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Mammalian target of rapamycin in the human placenta regulates leucine transport and is down-regulated in restricted fetal growth
Ist Teil von
The Journal of physiology, 2007-07, Vol.582 (1), p.449-459
Ort / Verlag
Oxford, UK: The Physiological Society
Erscheinungsjahr
2007
Link zum Volltext
Quelle
Wiley Online Library Journals Frontfile Complete
Beschreibungen/Notizen
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.