Novel Roles for Phospholipids in Regulating Placental Function and in the Delivery of DHA to the Fetal Brain.

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PROJECT SUMMARY An adequate placental transfer of lipids is critical for normal fetal growth and brain development, yet the mechanisms involved in placental lipid handling and transport are largely unknown. Many important pregnancy complications such as intrauterine growth restriction (IUGR) and maternal diabetes are associated with disturbances in fetal fat deposition that may contribute to adverse short-and long-term outcomes. Although mechanistic links between placental lipid handling and transport, fetal fat deposition and fetal brain development remain to be established, emerging evidence suggests that these pregnancy complications are associated with altered placental lipid metabolism. The syncytiotrophoblast, the transporting epithelium of the human placenta, mediates the transfer of lipids from the maternal to the fetal circulation. There is now compelling evidence that complex lipid forms are produced in large amounts by the syncytiotrophoblast and are potentially released to the fetus. In particular, primary human trophoblast cells rapidly take up fatty acids and incorporate them to phospholipids. De novo synthesis and remodeling of phospholipids generates a range of biologically active intermediates, including Phosphatidic Acid which regulates mTOR signaling in cancer cells. Phospholipid remodeling generates Lysophosphatidylcholine species containing docosahexaenoic acid (LPC-DHA) which is the predominant form in which DHA is transported across the blood brain barrier, mediated by MajorFacilitator Superfamily Domain Containing 2A (MFSD2a),an LPC-DHA transporter. We found high levels of LPC-DHA in placental tissue and that umbilical vein LPC-DHA levels are higher than maternal circulating concentrations, suggesting that DHA is delivered to the fetus as LPC-DHA. In addition, we discovered that MFSD2a is expressed in the human syncytiotrophoblast basal plasma membrane, consistent with the possibility that this transporter mediates transfer of LPC-DHA to the fetus. These observations provide the premise for our central hypothesis that trophoblast phospholipid synthesis and remodeling are highly active, produces phosphatidic acid (which modulates TOR signaling) and LPC-DHA for transport to the fetus, mediated by MFSD2a. Our hypothesis is supported by compelling preliminary data including evidence that phosphatidic acid regulates placental amino acid transport mediated through mTOR signaling and LPC-DHA is produced in placenta and released to the fetus. We will use human placental tissue, maternal and umbilical blood samples collected from normal and complicated pregnancies, siRNA gene targeting approaches in cultured primary human trophoblast cells incubated in a physiological mixture of 13C-stable isotope labelled fatty acids and trophoblast specific gene targeting in mice to address this hypothesis. These mechanistic placental studies are highly significant because we will use nove approaches to establish that phospholipid synthesis intermediates are important regulators of function and critical mediators of placental transfer of DHA, essential for normal brain development. l