Oleate attenuates palmitate-induced endoplasmic reticulum stress and apoptosis in placental trophoblasts
Bryanne N Colvin1, Mark S Longtine2, Baosheng Chen2
1Department of Pediatrics colvin_b@kids.wustl.edu.
Insights
Palmitate, a common fatty acid, increases trophoblast cell death and endoplasmic reticulum stress in pregnancy. Oleate, however, protects against this toxicity and promotes fat accumulation, suggesting a protective role in placental function.
Area of Science:
- Reproductive Biology
- Cellular Metabolism
- Obstetrics
Background:
- Pre-pregnancy obesity is a growing concern, linked to adverse pregnancy outcomes like gestational diabetes and pre-eclampsia.
- Obese pregnant women have elevated levels of palmitate and oleate, common dietary fatty acids, which interact with placental trophoblasts.
Purpose of the Study:
- To investigate how free fatty acid composition and concentration affect the viability and function of primary human villous trophoblasts.
- To determine the specific effects of palmitate and oleate on trophoblast apoptosis, endoplasmic reticulum (ER) stress, and lipid droplet accumulation.
Main Methods:
- Primary human villous trophoblasts were cultured in vitro.
- Trophoblasts were exposed to varying concentrations of palmitate and oleate, individually and in combination.
- Cell viability, apoptosis (caspase-mediated and CHOP-mediated), ER stress markers, and lipid droplet formation were assessed.
Main Results:
- Palmitate significantly increased syncytiotrophoblast death via caspase-mediated apoptosis and induced endoplasmic reticulum (ER) stress, activating the unfolded protein response and CHOP-mediated apoptosis.
- Oleate alone did not increase cell death or ER stress and led to increased lipid droplet accumulation.
- Equimolar co-exposure of palmitate and oleate abrogated palmitate-induced toxicity, reducing cell death and ER stress, while still increasing lipid droplets.
Conclusions:
- Palmitate is toxic to human syncytiotrophoblasts, inducing ER stress and apoptosis.
- Oleate is not toxic, protects against palmitate-induced toxicity, and promotes lipid accumulation in trophoblasts.
- These findings suggest oleate may mitigate the adverse effects of palmitate in the context of maternal obesity, potentially improving placental function.
Abstract:
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.
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