Vitamin D stimulates placental L-type amino acid transporter 1 (LAT1) in preeclampsia

Jia, Xiaotong; Cao, Yang; Ye, Lingyu; Liu, Xueqing; Huang, Yujia; Yuan, Xiaolei; Lu, Chunmei; Xu, Jing; Zhu, Hui

doi:10.1038/s41598-022-08641-y

Cited by 8 publications

(3 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…ABCG2 is also localized predominantly to the apical surface of SCT, and limits the transfer of nitrofurantoin ( Merino et al, 2005 ), cimetidine ( Pavek et al, 2005 ) and glyburide ( Gedeon et al, 2008 ) to fetal circulation. Moreover, SLC6A4 ( Wang et al, 2007 ), SLC22A11 ( Shimizu et al, 2005 ), SLC2A1 , SLC3A2 , SLC4A2 ( Nishimura and Naito, 2008 ), SLC7A5 ( Jia et al, 2022 ) protein or RNA have been shown to localize to SCT. These were all detected in our data ( Figures 5C,D ; Supplementary Figure S9 ).…”

Section: Resultsmentioning

confidence: 99%

Resolving the gene expression maps of human first-trimester chorionic villi with spatial transcriptome

Liu

Zhai

Zhang

et al. 2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

The placenta is important for fetal development in mammals, and spatial transcriptomic profiling of placenta helps to resolve its structure and function. In this study, we described the landscape of spatial transcriptome of human placental villi obtained from two pregnant women at the first trimester using the modified Stereo-seq method applied for paraformaldehyde (PFA) fixation samples. The PFA fixation of human placenta villi was better than fresh villi embedded in optimum cutting temperature (OCT) compound, since it greatly improved tissue morphology and the specificity of RNA signals. The main cell types in chorionic villi such as syncytiotrophoblasts (SCT), villous cytotrophoblasts (VCT), fibroblasts (FB), and extravillous trophoblasts (EVT) were identified with the spatial transcriptome data, whereas the minor cell types of Hofbauer cells (HB) and endothelial cells (Endo) were spatially located by deconvolution of scRNA-seq data. We demonstrated that the Stereo-seq data of human villi could be used for sophisticated analyses such as spatial cell-communication and regulatory activity. We found that the SCT and VCT exhibited the most ligand-receptor pairs that could increase differentiation of the SCT, and that the spatial localization of specific regulons in different cell types was associated with the pathways related to hormones transport and secretion, regulation of mitotic cell cycle, and nutrient transport pathway in SCT. In EVT, regulatory pathways such as the epithelial to mesenchyme transition, epithelial development and differentiation, and extracellular matrix organization were identified. Finally, viral receptors and drug transporters were identified in villi according to the pathway analysis, which could help to explain the vertical transmission of several infectious diseases and drug metabolism efficacy. Our study provides a valuable resource for further investigation of the placenta development, physiology and pathology in a spatial context.

show abstract

Section: Resultsmentioning

confidence: 99%

Resolving the gene expression maps of human first-trimester chorionic villi with spatial transcriptome

Liu

Zhai

Zhang

et al. 2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

show abstract

“…Changes in transplacental transport of amino acids and the activity of individual placental amino acid transporters are strongly associated with altered fetal growth ( 53 ). For example, lower placental LAT1 expression and/or decreased System L activity have been reported in IUGR ( 54 ) and in preeclampsia ( 55 ) and placental amino acid transport capacity is increased in some cases of fetal overgrowth ( 12 , 13 ) Similarly, MVM LAT1 expression is increased in women with type-2 diabetes and correlated with birth weight and neonatal fat mass ( 56 ). Increased MVM LAT1 expression ( 56 ) and system L amino acid transport activity ( 12 ) in the placenta may directly contribute to LGA fetuses.…”

Section: Discussionmentioning

confidence: 99%

Trophoblast-specific overexpression of the LAT1 increases transplacental transport of essential amino acids and fetal growth in mice

Rosario,

Barentsen,

Powell

et al. 2024

PNAS Nexus

View full text Add to dashboard Cite

Placental System L amino acid transporter activity is decreased in pregnancies complicated by intrauterine growth restriction (IUGR) and increased in fetal overgrowth. However, it is unknown if changes in the expression/activity of placental Large Neutral Amino Acid Transporter Small Subunit 1 (Slc7a5/LAT1) are mechanistically linked to placental function and fetal growth. We hypothesized that trophoblast-specific Slc7a5 overexpression increases placental transport of essential amino acids, activates the placental mechanistic target of rapamycin (mTOR) signaling, and promotes fetal growth in mice. Using lentiviral transduction of blastocysts with a Slc7a5 transgene, we achieved trophoblast-specific overexpression of Slc7a5 (Slc7a5 OX) with increased fetal (+27%) and placental weights (+10%). Trophoblast-specific Slc7a5 overexpression increased trophoblast plasma membrane (TPM) LAT1 protein abundance and TPM System L transporter (+53%) and System A transporter activity (+ 21%). Slc7a5 overexpression also increased transplacental transport of leucine (+ 85%) but not of the System A tracer, 14C-methylamino isobutyric acid, in vivo. Trophoblast-specific overexpression of Slc7a5 activated placental mTORC1, as assessed by increased (+44%) phosphorylation of S6 ribosomal protein (Ser 235/236), and mTORC2 as indicated by phosphorylation of PKCα-Tyr-657 (+47%) and Akt-Ser 473 (+96%). This is the first demonstration that placental transport of essential amino acids is mechanistically linked to fetal growth. The decreased placental System L activity in human IUGR and the increased placental activity of this transporter in some cases of fetal overgrowth may directly contribute to the development of these pregnancy complications.

show abstract

“…Although the molecular mechanism of vitamin D in preventing PE has not been fully established, it has been demonstrated that vitamin D has beneficial effects on PE by modulating diverse downstream effector proteins. For instance, vitamin D stimulates the expression of L-type amino acid transporter 1 (LAT1) in placental trophoblasts, thereby increasing amino acid transport across the placenta and decreasing the risk of fetal growth restriction in PE ( 39 ). Westwood et al ( 40 ) demonstrated that vitamin D downregulates S1PR2 expression and further deranges S1P function, consequently ameliorating abnormal placentation caused by deficient migration of extravillous trophoblast.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of LAMP3 mediates the protective effect of vitamin D against hypoxia/reoxygenation in trophoblast cells

Tian,

Zheng,

et al. 2023

Braz J Med Biol Res

View full text Add to dashboard Cite

Inadequate invasion and excessive apoptosis of trophoblast cells are associated with the development of preeclampsia. Vitamin D deficiency in pregnant women may lead to an increased risk of preeclampsia. However, the underlying mechanisms by which vitamin D is effective in preventing preeclampsia are not fully understood. The objectives of this study were to investigate the role of lysosome-associated membrane glycoprotein 3 (LAMP3) in the pathogenesis of preeclampsia and to evaluate whether vitamin D supplementation would protect against the development of preeclampsia by regulating LAMP3 expression. Firstly, the mRNA and protein levels of LAMP3 were significantly upregulated in the placentas of preeclampsia patients compared to normal placentas, especially in trophoblast cells (a key component of the human placenta). In the hypoxia/reoxygenation (H/R)-exposed HTR-8/Svneo trophoblast cells, LAMP3 expression was also upregulated. H/R exposure repressed cell viability and invasion and increased apoptosis of trophoblast cells. siRNA-mediated knockdown of LAMP3 increased cell viability and invasion and suppressed apoptosis of H/R-exposed trophoblast cells. We further found that 1,25(OH) 2 D 3 (the hormonally active form of vitamin D) treatment reduced LAMP3 expression in H/R exposed trophoblast cells. In addition, 1,25(OH) 2 D 3 treatment promoted cell viability and invasion and inhibited apoptosis of H/R-exposed trophoblast cells. Notably, overexpression of LAMP3 abrogated the protective effect of 1,25(OH) 2 D 3 on H/R-exposed trophoblast cells. Collectively, we demonstrated trophoblast cytoprotection by vitamin D, a process mediated via LAMP3.

show abstract

Vitamin D stimulates placental L-type amino acid transporter 1 (LAT1) in preeclampsia

Cited by 8 publications

References 37 publications

Resolving the gene expression maps of human first-trimester chorionic villi with spatial transcriptome

Resolving the gene expression maps of human first-trimester chorionic villi with spatial transcriptome

Trophoblast-specific overexpression of the LAT1 increases transplacental transport of essential amino acids and fetal growth in mice

Inhibition of LAMP3 mediates the protective effect of vitamin D against hypoxia/reoxygenation in trophoblast cells

Contact Info

Product

Resources

About