Placental mTOR links maternal nutrient availability to fetal growth

2009 ◽  
Vol 37 (1) ◽  
pp. 295-298 ◽  
Author(s):  
Sara Roos ◽  
Theresa L. Powell ◽  
Thomas Jansson
Keyword(s):  
Amino Acid ◽  
Fetal Growth ◽  
Intrauterine Growth Restriction ◽  
Fat Body ◽  
Mammalian Target Of Rapamycin ◽  
Amino Acid Transporters ◽  
Acid Transport ◽  
Intrauterine Growth ◽  
Mtor Activity ◽  
Mtor Signalling

The mTOR (mammalian target of rapamycin) signalling pathway functions as a nutrient sensor, both in individual cells and, more globally, in organs such as the fat body in Drosophila and the hypothalamus in the rat. The activity of placental amino acid transporters is decreased in IUGR (intrauterine growth restriction), and recent experimental evidence suggests that these changes contribute directly to the restricted fetal growth. We have shown that mTOR regulates the activity of the placental L-type amino acid transporter system and that placental mTOR activity is decreased in IUGR. The present review summarizes the emerging evidence implicating placental mTOR signalling as a key mechanism linking maternal nutrient and growth factor concentrations to amino acid transport in the human placenta. Since fetal growth is critically dependent on placental nutrient transport, placental mTOR signalling plays an important role in the regulation of fetal growth.

Amino acid transporters: éminences grises of nutrient signalling mechanisms?

2009 ◽  
Vol 37 (1) ◽  
pp. 237-241 ◽  
Author(s):  
Peter M. Taylor
Keyword(s):  
Amino Acid ◽  
Binding Sites ◽  
Mammalian Target Of Rapamycin ◽  
Amino Acid Transporters ◽  
System A ◽  
System L ◽  
Underlying Mechanisms ◽  
Substrate Binding Sites ◽  
Amino Acid Concentrations ◽  
Mtor Signalling

Nutrient signalling by the mTOR (mammalian target of rapamycin) pathway involves upstream sensing of free AA (amino acid) concentrations. Several AA-regulated kinases have recently been identified as putative intracellular AA sensors. Their activity will reflect the balance between AA flows through underlying mechanisms which together determine the size of the intracellular free AA pool. For indispensable AAs, these mechanisms are primarily (i) AA transport across the cell membrane, and (ii) protein synthesis/breakdown. The System L AA transporter is the primary conduit for cellular entry of indispensable neutral AAs (including leucine and phenylalanine) and potentially a key modulator of AA-sensitive mTOR signalling. Coupling of substrate flows through System L and other AA transporters (e.g. System A) may extend the scope for sensing nutrient abundance. Factors influencing AA transporter activity (e.g. hormones) may affect intracellular AA concentrations and hence indirectly mTOR pathway activity. Several AA transporters are themselves regulated by AA availability through ‘adaptive regulation’, which may help to adjust the gain of AA sensing. The substrate-binding sites of AA transporters are potentially direct sensors of AA availability at both faces of the cell surface, and there is growing evidence that AA transporters of the SNAT (sodium-coupled neutral AA transporter) and PAT (proton-assisted AA transporter) families may operate, at least under some circumstances, as transporter-like sensors (or ‘transceptors’) upstream of mTOR.

scholarly journals Maternal Protein Restriction in the Rat Inhibits Placental Insulin, mTOR, and STAT3 Signaling and Down-Regulates Placental Amino Acid Transporters

Endocrinology ◽  
2011 ◽  
Vol 152 (3) ◽  
pp. 1119-1129 ◽  
Author(s):  
Fredrick J. Rosario ◽  
Nina Jansson ◽  
Yoshikatsu Kanai ◽  
Puttur D. Prasad ◽  
Theresa L. Powell ◽  
...  
Keyword(s):  
Amino Acid ◽  
Fetal Growth ◽  
Mammalian Target Of Rapamycin ◽  
Protein Restriction ◽  
Amino Acid Transporters ◽  
Signal Transducer ◽  
Low Protein ◽  
Maternal Protein Restriction ◽  
Igf I ◽  
Transcription 3

The mechanisms underlying reduced fetal growth in response to maternal protein restriction are not well established. Maternal levels of insulin, IGF-I, and leptin are decreased in rats fed a low protein (LP) diet. Because these hormones stimulate placental amino acid transporters in vitro, we hypothesized that maternal protein restriction inhibits placental leptin, insulin/IGF-I, and mammalian target of rapamycin signaling and down-regulates the expression and activity of placental amino acid transporters. Pregnant rats were fed either an isocaloric low protein (LP, 4% protein) or control diet (18% protein) and studied at gestational day (GD)15, GD19, or GD21 (term 23). At GD19 and GD21, placental expression of phosphorylated eukaryotic initiation factor 4E binding protein 1 (Thr-36/46 or Thr-70) and phosphorylated S6 ribosomal protein (Ser-235/236) was decreased in the LP group. In addition, placental expression of phosphorylated S6 kinase 1 (Thr-389), phosphorylated Akt (Thr-308), and phosphorylated signal transducer and activator of transcription 3 (Tyr-705) was reduced at GD21. In microvillous plasma membranes (MVM) isolated from placentas of LP animals, protein expression of the sodium-coupled neutral amino acid transporter (SNAT)2 and the large neutral amino acid transporters 1 and 2 was reduced at GD19 and GD21. MVM SNAT1 protein expression was reduced at GD21 in LP rats. SNAT4 and 4F2 heavy chain expression in MVM was unaltered. System A and L amino acid transporter activity was decreased in MVM from LP animals at GD19 and GD21. In conclusion, maternal protein restriction inhibits placental insulin, mammalian target of rapamycin signaling, and signal transducer and activator of transcription 3 signaling, which is associated with a down-regulation of placental amino acid transporters. We speculate that maternal endocrine and metabolic control of placental nutrient transport reduces fetal growth in response to protein restriction.

Mechanisms of solute transfer across the human placenta: effects of intrauterine growth restriction

1998 ◽  
Vol 10 (4) ◽  
pp. 197-206 ◽  
Author(s):  
Colin Sibley ◽  
Stephen D'Souza ◽  
Jocelyn Glazier ◽  
Susan Greenwood
Keyword(s):  
Amino Acid ◽  
Human Placenta ◽  
Intrauterine Growth Restriction ◽  
Growth Restriction ◽  
Amino Acid Transporters ◽  
Transport Mechanisms ◽  
Solute Transfer ◽  
Intrauterine Growth ◽  
Placental Transport ◽  
Main Message

Intrauterine growth restriction (IUGR) has a variety of causes and this article will focus on those which may be related to pathology of the trophoblast – so-called placental insufficiency. The main message we wish to convey is that the aetiology of these cases of IUGR is not solely related to abnormalities of uterine or umbilical bloodflow but is also likely to involve specific placental transport mechanisms. Amino acid transporters, in particular, are implicated.

The vacuolar amino acid transport system is a novel, direct target of GATA transcription factors

2021 ◽  
Vol 85 (3) ◽  
pp. 587-599
Author(s):  
Akane Sato ◽  
Takumi Kimura ◽  
Kana Hondo ◽  
Miyuki Kawano-Kawada ◽  
Takayuki Sekito
Keyword(s):  
Transcription Factors ◽  
Amino Acid ◽  
Amino Acid Transport ◽  
Amino Acid Transporters ◽  
Acid Transport ◽  
Amino Acid Transport System ◽  
Gata Transcription Factor ◽  
Gata Transcription Factors ◽  
Acid Status ◽  
Direct Target

ABSTRACT In Saccharomyces cerevisiae, Avt4 exports neutral and basic amino acids from vacuoles. Previous studies have suggested that the GATA transcription factors, Gln3 and Gat1, which are key regulators that adapt cells in response to changes in amino acid status, are involved in the AVT4 transcription. Here, we show that mutations in the putative GATA-binding sites of the AVT4 promoter reduced AVT4 expression. Consistently, a chromatin immunoprecipitation (ChIP) assay revealed that Gat1-Myc13 binds to the AVT4 promoter. Previous microarray results were confirmed that gln3∆gat1∆ cells showed a decrease in expression of AVT1 and AVT7, which also encode vacuolar amino acid transporters. Additionally, ChIP analysis revealed that the AVT6 encoding vacuolar acidic amino acid exporter represents a new direct target of the GATA transcription factor. The broad effect of the GATA transcription factors on the expression of AVT transporters suggests that vacuolar amino acid transport is integrated into cellular amino acid homeostasis.

Placental amino acid transport

1995 ◽  
Vol 268 (6) ◽  
pp. C1321-C1331 ◽  
Author(s):  
A. J. Moe
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Human Placenta ◽  
Amino Acid Transport ◽  
Single Layer ◽  
Maternal Blood ◽  
Transport Systems ◽  
Amino Acid Transporters ◽  
Acid Transport ◽  
Principal Mechanism

Normal fetal growth and development depend on a continuous supply of amino acids from the mother to the fetus. The placenta is responsible for the transfer of amino acids between the two circulations. The human placenta is hemomonochorial, meaning that the maternal and fetal circulations are separated by a single layer of polarized epithelium called the syncytiotrophoblast, which is in direct contact with maternal blood. Transport proteins located in the microvillous and basal membranes of the syncytiotrophoblast are the principal mechanism for transfer from maternal blood to fetal blood. Knowledge of the function and regulation of syncytiotrophoblast amino acid transporters is of great importance in understanding the mechanism of placental transport and potentially improving fetal and newborn outcomes. The development of methods for the isolation of microvillous and basal membrane vesicles from human placenta over the past two decades has contributed greatly to this understanding. Now a primary cultured trophoblast model is available to study amino acid transport and regulation as the cells differentiate. The types of amino acid transporters and their distribution between the syncytiotrophoblast microvillous and basal membranes are somewhat unique compared with other polarized epithelia. These differences may reflect the unusual circumstance of this epithelium that is exposed to blood on both sides. The current state of knowledge as to the types of transport systems present in syncytiotrophoblast, their regulation, and the effects of maternal consumption of drugs on transport are discussed.

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