Oleic acid stimulation of amino acid uptake in primary human trophoblast cells is mediated by phosphatidic acid and mTOR signaling

Normal fetal development is critically dependent on optimal nutrient supply by the placenta, and placental amino acid transport has been demonstrated to be positively associated with fetal growth. Mechanistic target of rapamycin (mTOR) is a positive regulator of placental amino acid transporters, such as System A. Oleic acid (OA) has been previously shown to have a stimulatory role on placental mTOR signaling and System A amino acid uptake in primary human trophoblast (PHT) cells. We investigated the mechanistic link between OA and System A activity in PHT. We found that inhibition of mTOR complex 1 or 2, using small interfering RNA to knock down raptor or rictor, prevented OA-stimulated System A amino acid transport indicating the interaction of OA with mTOR. Phosphatidic acid (PA) is a key intermediary for phospholipid biosynthesis and a known regulator of the mTOR pathway; however, phospholipid biosynthetic pathways have not been extensively studied in placenta. We identified placental isoforms of acyl transferase enzymes involved in de novo phospholipid synthesis. Silencing of 1-acylglycerol-3-phosphate-O-acyltransferase-4, an enzyme in this pathway, prevented OA mediated stimulation of mTOR and System A amino acid transport. These data indicate that OA stimulates mTOR and amino acid transport in PHT cells mediated through de novo synthesis of PA. We speculate that fatty acids in the maternal circulation, such as OA, regulate placental functions critical for fetal growth by interaction with mTOR and that late pregnancy hyperlipidemia may be critical for increasing nutrient transfer to the fetus. Placental mechanistic target of rapamycin (mTOR) lipid sensing mechanism which modulates amino acid uptake. De novo synthesis of phosphatidic acid containing an oleic acid (18:1) acyl group stimulates placental mTOR. Activation of mTOR leads to increased System A mediated amino acid uptake.image

Automated summary

Normal fetal development depends on optimal nutrient supply by the placenta, and placental amino acid transport is positively associated with fetal growth. This study investigated the interaction between oleic acid (OA) and mechanistic target of rapamycin (mTOR) in primary human trophoblast (PHT) cells. The findings suggest that OA stimulates mTOR and amino acid transport in PHT cells through de novo synthesis of phosphatidic acid (PA). This lipid sensing mechanism is crucial for placental functions and nutrient transfer to the fetus.