Glutamate cycling may drive organic anion transport on the basal membrane of human placental syncytiotrophoblast

Lofthouse, Emma M.; Brooks, Suzanne; Cleal, Jane K.; Hanson, Mark A.; Poore, Kirsten R.; O’Kelly, Ita; Lewis, Rohan M.

doi:10.1113/jp270743

Cited by 17 publications

(17 citation statements)

References 36 publications

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“…Like OAT4, this transporter is involved in the transport of estrone sulfate and dehydroepiandrosterone sulfate, and this process may be sodium dependent [62]. It has also been proposed that the transport of glutamate may also be coupled to anion transport by both OATP2B1 and OAT4, though this may need to be studied with more substrates [63]. OATP4A1, on the other hand, is expressed on the apical membrane of the syncytiotrophoblast [58,61].…”

Section: Mechanisms Of Drug Transport Across the Placentamentioning

confidence: 99%

Placental control of drug delivery

Al-Enazy

Ali

Albekairi

et al. 2017

Advanced Drug Delivery Reviews

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The placenta serves as the interface between the maternal and fetal circulations and regulates the transfer of oxygen, nutrients, and waste products. When exogenous substances are present in the maternal bloodstream—whether from environmental contact, occupational exposure, medication, or drug abuse—the extent to which this exposure affects the fetus is determined by transport and biotransformation processes in the placental barrier. Advances in drug delivery strategies are expected to improve the treatment of maternal and fetal diseases encountered during pregnancy.

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Section: Mechanisms Of Drug Transport Across the Placentamentioning

confidence: 99%

Placental control of drug delivery

Al-Enazy

Ali

Albekairi

et al. 2017

Advanced Drug Delivery Reviews

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“…Recent studies in human placenta have also demonstrated a role for glutamate as a counter‐ion to mediate placental uptake of xenobiotics and hormones from fetal circulation (Lofthouse et al . , ).…”

Section: Introductionmentioning

confidence: 99%

“…Placental uptake of glutamate from maternal and fetal blood is mediated by system X AG-. Recent studies in human placenta have also demonstrated a role for glutamate as a counter-ion to mediate placental uptake of xenobiotics and hormones from fetal circulation (Lofthouse et al 2015.…”

Section: Introductionmentioning

confidence: 99%

Evidence of adaptation of maternofetal transport of glutamine relative to placental size in normal mice, and in those with fetal growth restriction

McIntyre

Hayward

Sibley

et al. 2019

The Journal of Physiology

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Key points Fetal growth restriction (FGR) is a major risk factor for stillbirth and has significant impact upon lifelong health. A small, poorly functioning placenta, as evidenced by reduced transport of nutrients to the baby, underpins FGR. It remains unclear how a small but normal placenta differs from the small FGR placenta in terms of ability to transfer nutrients to the fetus. Placental transport of glutamine and glutamate, key amino acids for fetal growth, was assessed in normal mice and those with FGR. Glutamine and glutamate transport was greater in the lightest versus heaviest placenta in a litter of normally grown mice. Placentas of mice with FGR had increased transport capacity in mid‐pregnancy, but this adaptation was insufficient in late pregnancy. Placental adaptations, in terms of increased nutrient transport (per gram) to compensate for small size, appear to achieve appropriate fetal growth in normal pregnancy. Failure of this adaptation might contribute to FGR. Abstract Fetal growth restriction (FGR), a major risk factor for stillbirth, and neonatal and adulthood morbidity, is associated with reduced placental size and decreased placental nutrient transport. In mice, a small, normal placenta increases its nutrient transport, thus compensating for its reduced size and maintaining normal fetal growth. Whether this adaptation occurs for glutamine and glutamate, two key amino acids for placental metabolism and fetal growth, is unknown. Additionally, an assessment of placental transport of glutamine and glutamate between FGR and normal pregnancy is currently lacking. We thus tested the hypothesis that the transport of glutamine and glutamate would be increased (per gram of tissue) in a small normal placenta [C57BL6/J (wild‐type, WT) mice], but that this adaptation fails in the small dysfunctional placenta in FGR [insulin‐like growth factor 2 knockout (P0) mouse model of FGR]. In WT mice, comparing the lightest versus heaviest placenta in a litter, unidirectional maternofetal clearance (Kmf) of 14C‐glutamine and 14C‐glutamate (glutamineKmf and glutamateKmf) was significantly higher at embryonic day (E) 18.5, in line with increased expression of LAT1, a glutamine transporter protein. In P0 mice, glutamineKmf and glutamateKmf were higher (P0 versus wild‐type littermates, WTL) at E15.5. At E18.5, glutamineKmf remained elevated whereas glutamateKmf was similar between groups. In summary, we provide evidence that glutamineKmf and glutamateKmf adapt according to placental size in WT mice. The placenta of the growth‐restricted P0 fetus also elevates transport capacity to compensate for size at E15.5, but this adaptation is insufficient at E18.5; this may contribute to decreased fetal growth.

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“…Placental amino acid transfer, must be thought of as a system rather than simply focusing on individual mechanisms (Lofthouse et al . ). A computational modelling approach is helping us to predict the rate‐limiting factors in this system so that these can be the focus of future intervention‐based studies (Panitchob et al .…”

Section: Introductionmentioning

confidence: 97%

“…Placental perfusions provide the best system for modelling transfer and the combination of perfusions with modelling has provided unexpected insight into placental amino acid, fatty acid and cortisol transport (Lofthouse et al . ; Panitchob et al . ; Perazzolo et al .…”

Section: Introductionmentioning

confidence: 99%

A systems perspective on placental amino acid transport

Cleal

Lofthouse

Sengers

et al. 2018

The Journal of Physiology

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Placental amino acid transfer is a complex process that is essential for fetal development. Impaired amino acid transfer causes fetal growth restriction, which may have lifelong health consequences. Transepithelial transfer of amino acids across the placental syncytiotrophoblast requires accumulative, exchange and facilitated transporters on the apical and basal membranes to work in concert. However, transporters alone do not determine amino acid transfer and factors that affect substrate availability, such as blood flow and metabolism, may also become rate‐limiting for transfer. In order to determine the rate‐limiting processes, it is necessary to take a systems approach which recognises the interdependence of these processes. New technologies have the potential to deliver targeted interventions to the placenta and help poorly growing fetuses. While many factors are necessary for amino acid transfer, novel therapies need to target the rate‐limiting factors if they are going to be effective. This review will outline the factors which determine amino acid transfer and describe how they become interdependent. It will also highlight the role of computational modelling as a tool to understand this process.

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Glutamate cycling may drive organic anion transport on the basal membrane of human placental syncytiotrophoblast

Cited by 17 publications

References 36 publications

Placental control of drug delivery

Placental control of drug delivery

Evidence of adaptation of maternofetal transport of glutamine relative to placental size in normal mice, and in those with fetal growth restriction

A systems perspective on placental amino acid transport

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