1,25-Dihydroxy vitamin D3 stimulates system A amino acid transport in primary human trophoblast cells

Abstract

Vitamin D deficiency during pregnancy is linked to adverse perinatal outcomes such as small for gestational age infants. Recent evidence suggests that changes in placental amino acid transport contribute to altered fetal growth. We tested the hypothesis that 1,25-dihydroxy vitamin D3 increases the gene expression of System A and L amino acid transporter isoforms and stimulates placental amino acid transport activity in cultured primary human trophoblast cells mediated by mTOR signalling. Treatment with 1,25-dihydroxy vitamin D3 significantly increased mRNA expression of the System A isoform SNAT2 and System A activity, but had no effect on System L and did not affect mTOR signaling. siRNA silencing of the vitamin D receptor prevented 1,25-dihydroxy vitamin D3-stimulated System A transport. In conclusion, 1,25-dihydroxy vitamin D3 regulates System A activity through increased mRNA expression of SNAT2 transporters. Effects on placental amino acid transport may be the mechanism underlying the association between maternal vitamin D status and fetal growth.

The Influence of Maternal Levels of Vitamin D and Adiponectin on Anthropometrical Measures and Bone Health in Offspring

“…As regards the role of vitamin D on foetal growth, several biological mechanisms have been suggested, including the interaction of vitamin D with parathyroid hormone, calcium homeostasis and by that on bone growth [20,21]. A study by Belenchia et al on mice offspring suggests that exposure to vitamin D deficiency during the perinatal period can directly affect genes involved in the development of adipose tissue that led to leaner mice offspring [22]. There is also a study by Chen et al that suggests that the vitamin D deficiency changes placental amino acid transportation and therefore alters foetal growth [23].…”

Antenatal Vitamin D Preserves Placental Vascular and Fetal Growth in Experimental Chorioamnionitis Due to Intra-amniotic Endotoxin Exposure

“…It has also been recently demonstrated that Vit D promotes amino acid transport in cultured primary human trophoblast cells. 50 Given that fetal growth has been suggested to be linked to amino acid availability, improved placental amino acid transport could be one possible mechanism for improvements in fetal growth after ETX exposure. 51 The fetus depends greatly on the placenta as a major source of Vit D. 31,32 Vit D exerts its biological effects through the Vit D receptor (VDR) after being converted to its biologically active form by CYP27B1.…”

“…Vit D signaling dysregulation may also contribute to FGR as Vit D has been shown to stimulate amino acid transport in human trophoblast cells. 50 Given the paracrine or autocrine nature of Vit D metabolism in the placenta, we believe that IA ETX disruption of normal Vit D signaling in the placenta leads to abnormal Vit D signaling in the fetus leading to the many developmental detrimental effects of IA ETX in the fetus. 8,9,54,55 Additionally, given that IA ETX decreased CYP27B1 expression, and that this decrease in expression was partially rescued by coadministration with Vit D, it could be that Vit D upregulates CYP27B1 expression.…”

A systems perspective on placental amino acid transport

“…; Chen et al . ). Epigenetic regulation may also be involved in the regulation of amino acid transporter expression in the placenta (Simner et al .…”

“…The trafficking of amino acid transporter protein to the plasma membrane is also an important factor in the regulation of amino acid transfer (Chen et al . , ). Any effective intervention needs to target the rate‐limiting factors in the system, but the interaction and interdependency between these factors makes identifying the rate‐limiting factors difficult.…”