Mammalian target of rapamycin in the human placenta regulates leucine transport and is down-regulated in restricted fetal growth.
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.
Roos
Sara
S
Perinatal Center, Department of Physiology, Institute of Neuroscience and Physiology, University of Gothenburg, PO Box 432, SE-405 30 Gothenburg, Sweden. sara.roos@gu.se
Jansson
Nina
N
Palmberg
Isabelle
I
Säljö
Karin
K
Powell
Theresa L
TL
Jansson
Thomas
T
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000328:Adult; D027062:Amino Acid Transport System L / Q000187:drug effects / Q000378:metabolism*; D001724:Birth Weight; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D002824:Chorionic Villi / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D005317:Fetal Growth Retardation / Q000378:metabolism* / Q000473:pathology; D005865:Gestational Age; D006801:Humans; D007150:Immunohistochemistry; D007231:Infant, Newborn; D007930:Leucine / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism; D010920:Placenta / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D014327:Trophoblasts / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D027062:Amino Acid Transport System L; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D010750:Phosphoproteins; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D007930:Leucine; D020123:Sirolimus