Long chain PUFA transport in human term placenta.

Introduction Docosahexanoic (DHA) and arachidonic (ARA) acids are important for proper fetal development and accumulate in the fetus during gestation. They cannot be synthesized by the fetus and must be gained instead from the maternal blood supply via the syncytiotrophoblast, the transporting epithelium of the placenta. Cell biological experiments suggest that both membraneassociated placental plasma membrane fatty acid-binding protein (pFABPpm) and fatty acid transport protein (FATP) 4 are involved in DHA uptake while fatty acid-binding proteins (FABP) are thought to be involved in intracellular trafficking of longchain fatty acids. FABP1, 3, and 4 have been detected in the syncytiotrophoblast and there is experimental and theoretical evidence to suggest that these three FABP are under the control of hypoxia inducible factor (HIF), perhaps playing a role in fetal protection from hypoxia. Biophysical measurements reveal these FABP have a higher affinity for DHA over ARA but that affinities for both are lower than those of nonessential fatty acids. Recent research is beginning to uncover the mechanisms of DHA and ARA transmembrane and intracellular transport in the placenta, and it is suggested that maternal health and nutrition during pregnancy could be important in determining fatty acid transport and binding protein expression and, thereby, essential fatty acid delivery to the fetus. Long-chain PUFA ARA [20:4(n-6)] and DHA [22:6(n-3)] cannot be synthesized by the developing fetus and instead must be gained in adequate supply from the maternal diet for proper development. Prostaglandin E2, important in the normal development of many organs and cells (particularly the central nervous system), is synthesized from ARA as indeed are many eicosanoids (1–5). DHA, meanwhile, is essential for development of the fetal brain and retina and recent reviews, assessing the impact of dietary fatty acids on fetal development (6,7), have led to recommendations of DHA supplementation for pregnant mothers (8). DHA and ARA are metabolites of the essential dietary fatty acids a-linolenic and linoleic, respectively; generation of both metabolites involves elongases and desaturases (9). Because the ability of the fetus and human placenta to desaturate and elongate fatty acids is limited (10), the fetal demand for DHA and ARA has to be satisfied by the mother and their transport to the fetus provided by the placenta. Within the human placenta, the syncytiotrophoblast keeps maternal and fetal circulation separate while allowing nutrient exchange (Fig. 1A). This multinuclear transporting epithelium derives from mononuclear cytotrophoblast cells that in turn derive from the fertilized egg. The syncytiotrophoblast is polarized and consists of a microvillous membrane (MVM) facing the maternal blood and a basal membrane facing the fetal blood (Fig. 1B) (11). DHA and ARA accumulate in the fetus during pregnancy by a process described as biomagnification. More recently, a human in vivo study using oral doses of C-labeled fatty acids showed placenta:maternal DHA concentrations were significantly higher than those of palmitic, oleic, and linoleic acids (12). The question remains, therefore: how does the placenta achieve this selective uptake of essential PUFA? Unesterified fatty acid cellular entry and exit has long been debated (13). Although it is argued that fatty acids can flip flop across membranes (14), a membrane-associated protein has also been directly implicated in this process (15). Indeed, linoleic acid uptake by cultured cytotrophoblast cells is a saturable mechanism indicating the involvement of facilitating proteins, not solely simple diffusion (16). This short review article assesses recent studies of membraneassociated and -intracellular proteins expressed in the placenta and capable of binding and transporting fatty acids, focusing on the essential fatty acids DHA and ARA.