Mammalian target of rapamycin in the human placenta regulates leucine transport and is down‐regulated in restricted fetal growth

Abstract

Pathological fetal growth is associated with perinatal morbidity and the development of diabetes and cardiovascular disease later in life. Placental nutrient transport is a primary determinant of fetal growth. In human intrauterine growth restriction (IUGR) the activity of key placental amino acid transporters, such as systems A and L, is decreased. However the mechanisms regulating placental nutrient transporters are poorly understood. We tested the hypothesis that the mammalian target of rapamycin (mTOR) signalling pathway regulates amino acid transport in the human placenta and that the activity of the placental mTOR pathway is reduced in IUGR. Using immunohistochemistry and culture of trophoblast cells, we show for the first time that the mTOR protein is expressed in the transporting epithelium of the human placenta. We further demonstrate that placental mTOR regulates activity of the L-amino acid transporter, but not system A or taurine transporters, by determining the mediated uptake of isotope-labelled leucine, methylaminoisobutyric acid and taurine in primary villous fragments after inhibition of mTOR using rapamycin. The protein expression of placental phospho-S6K1 (Thr-389), a measure of the activity of the mTOR signalling pathway, was markedly reduced in placentas obtained from pregnancies complicated by IUGR. These data identify mTOR as an important regulator of placental amino acid transport, and provide a mechanism for the changes in placental leucine transport in IUGR previously demonstrated in humans. We propose that mTOR functions as a placental nutrient sensor, matching fetal growth with maternal nutrient availability by regulating placental nutrient transport.

Expression of mTOR and downstream signalling components in the JEG-3 and BeWo human placental choriocarcinoma cell lines

“…This is in agreement with previous studies showing that mTOR is located chiefly in the cytoplasm (8,14). Previous studies show that mTOR also shuttles between the nucleus and cytoplasm (22).…”

“…For example, in vitro outgrowth experiments showed that mTOR deficient blastocysts were severely impaired in their ability to form trophoblasts (7). mTOR expression is downregulated in restricted fetal growth (8), and also functions as a placental growth signalling sensor (9). Experiments using immortalised human trophoblast cells revealed that cell proliferation was induced in response to glucose or following activation of Tie-2 receptor, involving an mTOR signalling pathway (9).…”

Oleic acid stimulates system A amino acid transport in primary human trophoblast cells mediated by toll-like receptor 4

“…We have previously shown in cultured human primary trophoblast cells that the mammalian target of rapamycin (mTOR) signaling pathway is a positive regulator of system A and system L amino acid transporter activities ( 21 ). Furthermore, placental mTOR signaling is reduced in cases of fetal growth restriction ( 22 ). Data from our laboratory suggests that mTOR signaling is increased in response to maternal obesity ( 23,24 ).…”

“…It is well established that mTOR functions as a nutrient sensor, and we have previously demonstrated that this signaling pathway is a positive regulator of placental amino acid transport ( 21,22 ). Because oleic acid has been reported to activate mTOR signaling in HepG2 cells ( 29 ), mTOR is a potential mediator of oleic acid-stimulated amino acid transport.…”

Contracepção e gravidez após transplante hepático: uma visão atual

“…Drogas que interagem com os imunossupressores ciclosporina e tacrolimus esquema de imunossupressor foi alterado com suspensão imediata do sirolimus, quatro tiveram recém-nascidos saudáveis e três evoluíram com abortamento espontâneo. ROOS et al (22) publicaram os resultados de estudo experimental no qual identificaram a proteína mTOR (mammalian target of rapamycin), alvo do imunossupressor rapamicina (sirolimus), como sensor de nutrientes na placenta e regulador do transporte placentário de aminoácidos, adaptando o crescimento fetal com a disponibilidade materna de nutrientes. Como o comprometimento do transporte de aminoácidos na placenta pode levar ao crescimento intrauterino restrito, estudos sobre o impacto do uso do sirolimus no crescimento fetal e organogênese são necessários antes que seu uso possa ser considerado seguro em gestantes.…”