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- Ericsson, Anette, 1975, et al.
(författare)
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Hormonal regulation of glucose and system A amino acid transport in first trimester placental villous fragments.
- 2005
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Ingår i: American journal of physiology. Regulatory, integrative and comparative physiology. - : American Physiological Society. - 0363-6119 .- 1522-1490. ; 288:3
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Tidskriftsartikel (refereegranskat)abstract
- Alterations in placental nutrient transfer have been implicated in fetal growth abnormalities. In pregnancies complicated by diabetes and accelerated fetal growth, upregulations of glucose transporter 1 (GLUT1) and amino acid transporter system A have been shown in the syncytiotrophoblast of term placenta. In contrast, intrauterine growth restriction is associated with a downregulation of placental system A transporters. However, underlying mechanisms of transporter regulation are poorly understood, particularly in early pregnancy. In this study, hormonal regulation of placental glucose and system A transporters was investigated. The uptake of 3-O-[methyl-(14)C]-d-glucose was studied in villous fragments isolated from first trimester (6-13 wk of gestation) and term human placenta. Villous fragments were incubated in buffer containing insulin, leptin, cortisol, growth hormone (GH), prolactin, IGF-I, or under hypo/hyperglycemic conditions for 1 h. Subsequently, 3-O-[methyl-(14)C]-D-glucose uptake was measured with and without phloretin for 70 s in first trimester tissue and 20 s in term tissue. Methylaminoisobutyric uptake was measured with and without Na+ for 20 min. Glucose uptake was unaltered by hormones or hypo/hyperglycemia. GH decreased system A activity by 31% in first trimester (P < 0.05). The uptake of glucose was 50% higher in term compared with first trimester fragments and increased markedly between 6 and 13 wk of gestation (P < 0.05). We conclude that placental glucose transporter activity is not regulated by short exposures to the hormones or glucose concentrations tested. In contrast to term placental villous fragments, system A activity was not regulated by insulin or leptin in first trimester but was downregulated by GH.
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| 6. |
- Jansson, Nina, 1976, et al.
(författare)
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Down-regulation of placental transport of amino acids precedes the development of intrauterine growth restriction in rats fed a low protein diet.
- 2006
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Ingår i: The Journal of physiology. - : Wiley. - 0022-3751. ; 576:Pt 3, s. 935-46
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Tidskriftsartikel (refereegranskat)abstract
- Intrauterine growth restriction (IUGR) represents an important risk factor for perinatal complications and for adult disease. IUGR is associated with a down-regulation of placental amino acid transporters; however, whether these changes are primary events directly contributing to IUGR or a secondary consequence is unknown. We investigated the time course of changes in placental and fetal growth, placental nutrient transport in vivo and the expression of placental nutrient transporters in pregnant rats subjected to protein malnutrition, a model for IUGR. Pregnant rats were given either a low protein (LP) diet (n = 64) or an isocaloric control diet (n = 66) throughout pregnancy. Maternal insulin, leptin and IGF-I levels decreased, whereas maternal amino acid concentrations increased moderately in response to the LP diet. Fetal and placental weights in the LP group were unaltered compared to control diet at gestational day (GD) 15, 18 and 19 but significantly reduced at GD 21. Placental system A transport activity was reduced at GD 19 and 21 in response to a low protein diet. Placental protein expression of SNAT2 was decreased at GD 21. In conclusion, placental amino acid transport is down-regulated prior to the development of IUGR, suggesting that these placental transport changes are a cause, rather than a consequence, of IUGR. Reduced maternal levels of insulin, leptin and IGF-1 may link maternal protein malnutrition to reduced fetal growth by down-regulation of key placental amino acid transporters.
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| 7. |
- Jansson, Nina, 1976, et al.
(författare)
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Maternal hormones linking maternal body mass index and dietary intake to birth weight.
- 2008
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Ingår i: American Journal of Clinical Nutrition. - Bethesda, USA : American Society for Nutrition. - 0002-9165 .- 1938-3207. ; 87:6, s. 1743-9
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Obese women often give birth to large-for-gestational age infants (typically defined as a birth weight greater than the 90th percentile), who are at risk of birth injuries and of developing metabolic syndrome later in life. The mechanisms underlying increased fetal growth remain to be established. OBJECTIVE: We aimed to identify maternal hormones that can explain the link between dietary intake, body mass index (BMI), and birth weight. DESIGN: Pregnant women with BMIs (in kg/m(2)) ranging from 17 to 44 (n = 49) were recruited in gestational weeks 8-12. Serum hormone concentrations were measured and dietary history interviews were performed in the first and third trimesters. Multiple regression models were produced to identify hormones that correlate with birth weight and are influenced by BMI or dietary factors. RESULTS: We found a strong positive correlation between BMI and first- and third-trimester insulin and leptin concentrations and a negative correlation between BMI and first-trimester adiponectin and first- and third-trimester insulin-like growth factor binding protein-1 (IGFBP-1). Maternal total fat intake in the first trimester was positively correlated with maternal leptin and inversely correlated with adiponectin. In addition, third-trimester total fat intake was positively correlated with circulating resistin concentrations. First-trimester maternal serum resistin was positively correlated with birth weight, whereas third-trimester maternal IGFBP-1 was negatively correlated with birth weight. CONCLUSIONS: High first-trimester maternal serum resistin and low third-trimester IGFBP-1 were correlated with increased birth weight. We propose that low serum concentrations of IGFBP-1 represent a link between high BMI and increased fetal growth by increasing the bioavailability of insulin-like growth factor-I, which up-regulates placental nutrient transport.
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| 9. |
- Jansson, Thomas, 1955, et al.
(författare)
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Placental transport and metabolism in fetal overgrowth -- a workshop report.
- 2006
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Ingår i: Placenta. - : Elsevier BV. - 0143-4004. ; 27 Suppl A
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Tidskriftsartikel (refereegranskat)abstract
- Fetal overgrowth in pregnancies complicated by diabetes is the result of an increased substrate availability which stimulates fetal insulin secretion and fetal growth. However, despite strict glycemic control in modern clinical management of the pregnant woman with diabetes, fetal overgrowth remains an important clinical problem. Recent studies in vivo provide evidence for increased delivery of amino acids to the fetus in gestational diabetes (GDM) even when metabolic control is strict. This could be due to that truly normal maternal substrate levels cannot be achieved in diabetic pregnancies and/or caused by altered placental nutrient transport and metabolism. Studies in vitro demonstrate an up-regulation of placental transport systems for certain amino acids in GDM associated with fetal overgrowth. GDM is also characterized by changes in placental gene expression, including up-regulation of inflammatory mediators and Leptin. In type-I diabetes with fetal overgrowth the in vitro activity of placental transporters for both glucose and certain amino acids as well as placental lipoprotein lipase is increased. Furthermore, both clinical observations in type-I diabetic pregnancies and preliminary animal experimental studies suggest that even brief periods of metabolic perturbation early in pregnancy may affect placental growth and transport function for the remainder of pregnancy, thereby contributing to fetal overgrowth. Ultrasound measurements of fetal fat deposits and abdominal circumference as well as 3D ultrasound assessment of placental volume represent non-invasive techniques for in utero diagnosis of fetal and placental overgrowth. It is proposed that these methods represent valuable additions to the clinical management of the diabetic pregnancy. In conclusion, altered placental function may be a mechanism contributing to fetal overgrowth in diabetic pregnancies with apparent optimal metabolic control. It is proposed that detailed information on placental metabolism and transport functions obtained in vitro and in vivo represent a placental phenotype that provides important information and may facilitate diagnosis and improve clinical management of fetal overgrowth.
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| 14. |
- Magnusson-Olsson, AnneLiese, et al.
(författare)
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Effect of maternal triglycerides and free fatty acids on placental LPL in cultured primary trophoblast cells and in a case of maternal LPL deficiency.
- 2007
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Ingår i: Am J Physiol Endocrinol Metab. ; 293:1
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Tidskriftsartikel (refereegranskat)abstract
- Maternal hypertriglyceridemia is a normal condition in late gestation and is an adaptation to ensure an adequate nutrient supply to the fetus. Placental lipoprotein lipase (LPL) is involved in the initial step in transplacental fatty acid transport as it hydrolyzes maternal triglycerides (TG) to release free fatty acids (FFA). We investigated LPL activity and protein (Western blot) and mRNA expression (real-time RT-PCR) in the placenta of an LPL-deficient mother with marked hypertriglyceridemia. The LPL activity was fourfold lower, LPL protein expression 50% lower, and mRNA expression threefold higher than that of normal, healthy placentas at term (n = 4-7). To further investigate the role of maternal lipids in placental LPL regulation, we isolated placental cytotrophoblasts from term placentas and studied LPL activity and protein and mRNA expression after incubation in Intralipid (as a source of TG) and oleic, linoleic, and a combination of oleic, linoleic, and arachidonic acids as well as insulin. Intralipid (40 and 400 mg/dl) decreased LPL activity by approximately 30% (n = 10-14, P < 0.05) and 400 microM linoleic and linoleic-oleic-arachidonic acid (n = 10) decreased LPL activity by 37 and 34%, respectively. No major changes were observed in LPL protein or mRNA expression. We found no effect of insulin on LPL activity or protein expression in the cultured trophoblasts. To conclude, the activity of placental LPL is reduced by high levels of maternal TG and/or FFA. This regulatory mechanism may serve to counteract an excessive delivery of FFA to the fetus in conditions where maternal TG levels are markedly increased.
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| 15. |
- Magnusson-Olsson, AnneLiese, et al.
(författare)
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Gestational and hormonal regulation of human placental lipoprotein lipase
- 2006
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Ingår i: J Lipid Res. ; 47:11, s. 2551-61
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Tidskriftsartikel (refereegranskat)abstract
- The fetal demand for FFA increases as gestation proceeds, and LPL represents one potential mechanism for increasing placental lipid transport. We examined LPL activity and protein expression in first trimester and term human placenta. The LPL activity was 3-fold higher in term (n = 7; P < 0.05) compared with first trimester (n = 6) placentas. The LPL expression appeared lower in microvillous membrane from first trimester (n = 2) compared with term (n = 2) placentas. We incubated isolated placental villous fragments with a variety of effectors [GW 1929, estradiol, insulin, cortisol, epinephrine, insulin-like growth factor-1 (IGF-1), and tumor necrosis factor-alpha] for 1, 3, and 24 h to investigate potential regulatory mechanisms. Decreased LPL activity was observed after 24 h of incubation with estradiol (1 micro g/ml), insulin, cortisol, and IGF-1 (n = 12; P < 0.05). We observed an increase in LPL activity after 3 h of incubation with estradiol (20 ng/ml) or hyperglycemic medium plus insulin (n = 7; P < 0.05). To conclude, we suggest that the gestational increase in placental LPL activity represents an important mechanism to enhance placental FFA transport in late pregnancy. Hormonal regulation of placental LPL activity by insulin, cortisol, IGF-1, and estradiol may be involved in gestational changes and in alterations in LPL activity in pregnancies complicated by altered fetal growth.
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| 17. |
- Roos, Sara, 1979, et al.
(författare)
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Expression of placental mammalian target of rapamycin (mTOR) is altered in relation to fetal growth and mTOR regulates leucine transport
- 2005
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Ingår i: Placenta. - 0143-4004. ; 26:8-9
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Konferensbidrag (refereegranskat)abstract
- Placental transport functions are altered in pregnancies complicated by restricted (IUGR) or accelerated fetal growth (LGA; large-for-gestational-age). We have suggested that the placenta may function as a nutrient sensor, regulating its nutrient transport in response to changes in substrate supply, and consequently altering fetal growth. mTOR is a protein kinase involved in regulating protein translation in response to nutrient stimuli. mTOR mRNA has been shown to be expressed in the placenta, its functional role however is unknown. To test the hypothesis that mTOR is involved in placental nutrient sensing we investigated mTOR protein expression in the human placenta in relation to fetal growth and we assessed the effect of the mTOR inhibitor rapamycin on amino acid transporter activity. Methods: mTOR expression was studied by immunohistochemistry and Western blotting and amino acid transporter activity was measured in term villous fragments. Results: mTOR protein was expressed in the cytoplasm of the syncytiotrophoblast. mTOR protein expression was up-regulated by 51% (p < 0.05) in homogenates of IUGR placentas (n = 9, controls n = 12) and down-regulated by 42% (p < 0.05) in placentas of LGA infants (n = 6, controls n = 15). Rapamycin (100 nM) decreased system L activity by 35% (n = 7, p < 0.05) but did not affect the activity of system A or taurine transporters. Conclusion: Placental mTOR protein expression is inversely related to fetal growth. Inhibition of placental mTOR decreases placental leucine transport, representing a novel regulatory mechanism for the L amino acid transporter. These findings are compatible with the hypothesis that the mTOR signaling system may play a role in placental nutrient sensing.
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| 18. |
- Roos, Sara, 1979, et al.
(författare)
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Mammalian target of rapamycin in the human placenta regulates leucine transport and is down-regulated in restricted fetal growth.
- 2007
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Ingår i: The Journal of physiology. - : Wiley. - 0022-3751. ; 582:Pt 1, s. 449-59
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 19. |
- Roos, Sara, 1979, et al.
(författare)
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Placental mTOR links maternal nutrient availability to fetal growth.
- 2009
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Ingår i: Biochemical Society transactions. - 1470-8752. ; 37:Pt 1, s. 295-8
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 20. |
- Roos, Sara, 1979, et al.
(författare)
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Regulation of amino acid transporters by glucose and growth factors in cultured primary trophoblast cells is mediated by mTOR signaling
- 2009
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Ingår i: American Journal of Physiology - Cell Physiology. - : American Physiological Society. - 0363-6143 .- 1522-1563. ; 298, s. C723-C731
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Tidskriftsartikel (refereegranskat)abstract
- Inhibition of mammalian target of rapamycin (mTOR) signaling in cultured human primary trophoblast cells reduces the activity of key placental amino acid transporters. However, the upstream regulators of placental mTOR are unknown. We hypothesized that glucose, insulin, and IGF-I regulate placental amino acid transporters by inducing changes in mTOR signaling. Primary human trophoblast cells were cultured for 24 h with media containing various glucose concentrations, insulin, or IGF-I, with or without the mTOR inhibitor rapamycin, and, subsequently, the activity of system A, system L, and taurine (TAUT) transporters was measured. Glucose deprivation (0.5 mM glucose) did not significantly affect Thr172-AMP-activated protein kinase phosphorylation or REDD1 expression but decreased S6 kinase 1 phosphorylation at Thr389. The activity of system L decreased in a dose-dependent manner in response to decreasing glucose concentrations. This effect was abolished in the presence of rapamycin. Glucose deprivation had two opposing effects on system A activity: 1) an “adaptive” upregulation mediated by an mTOR-independent mechanism and 2) downregulation by an mTOR-dependent mechanism. TAUT activity was increased after incubating cells with glucose-deprived media, and this effect was largely independent of mTOR signaling. Insulin and IGF-I increased system A activity and insulin stimulated system L activity, effects that were abolished by rapamycin. We conclude that the mTOR pathway represents an important intracellular regulatory link between nutrient and growth factor concentrations and amino acid transport in the human placenta.intrauterine growth restriction (IUGR) and accelerated fetal growth represent two important clinical conditions that occur in 15% of all pregnancies (1, 2). Aberrant fetal growth is associated with an increased risk of perinatal morbidity (7) as well as metabolic abnormalities in adult life, such as obesity, type 2 diabetes, and cardiovascular disease (6, 12, 46). The most important determinant of fetal growth is nutrient availability, which is highly dependent on placental transport capacity. The mechanisms underlying altered fetal growth remain to be established, but accumulating evidence implicates changes in the activity of specific placental amino acid transporters as a critical factor contributing to abnormal fetal growth (27, 54). Experimental evidence supports the hypothesis that changes in placental nutrient transporter activity are a cause of rather than a response to altered fetal growth. For example, in pregnant rats subjected to protein malnutrition, it is likely that downregulation of the placental system A amino acid transporter directly contributes to the development of IUGR (26).In IUGR, fetuses may be hypoglycemic (15) and have reduced circulating levels of insulin (43) and IGF-I (4, 34). The maternal levels of glucose (15) and IGF-I (40, 41) may also be reduced in this condition. The placenta of the IUGR fetus could therefore be exposed to decreased levels of glucose, hormones, and growth factors. Both insulin and IGF-I stimulate placental system A activity (24, 30, 31). These results suggest that extracellular cues regulate placental nutrient transporters and, as a consequence, fetal nutrient supply, but the cellular mechanisms remain to be fully established.The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that is regulated by a multitude of intracellular and extracellular signals. For example, mTOR is activated by growth factors and nutrient levels, such as amino acids (59), and inhibited by numerous stress conditions, such as cellular energy depletion (13, 17). Glucose may also regulate mTOR signaling through energy production in the form of ATP (13, 17). The AMP-activated protein kinase (AMPK) is regulated by the AMP-to-ATP ratio, which rises under nutrient deprivation and activates AMPK (10). Activated AMPK can in turn phosphorylate tuberous sclerosis complex 2 (TSC2), leading to mTOR inactivation (23). AMPK is phosphorylated and activated by LKB1 (52), and it has been shown that phosphorylation of LKB1 at Ser428 is essential for AMPK activation by metformin, and the authors speculate that LKB1-Ser428 phosphorylation may be a common pathway required for AMPK activation (60). There might also be additional, AMPK-independent, pathways involved in energy depletion. A recent report has shown that REDD1 (regulated in development and DNA damage responses 1) in mouse embryonic fibroblasts is induced by chronic energy depletion, and this in turn leads to inactivation of mTOR complex 1 (mTORC1) measured as phosphorylation of S6 kinase 1 (S6K1) at Thr389, independent of AMPK (55).Insulin and IGF-I activate the tyrosine kinase activity of its receptors to phosphorylate the insulin receptor substrate 1, which in turn activates phosphatidylinositol 3-kinase (PI3K) to generate PI(3,4,5)P3. Phosphatidylinositol 3,4,5-trisphosphate (PIP3) binding to Akt leads to the translocation of Akt to the plasma membrane, where it is phosphorylated and activated. The activation of Akt positively modulates mTORC1 function, by phosphorylating, and inhibiting, TSC2 (reviewed in Ref. 59).We have previously shown that inhibition of mTOR reduces the activity of placental system L, system A, and the taurine transporter (TAUT) (50). Since the activity of these amino acid transporter systems is downregulated in the placenta in association to IUGR (14, 19, 28, 37, 45) and placental mTOR activity has been reported to be decreased in IUGR (49, 62), it is possible that mTOR signaling plays an important role in regulating placental amino acid transporters in vivo. However, the upstream regulators of placental mTOR are unknown. We hypothesized that glucose, insulin, and IGF-I regulate placental amino acid transporter activity by inducing changes in mTOR signaling. To test this hypothesis, human primary trophoblast cells were incubated with media containing various concentrations of glucose, insulin, or IGF-I in the presence or absence of the specific mTOR inhibitor rapamycin. Subsequently, the activity of system L, system A, and the taurine transporter was measured. To investigate whether the AMPK pathway and/or REDD1 is activated in glucose-deprived primary trophoblasts, the protein expression of phosphorylated (P)-Thr172-AMPKα, total AMPK, P-Ser428-LKB1, and REDD1 in control and glucose-deprived cells was also studied.
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| 21. |
- Roos, Sara, 1979, et al.
(författare)
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Regulation of placental amino acid transporter activity by mammalian target of rapamycin.
- 2009
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Ingår i: American journal of physiology. Cell physiology. - : American Physiological Society. - 0363-6143 .- 1522-1563. ; 296:1
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Tidskriftsartikel (refereegranskat)abstract
- The activity of placental amino acid transporters is decreased in intrauterine growth restriction (IUGR), but the underlying regulatory mechanisms have not been established. Inhibition of the mammalian target of rapamycin (mTOR) signaling pathway has been shown to decrease the activity of the system L amino acid transporter in human placental villous fragments, and placental mTOR activity is decreased in IUGR. In the present study, we used cultured primary trophoblast cells to study mTOR regulation of placental amino acid transporters in more detail and to test the hypothesis that mTOR alters amino acid transport activity by changes in transporter expression. Inhibition of mTOR by rapamycin significantly reduced the activity of system A (-17%), system L (-28%), and taurine (-40%) amino acid transporters. mRNA expression of isoforms of the three amino acid transporter systems in response to mTOR inhibition was measured using quantitative real-time PCR. mRNA expression of l-type amino acid transporter 1 (LAT1; a system L isoform) and taurine transporter was reduced by 13% and 50%, respectively; however, mTOR inhibition did not alter the mRNA expression of system A isoforms (sodium-coupled neutral amino acid transporter-1, -2, and -4), LAT2, or 4F2hc. Rapamycin treatment did not significantly affect the protein expression of any of the transporter isoforms. We conclude that mTOR signaling regulates the activity of key placental amino acid transporters and that this effect is not due to a decrease in total protein expression. These data suggest that mTOR regulates placental amino acid transporters by posttranslational modifications or by affecting transporter translocation to the plasma membrane.
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