Oleate attenuates palmitate-induced endoplasmic reticulum stress and apoptosis in placental trophoblasts.
Pre-pregnancy obesity is increasingly common and predisposes pregnant women and offspring to gestational diabetes, pre-eclampsia, fetal growth abnormalities and stillbirth. Obese women exhibit elevated levels of the two most common dietary fatty acids, palmitate and oleate, and the maternal blood containing these nutrients bathes the surface of trophoblasts of placental villi in vivo We test the hypothesis that the composition and concentration of free fatty acids modulate viability and function of primary human villous trophoblasts in culture. We found that palmitate increases syncytiotrophoblast death, specifically by caspase-mediated apoptosis, whereas oleate does not cause enhanced cell death. Importantly, exposure to both fatty acids in equimolar amounts yielded no increase in death or apoptosis, suggesting that oleate can protect syncytiotrophoblasts from palmitate-induced death. We further found that palmitate, but not oleate or oleate with palmitate, increases endoplasmic reticulum (ER) stress, signaling through the unfolded protein response, and yielding CHOP-mediated induction of apoptosis. Finally, we show that oleate or oleate plus palmitate both lead to increased lipid droplets in syncytiotrophoblasts, whereas palmitate does not. The data show palmitate is toxic to human syncytiotrophoblasts, through the induction of ER stress and apoptosis mediated by CHOP, whereas oleate is not toxic, abrogates palmitate toxicity and induces fat accumulation. We speculate that our in vitro results offer pathways by which the metabolic milieu of the obese pregnant woman can yield villous trophoblast dysfunction and sub-optimal placental function.
Department of Pediatrics colvin_b@kids.wustl.edu.
Bryanne N
BN
Colvin
Department of Obstetrics and GynecologyWashington University School of Medicine, St Louis, Missouri, USA.
Mark S
MS
Longtine
Department of Obstetrics and GynecologyWashington University School of Medicine, St Louis, Missouri, USA.
Baosheng
B
Chen
Department of Obstetrics and GynecologyWashington University School of Medicine, St Louis, Missouri, USA.|Department of Obstetrics and GynecologyUniversidade Estadual de Campinas, Cidade Universitaria Zeferino Vaz, Campinas, Brazil.
Maria Laura
ML
Costa
Department of Obstetrics and GynecologyWashington University School of Medicine, St Louis, Missouri, USA.
D Michael
DM
Nelson
D017209:Apoptosis / Q000187:drug effects*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005260:Female; D006801:Humans; D019301:Oleic Acid / Q000494:pharmacology*; D010168:Palmitates / Q000494:pharmacology*; D010920:Placenta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D011247:Pregnancy; D015398:Signal Transduction / Q000187:drug effects; D014327:Trophoblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*
D010168:Palmitates; D019301:Oleic Acid