title: Oleic acid stimulates system A amino acid transport in primary human trophoblast cells mediated by toll-like receptor 4.
abstract: Obese women have an increased risk to deliver large babies. However, the mechanisms underlying fetal overgrowth in these pregnancies are not well understood. Obese pregnant women typically have elevated circulating lipid levels. We tested the hypothesis that fatty acids stimulate placental amino acid transport, mediated via toll-like receptor 4 (TLR4) and mammalian target of rapamycin (mTOR) signaling pathways. Circulating NEFA levels and placental TLR4 expression were assessed in women with varying prepregnancy body mass index (BMI). The effects of oleic acid on system A and system L amino acid transport, and on the activation of the mTOR (4EBP1, S6K1, rpS6), TLR4 (IĸB, JNK, p38 MAPK), and STAT3 signaling pathways were determined in cultured primary human trophoblast cells. Maternal circulating NEFAs (n = 33), but not placental TLR4 mRNA expression (n = 16), correlated positively with BMI (P < 0.05). Oleic acid increased trophoblast JNK and STAT3 phosphorylation (P < 0.05), whereas mTOR activity was unaffected. Furthermore, oleic acid doubled trophoblast system A activity (P < 0.05), without affecting system L activity. siRNA-mediated silencing of TLR4 expression prevented the stimulatory effect of oleic acid on system A activity. Our data suggest that maternal fatty acids can increase placental nutrient transport via TLR4, thereby potentially affecting fetal growth.
authors.affiliation: Center for Pregnancy and Newborn Research, Department of Obstetrics and Gynecology, University of Texas Health Science Center, San Antonio, TX; Department of Physiology, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Susanne
authors.initials: S
authors.lastname: Lager
authors.affiliation: Center for Pregnancy and Newborn Research, Department of Obstetrics and Gynecology, University of Texas Health Science Center, San Antonio, TX.
authors.forename: Francesca
authors.initials: F
authors.lastname: Gaccioli
authors.affiliation: Center for Pregnancy and Newborn Research, Department of Obstetrics and Gynecology, University of Texas Health Science Center, San Antonio, TX.
authors.forename: Vanessa I
authors.initials: VI
authors.lastname: Ramirez
authors.affiliation: Center for Molecular Fetal Therapy, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
authors.forename: Helen N
authors.initials: HN
authors.lastname: Jones
authors.affiliation: Center for Pregnancy and Newborn Research, Department of Obstetrics and Gynecology, University of Texas Health Science Center, San Antonio, TX.
authors.forename: Thomas
authors.initials: T
authors.lastname: Jansson
authors.affiliation: Center for Pregnancy and Newborn Research, Department of Obstetrics and Gynecology, University of Texas Health Science Center, San Antonio, TX.
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Powell
mesh_terms: D000328:Adult; D000596:Amino Acids / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects / Q000235:genetics; D015992:Body Mass Index; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005230:Fatty Acids, Nonesterified; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D019301:Oleic Acid / Q000494:pharmacology*; D011247:Pregnancy; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism; D014327:Trophoblasts / Q000187:drug effects* / Q000378:metabolism*
chemical_list: D000596:Amino Acids; D005230:Fatty Acids, Nonesterified; D034741:RNA, Small Interfering; D051197:Toll-Like Receptor 4; D019301:Oleic Acid; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases