Publications by authors named "Ruedi Moser-Hässig"

2 Publications

  • Page 1 of 1

Counter-directed leucine gradient promotes amino acid transfer across the human placenta.

J Nutr Biochem 2021 May 6;96:108760. Epub 2021 May 6.

Institute of Biochemistry and Molecular Medicine, Faculty of Medicine, University of Bern, Switzerland; Swiss National Centre of Competence in Research (NCCR) TransCure, University of Bern, Switzerland. Electronic address:

The developing fetus is highly vulnerable to imbalances in the supply of essential amino acids (AA). Transplacental AA transfer depends on complex interactions between accumulative transporters, exchangers and facilitators, which maintain both intra-extracellular and materno-fetal substrate gradients. We determined physiological AA gradients between maternal and fetal blood and assessed their importance by studying maternal-fetal leucine transfer in human trophoblasts. Maternal-venous and corresponding fetal-arterial/fetal-venous sera were collected from 22 healthy patients at partum. The acquisition of the full AA spectra in serum was performed by ion exchange chromatography. Physiological materno-fetal AA levels were evaluated using paired two-way ANOVA with Tukey's correction. AA concentrations and gradients were tested for associations with anthropometric data by Spearman correlation analysis. Functional effects of a physiological leucine gradient versus equimolar concentrations were tested in BeWo cells using L-[H]-leucine in conventional and Transwell-based uptake and transfer experiments. The LAT1/SLC7A5-specific inhibitor JPH203 was used to evaluate LAT1-transporter-mediated leucine transport. Maternal AA concentrations correlated with preconceptional and maternal weights at partum. Interestingly, low materno-fetal AA gradients were associated with maternal weight, BMI and gestational weight gain. Leucine uptake was promoted by increased extracellular substrate concentrations. Materno-fetal leucine transfer was significantly increased against a 137µM leucine gradient demonstrating that transplacental leucine transport is stimulated by a counter-directed gradient. Moreover, leucine transfer was inhibited by 10µM JPH203 confirming that Leu transport across the trophoblast monolayer is LAT1-dependent. This study demonstrates a currently underestimated effect of transplacental AA gradients on efficient leucine transfer which could severely affect fetal development.
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http://dx.doi.org/10.1016/j.jnutbio.2021.108760DOI Listing
May 2021

Small molecule inhibitors provide insights into the relevance of LAT1 and LAT2 in materno-foetal amino acid transport.

J Cell Mol Med 2020 11 1;24(21):12681-12693. Epub 2020 Oct 1.

Institute of Biochemistry and Molecular Medicine, Faculty of Medicine, University of Bern, Bern, Switzerland.

The placenta supplies the foetus with critical nutrients such as essential amino acids (AA, eg leucine) for development and growth. It also represents a cellular barrier which is formed by a polarized, differentiated syncytiotrophoblast (STB) monolayer. Active Na -independent leucine transport across the placenta is mainly attributed to the System L transporters LAT1/SLC7A5 and LAT2/SLC7A8. This study explored the influence of trophoblast differentiation on the activity of LAT1/LAT2 and the relevance of LAT1/LAT2 in leucine uptake and transfer in trophoblasts by applying specific small molecule inhibitors (JPH203/JG336/JX009). L-leucine uptake (total dose = 167 μmol/L) was sensitive to LAT1-specific inhibition by JPH203 (EC  = 2.55 µmol/L). The inhibition efficiency of JPH203 was increased by an additional methoxy group in the JPH203-derivate JG336 (EC  = 1.99 µmol/L). Interestingly, JX009 showed efficient System L inhibition (EC  = 2.35 µmol/L) and was the most potent inhibitor of leucine uptake in trophoblasts. The application of JPH203 and JX009 in Transwell -based leucine transfer revealed LAT1 as the major accumulative transporter at the apical membrane, but other System L transporters such as LAT2 as rate-limiting for leucine efflux across the basal membrane. Therefore, differential specificity of the applied inhibitors allowed for estimation of the contribution of LAT1 and LAT2 in materno-foetal AA transfer and their potential impact in pregnancy diseases associated with impaired foetal growth.
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http://dx.doi.org/10.1111/jcmm.15840DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7687008PMC
November 2020