| 1. |
- 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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| 2. |
- 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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| 3. |
- 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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