Review: Modelling placental amino acid transfer − From transporters to placental function

Lewis, Rohan M.; Brooks, Suzanne; Crocker, Ian; Glazier, Jocelyn D.; Hanson, Mark A.; Johnstone, Edward D.; Panitchob, Nuttanont; Please, Colin P.; Sibley, Colin P.; Widdows, Kate; Sengers, Bram G.

doi:10.1016/j.placenta.2012.10.010

Cited by 40 publications

(31 citation statements)

References 23 publications

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“…For amino acid transport, and most likely for other nutrients as well, a change in the activity of one transporter cannot be assumed to correspond to an equivalent change in nutrient transport [26]. Computational modelling of these processes may provide an important tool to better understand these processes and to identify the rate-limiting steps, as these will be the best targets for therapeutic interventions [26,27].…”

Section: Placental Structure Function and Regulationmentioning

confidence: 99%

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The Placental Exposome: Placental Determinants of Fetal Adiposity and Postnatal Body Composition

et al. 2013

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Offspring of obese and diabetic mothers are at increased risk of being born with excess adiposity as a consequence of their intrauterine environment. Excessive fetal fat accretion reflects additional placental nutrient transfer, suggesting an effect of the maternal environment on placental function. High plasma levels of particular nutrients in obese and diabetic mothers are likely to be the important drivers of nutrient transfer to the fetus, resulting in excess fat accretion. However, not all offspring of obese and diabetic mothers are born large for gestational age and the explanation may involve the regulation of placental nutrient transfer required for fetal growth. The placenta integrates maternal and fetal signals across gestation in order to determine nutrient transfer rate. Understanding the nature of these signals and placental responses to them is key to understanding the pathology of both fetal growth restriction and macrosomia. The overall effects of the maternal environment on the placenta are the product of its exposures throughout gestation, the ‘placental exposome'. Understanding these environmental influences is important as exposures early in gestation, for instance causing changes in the function of genes involved in nutrient transfer, may determine how the placenta will respond to exposures later in gestation, such as to raised maternal plasma glucose or lipid concentrations. Longitudinal studies are required which allow investigation of the influences on the placenta across gestation. These studies need to make full use of developing technologies characterising placental function, fetal growth and body composition. Understanding these processes will assist in the development of preventive strategies and treatments to optimise prenatal growth in those pregnancies at risk of either excess or insufficient nutrient supply and could also reduce the risk of chronic disease in later life.

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Section: Placental Structure Function and Regulationmentioning

confidence: 99%

“…Computational modelling of these processes may provide an important tool to better understand these processes and to identify the rate-limiting steps, as these will be the best targets for therapeutic interventions [26,27]. …”

Section: Placental Structure Function and Regulationmentioning

confidence: 99%

The Placental Exposome: Placental Determinants of Fetal Adiposity and Postnatal Body Composition

et al. 2013

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“…All amino acids, except tryptophan, are present in the intervillous space at concentrations nearly twofold higher than in the maternal venous blood in humans (Camelo et al 2004). Thus placental amino acid transfer to fetus through transporters in placenta plays key roles (Avagliano et al 2012;Lewis et al 2013). Among amino acids, the transport and metabolism of glutamine and glutamate during fetal development exhibit unique characteristics that clearly emphasize the importance of the interaction between the placenta and the fetal liver, with important physiological consequences (Regnault et al 2002;Wu 2013).…”

Section: Introductionmentioning

confidence: 99%

Glutamate–glutamine cycle and exchange in the placenta–fetus unit during late pregnancy

Xie

Zhang

et al. 2014

Amino Acids

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The present review focuses on the physiological functions of glutamate-glutamine exchange involving placental amino acid transport and umbilical amino acid uptake in mammals (particularly in sows), with special emphasis on the associated regulating mechanisms. Glutamate plus glutamine are among the most abundant and the most utilized amino acids in fetus during late gestation. During pregnancy, amino acids, notably as precursors of macromolecules including proteins and nucleotides are involved in fetal development and growth. Amino acid concentrations in fetus are generally higher than in the mother. Among amino acids, the transport and metabolism of glutamate and glutamine during fetal development exhibit characteristics that clearly emphasize the importance of the interaction between the placenta and the fetal liver. Glutamate is quite remarkable among amino acids, which originate from the placenta, and is cleared from fetal plasma. In addition, the flux of glutamate through the placenta from the fetal plasma is highly correlated with the umbilical glutamate delivery rate. Glutamine plays a central role in fetal carbon and nitrogen metabolism and exhibits one of the highest fetal/maternal plasma ratio among all amino acids in human and other mammals. Glutamate is taken up by placenta from the fetal circulation and then converted to glutamine before being released back into the fetal circulation. Works are required on the glutamate-glutamine metabolism during late pregnancy in physiological and pathophysiological situations since such works may help to improve fetal growth and development both in humans and other mammals. Indeed, glutamine supplementation appears to ameliorate fetal growth retardation in sows and reduces preweaning mortality of piglets.

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“…It is clear that net placental amino acid flux to the fetus is dependent on membrane transport proteins localized to the microvillous membrane (MVM) and basal plasma membrane (BM) of the syncytiotrophoblast (9). However, other variables, such as blood flow and metabolism, could be equally limiting to net placental amino acid transfer (18). …”

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confidence: 99%

“…There is also evidence that maternal flow rate affects transfer of glucose across the isolated perfused human placenta (15). Modeling of placental amino acid transfer also suggests that flow may be an important determinant (18). Phenylalanine is a good candidate amino acid with which to study possible flow effects, as it is transported by exchangers [SLC7A5 (LAT1) and/or SLC7A8 (LAT2)] and facilitated transporters [SLC16A10 (TAT1), SLC43A1 (LAT3), and SLC43A2 (LAT4)], the activity of which is dependent on concentration gradients that are sensitive to flow (8, 22).…”

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confidence: 99%

Phenylalanine transfer across the isolated perfused human placenta: an experimental and modeling investigation

Lofthouse

Perazzolo

Brooks

et al. 2016

American Journal of Physiology-Regulatory, Integrative and Comp

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Membrane transporters are considered essential for placental amino acid transfer, but the contribution of other factors, such as blood flow and metabolism, is poorly defined. In this study we combine experimental and modeling approaches to understand the determinants of [14C]phenylalanine transfer across the isolated perfused human placenta. Transfer of [14C]phenylalanine across the isolated perfused human placenta was determined at different maternal and fetal flow rates. Maternal flow rate was set at 10, 14, and 18 ml/min for 1 h each. At each maternal flow rate, fetal flow rates were set at 3, 6, and 9 ml/min for 20 min each. Appearance of [14C]phenylalanine was measured in the maternal and fetal venous exudates. Computational modeling of phenylalanine transfer was undertaken to allow comparison of the experimental data with predicted phenylalanine uptake and transfer under different initial assumptions. Placental uptake (mol/min) of [14C]phenylalanine increased with maternal, but not fetal, flow. Delivery (mol/min) of [14C]phenylalanine to the fetal circulation was not associated with fetal or maternal flow. The absence of a relationship between placental phenylalanine uptake and net flux of phenylalanine to the fetal circulation suggests that factors other than flow or transporter-mediated uptake are important determinants of phenylalanine transfer. These observations could be explained by tight regulation of free amino acid levels within the placenta or properties of the facilitated transporters mediating phenylalanine transport. We suggest that amino acid metabolism, primarily incorporation into protein, is controlling free amino acid levels and, thus, placental transfer.

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Review: Modelling placental amino acid transfer − From transporters to placental function

Cited by 40 publications

References 23 publications

The Placental Exposome: Placental Determinants of Fetal Adiposity and Postnatal Body Composition

The Placental Exposome: Placental Determinants of Fetal Adiposity and Postnatal Body Composition

Glutamate–glutamine cycle and exchange in the placenta–fetus unit during late pregnancy

Phenylalanine transfer across the isolated perfused human placenta: an experimental and modeling investigation

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