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Characterization of choline transporters in the human placenta over gestation.

ABSTRACT: The developing fetus relies on the maternal blood supply to provide the choline it requires for making membrane lipids, synthesizing acetylcholine, and performing important methylation reactions. It is vital, therefore, that the placenta is efficient at transporting choline from the maternal to the fetal circulation. Although choline transporters have been found in term placenta samples, little is known about what cell types express specific choline transporters and how expression of the transporters may change over gestation. The objective of this study was to characterize choline transporter expression levels and localization in the human placenta throughout placental development.We analyzed CTL1 and -2 expression over gestation in human placental biopsies from 6 to 40 weeks gestation (n = 6-10 per gestational window) by immunoblot analysis. To determine the cellular expression pattern of the choline transporters throughout gestation, immunofluorescence analysis was then performed.Both CTL1 and CTL2 were expressed in the chorionic villi from 6 weeks gestation to term. Labor did not alter expression levels of either transporter. CTL1 localized to the syncytial trophoblasts and the endothelium of the fetal vasculature within the chorionic villous structure. CTL2 localized mainly to the stroma early in gestation and by the second trimester co-localized with CTL1 at the fetal vasculature.The differential expression pattern of CTL1 and CTL2 suggests that CTL1 is the key transporter involved in choline transport from maternal circulation and both transporters are likely involved in stromal and endothelial cell choline transport.

SUBMITTER: Baumgartner HK

PROVIDER: S-EPMC4801320 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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Characterization of choline transporters in the human placenta over gestation.

Baumgartner Heidi K HK Trinder Kinsey M KM Galimanis Carly E CE Post Annalisa A Phang Tzu T Ross Randal G RG Winn Virginia D VD

Placenta 20151009 12

<h4>Introduction</h4>The developing fetus relies on the maternal blood supply to provide the choline it requires for making membrane lipids, synthesizing acetylcholine, and performing important methylation reactions. It is vital, therefore, that the placenta is efficient at transporting choline from the maternal to the fetal circulation. Although choline transporters have been found in term placenta samples, little is known about what cell types express specific choline transporters and how expr ...[more]

PMID: 26601765

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Project description:BackgroundNoninvasive measurement of placental blood flow is the major technical challenge for predicting ischemic placenta (IPD). Pseudocontinuous arterial spin labeling (pCASL) MRI was recently shown to be promising, but the potential value in predicting the subsequence development of IPD is not known.PurposeTo derive global and regional placental blood flow parameters from longitudinal measurements of pCASL MRI and to assess the associations between perfusion-related parameters and IPD.Study typeProspective.PopulationEighty-four women completed two pCASL MRI scans (first; 14-18 weeks and second; 19-24 weeks) from prospectively recruited 118 subjects. A total of 69 subjects were included for the analysis, of which 15 subjects developed IPD.Field strength/sequence3T/T2 -weighted half-Fourier single-shot turbo spin-echo (HASTE) and pCASL.AssessmentFour perfusion-related parameters in the placenta were derived: placenta volume, placental blood flow (PBF), high PBF (hPBF), and relative hPBF. The longitudinal changes of the parameters and their association with IPD were tested after being normalizing to the 16th and 20th weeks of gestation.Statistical testsComparisons between two gestational ages within subjects were performed using the paired Wilcoxon tests, and comparisons between normal and IPD groups were performed using the unpaired Wilcoxon tests.ResultsThe difference between the first and second MRI scans was statistically significant for volume (156.6 cm3 vs. 269.7 cm3 , P < 0.001) and PBF (104.9 ml/100g/min vs. 111.3 ml/100g/min, P = 0.02) for normal subjects, indicating an increase in pregnancy with advancing gestation. Of the parameters tested, the difference between the normal and IPD subjects was most pronounced in hPBF (278.1 ml/100g/min vs. 180.7 ml/100g/min, P < 0.001) and relative hPBF (259.1% vs. 183.2%, P < 0.001) at 16 weeks.Data conclusionThe high perfusion-related image parameters for IPD were significantly decreased from normal pregnancy at 14-18 weeks of gestation.Level of evidence2 TECHNICAL EFFICACY STAGE: 1 J. Magn. Reson. Imaging 2020;51:1247-1257.

Project description:Choline, an organic cation, is one of the biofactors that play an important role in the structure and the function of biological membranes, and it is essential for the synthesis of phospholipids. Choline positron emission tomography-computed tomography (PET/CT) provides useful information for the imaging diagnosis of cancers, and increased choline accumulation has been identified in a variety of tumors. However, the molecular mechanisms of choline uptake and choline transporters in pancreatic cancer have not been elucidated. Here, we examined molecular and functional analyses of choline transporters in human pancreatic-cancer cell line MIA PaCa-2 and the elucidation of the action mechanism behind the antitumor effect of novel choline-transporter-like protein 1 (CTL1) inhibitors, Amb4269951 and its derivative Amb4269675. CTL1 and CTL2 mRNAs were highly expressed in MIA PaCa-2 cells, and CTL1 and CTL2 proteins were localized in the plasma membrane and the intracellular compartments, respectively. Choline uptake was characterized by Na+-independence, a single-uptake mechanism, and inhibition by choline-uptake inhibitor HC-3, similar to the function of CTL1. These results suggest that the uptake of extracellular choline in MIA PaCa-2 cells is mediated by CTL1. Choline deficiency and HC-3 treatment inhibited cell viability and increased caspase 3/7 activity, suggesting that the inhibition of CTL1 function, which is responsible for choline transport, leads to apoptosis-induced cell death. Both Amb4269951 and Amb4269675 inhibited choline uptake and cell viability and increased caspase-3/7 activity. Ceramide, which is increased by inhibiting choline uptake, also inhibited cell survival and increased caspase-3/7 activity. Lastly, both Amb4269951 and Amb4269675 significantly inhibited tumor growth in a mouse-xenograft model without any adverse effects such as weight loss. CTL1 is a target molecule for the treatment of pancreatic cancer, and its inhibitors Amb4269951 and Amb4269675 are novel lead compounds.

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Characterization of choline transporters in the human placenta over gestation.

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Characterization of choline transporters in the human placenta over gestation.

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