{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T18:28:26Z","timestamp":1785522506308,"version":"3.56.0"},"reference-count":32,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,12,26]],"date-time":"2022-12-26T00:00:00Z","timestamp":1672012800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Norman Beischer Innovation Grants"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Intrauterine growth restriction (IUGR), predominantly caused by placental insufficiency, affects partitioning of nutrients to the fetus. The system A sodium-coupled transporters (SNAT or SLC38), of types A1, A2, and A4, control non-essential amino acid uptake and supply. Here, we aimed to investigate the expression of these transporters across different placental disease cohorts and cells. To determine disease impact, transporter expressions at the gene (qPCR) and protein (western blots) level were assessed in gestationally matched placental tissues. Early (&lt;34 weeks), and late (34\u201336 weeks) onset IUGR cases with\/out preeclampsia were compared to preterm controls. We also investigated level of transporter expression in primary trophoblasts under glucose deprivation (n = 6) and hypoxia conditions (n = 7). SLC38A4 protein was significantly downregulated in early preterm pregnancies complicated with IUGR with\/out preeclampsia. There were no differences in late preterm IUGR cohorts. Furthermore, we demonstrate for the first time in primary trophoblast cells, that gene expression of the transporters was sensitive to and induced by glucose starvation. SLC38A4 mRNA expression was also significantly upregulated in response to hypoxia. Thus, SLC38A4 expression was persistently low in early preterm IUGR pregnancies, regardless of disease aetiology. This suggests that gestational age at delivery, and consequently IUGR severity, may influence loss of its expression.<\/jats:p>","DOI":"10.3390\/ijms24010403","type":"journal-article","created":{"date-parts":[[2022,12,27]],"date-time":"2022-12-27T04:45:54Z","timestamp":1672116354000},"page":"403","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["SLC38A4 Amino Acid Transporter Expression Is Significantly Lower in Early Preterm Intrauterine Growth Restriction Complicated Placentas"],"prefix":"10.3390","volume":"24","author":[{"given":"Elif","family":"Kadife","sequence":"first","affiliation":[{"name":"Obstetric Diagnostics and Therapeutics Group, Department of Obstetrics and Gynaecology, University of Melbourne, 163 Studley Road, Heidelberg, VIC 3084, Australia"},{"name":"Mercy Perinatal, 163 Studley Road, Heidelberg, VIC 3084, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alesia","family":"Harper","sequence":"additional","affiliation":[{"name":"Obstetric Diagnostics and Therapeutics Group, Department of Obstetrics and Gynaecology, University of Melbourne, 163 Studley Road, Heidelberg, VIC 3084, Australia"},{"name":"Mercy Perinatal, 163 Studley Road, Heidelberg, VIC 3084, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8376-0096","authenticated-orcid":false,"given":"Natasha","family":"De Alwis","sequence":"additional","affiliation":[{"name":"Mercy Perinatal, 163 Studley Road, Heidelberg, VIC 3084, Australia"},{"name":"Therapeutics Discovery and Vascular Function Group, Department of Obstetrics and Gynaecology, University of Melbourne, 163 Studley Road, Heidelberg, VIC 3084, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keegan","family":"Chien","sequence":"additional","affiliation":[{"name":"Obstetric Diagnostics and Therapeutics Group, Department of Obstetrics and Gynaecology, University of Melbourne, 163 Studley Road, Heidelberg, VIC 3084, Australia"},{"name":"Mercy Perinatal, 163 Studley Road, Heidelberg, VIC 3084, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie","family":"Hannan","sequence":"additional","affiliation":[{"name":"Mercy Perinatal, 163 Studley Road, Heidelberg, VIC 3084, Australia"},{"name":"Therapeutics Discovery and Vascular Function Group, Department of Obstetrics and Gynaecology, University of Melbourne, 163 Studley Road, Heidelberg, VIC 3084, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiona C.","family":"Brownfoot","sequence":"additional","affiliation":[{"name":"Obstetric Diagnostics and Therapeutics Group, Department of Obstetrics and Gynaecology, University of Melbourne, 163 Studley Road, Heidelberg, VIC 3084, Australia"},{"name":"Mercy Perinatal, 163 Studley Road, Heidelberg, VIC 3084, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"55","DOI":"10.3389\/fendo.2019.00055","article-title":"Neonatal Morbidities of Fetal Growth Restriction: Pathophysiology and Impact","volume":"10","author":"Malhotra","year":"2019","journal-title":"Front. Endocrinol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"17929","DOI":"10.1074\/jbc.M600341200","article-title":"Amino Acid Starvation Induces the SNAT2 Neutral Amino Acid Transporter by a Mechanism That Involves Eukaryotic Initiation Factor 2\u03b1 Phosphorylation and cap-independent Translation","volume":"281","author":"Gaccioliy","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1007\/s00424-003-1117-9","article-title":"Sodium-coupled neutral amino acid (System N\/A) transporters of the SLC38 gene family","volume":"447","author":"MacKenzie","year":"2004","journal-title":"Pfl\u00fcgers Archiv."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"21047","DOI":"10.1073\/pnas.1907884116","article-title":"Paternal knockout of Slc38a4\/SNAT4 causes placental hypoplasia associated with intrauterine growth restriction in mice","volume":"116","author":"Matoba","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"514","DOI":"10.1203\/00006450-199710000-00016","article-title":"Association between the Activity of the System A Amino Acid Transporter in the Microvillous Plasma Membrane of the Human Placenta and Severity of Fetal Compromise in Intrauterine Growth Restriction","volume":"42","author":"Glazier","year":"1997","journal-title":"Pediatr. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.1016\/S0002-9378(96)70609-9","article-title":"Maternal concentrations and fetal-maternal concentration differences of plasma amino acids in normal and intrauterine growth-restricted pregnancies","volume":"174","author":"Cetin","year":"1996","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"63","DOI":"10.3389\/fphar.2018.00063","article-title":"Effects of Sodium and Amino Acid Substrate Availability upon the Expression and Stability of the SNAT2 (SLC38A2) Amino Acid Transporter","volume":"9","author":"Hoffmann","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"40","DOI":"10.3389\/fphys.2016.00040","article-title":"Placental Nutrient Transport and Intrauterine Growth Restriction","volume":"7","author":"Gaccioli","year":"2016","journal-title":"Front. Physiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4567","DOI":"10.1113\/jphysiol.2008.156133","article-title":"Adaptations in placental nutrient transfer capacity to meet fetal growth demands depend on placental size in mice","volume":"586","author":"Coan","year":"2008","journal-title":"J. Physiol."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Rosario, F.J., Kramer, A., Li, C., Galan, H.L., Powell, T.L., Nathanielsz, P.W., and Jansson, T. (2021). Reduction of In Vivo Placental Amino Acid Transport Precedes the Development of Intrauterine Growth Restriction in the Non-Human Primate. Nutrients, 13.","DOI":"10.3390\/nu13082892"},{"key":"ref_11","first-page":"935","article-title":"Down-regulation of placental transport of amino acids precedes the development of intrauterine growth restriction in rats fed a low protein diet","volume":"576","author":"Jansson","year":"2006","journal-title":"J. Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"449","DOI":"10.1113\/jphysiol.2007.129676","article-title":"Mammalian target of rapamycin in the human placenta regulates leucine transport and is down-regulated in restricted fetal growth","volume":"582","author":"Roos","year":"2007","journal-title":"J. Physiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1016\/j.placenta.2008.07.001","article-title":"Placental System A Amino Acid Transport is Reduced in Pregnancies With Small For Gestational Age (SGA) Infants but Not in Preeclampsia with SGA Infants","volume":"29","author":"Shibata","year":"2008","journal-title":"Placenta"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"6492","DOI":"10.1016\/j.vaccine.2017.01.049","article-title":"Low birth weight: Case definition & guidelines for data collection, analysis, and presentation of maternal immunization safety data","volume":"35","author":"Cutland","year":"2017","journal-title":"Vaccine"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"67","DOI":"10.4137\/CMPed.S40070","article-title":"Intrauterine Growth Restriction: Antenatal and Postnatal Aspects","volume":"10","author":"Sharma","year":"2016","journal-title":"Clin. Med. Insights Pediatr."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1203\/00006450-199808000-00016","article-title":"Intrauterine Growth Restriction Is Associated with a Reduced Activity of Placental Taurine Transporters","volume":"44","author":"Norberg","year":"1998","journal-title":"Pediatr. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"C305","DOI":"10.1152\/ajpcell.00258.2005","article-title":"SNAT4 isoform of system A amino acid transporter is expressed in human placenta","volume":"290","author":"Desforges","year":"2006","journal-title":"Am. J. Physiol. Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2049","DOI":"10.1042\/CS20210575","article-title":"Placenta-specific Slc38a2\/SNAT2 knockdown causes fetal growth restriction in mice","volume":"135","author":"Vaughan","year":"2021","journal-title":"Clin. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1016\/0029-7844(96)00048-8","article-title":"The impact of gestational age and fetal growth on the maternal-fetal glucose concentration difference","volume":"87","author":"Marconi","year":"1996","journal-title":"Obstet. Gynecol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/0002-9378(89)90453-5","article-title":"Blood glucose and oxygen tension levels in small-for-gestational-age fetuses","volume":"160","author":"Economides","year":"1989","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.mce.2015.12.016","article-title":"Role of placental insufficiency and intrauterine growth restriction on the activation of fetal hepatic glucose production","volume":"435","author":"Wesolowski","year":"2016","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1042\/bj2970289","article-title":"Structural disruption of the trans-Golgi network does not interfere with the acute stimulation of glucose and amino acid uptake by insulin-like growth factor I in muscle cells","volume":"297","author":"Hundal","year":"1994","journal-title":"Biochem. J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.2337\/diabetes.47.7.1006","article-title":"Constitutive activation of protein kinase B alpha by membrane targeting promotes glucose and system A amino acid transport, protein synthesis, and inactivation of glycogen synthase kinase 3 in L6 muscle cells","volume":"47","author":"Hajduch","year":"1998","journal-title":"Diabetes"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"107789","DOI":"10.1016\/j.neuropharm.2019.107789","article-title":"Multifaceted regulation of the system A transporter Slc38a2 suggests nanoscale regulation of amino acid metabolism and cellular signaling","volume":"161","author":"Menchini","year":"2019","journal-title":"Neuropharmacology"},{"key":"ref_25","first-page":"E1092","article-title":"Promoter characterization and role of CRE in the basal transcription of the rat SNAT2 gene","volume":"300","author":"Ortiz","year":"2011","journal-title":"Am. J. Physiol. Metab."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1159\/000480405","article-title":"Hypoxic Stress Upregulates the Expression of Slc38a1 in Brown Adipocytes via Hypoxia-Inducible Factor-1\u03b1","volume":"101","author":"Horie","year":"2017","journal-title":"Pharmacology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"12452","DOI":"10.1073\/pnas.1818521116","article-title":"Hypoxia-induced switch in SNAT2\/SLC38A2 regulation generates endocrine resistance in breast cancer","volume":"116","author":"Morotti","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"C310","DOI":"10.1152\/ajpcell.00253.2002","article-title":"Hypoxia reduces expression and function of system A amino acid transporters in cultured term human trophoblasts","volume":"284","author":"Nelson","year":"2003","journal-title":"Am. J. Physiol. Physiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"951","DOI":"10.1530\/rep.1.00808","article-title":"Expression and adaptive regulation of amino acid transport system A in a placental cell line under amino acid restriction","volume":"131","author":"Jones","year":"2006","journal-title":"J. Reprod."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"291","DOI":"10.5694\/mja11.11331","article-title":"Australian national birthweight percentiles by sex and gestational age, 1998\u20132007","volume":"197","author":"Dobbins","year":"2012","journal-title":"Med. J. Aust."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1097\/01.AOG.0000437382.03963.88","article-title":"Hypertension in Pregnancy: Executive Summary","volume":"122","author":"Roberts","year":"2013","journal-title":"Obstet. Gynecol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1016\/j.placenta.2014.06.374","article-title":"Soluble endoglin production is upregulated by oxysterols but not quenched by pravastatin in primary placental and endothelial cells","volume":"35","author":"Brownfoot","year":"2014","journal-title":"Placenta"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/1\/403\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:51:57Z","timestamp":1760147517000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/1\/403"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,26]]},"references-count":32,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,1]]}},"alternative-id":["ijms24010403"],"URL":"https:\/\/doi.org\/10.3390\/ijms24010403","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,26]]}}}