation of these phenomena (apoptosis, oxidative stress, mitochondrial dysfunction, autophagy defects, and inflammasome activation) compared with in vitro models of fatty acid treatment (primarily palmitate) because of the presence of unsaturated fatty acids (ie, oleate), which may have anti-inflammatory effects.Implications: The interaction of unsaturated fatty acids with saturated fatty acids may ameliorate many inflammatory effects of saturated fatty acids alone, which complicates interpretation of in vitro studies that focus on a particular fatty acid in isolation. This complication may explain why certain studies of obesity in vivo have differing outcomes from studies of specific fatty acids in vitro. (Clin Ther.

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Unsaturated fatty acids protect trophoblast cells from saturated fatty acid-induced autophagy defects

Cited by 17 publications

References 44 publications

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

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

Endoplasmic reticulum stress disrupts lysosomal homeostasis and induces blockade of autophagic flux in human trophoblasts

The Influence of Obesity and Associated Fatty Acids on Placental Inflammation

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