Glucocorticoid regulation of amino acid transport in primary human trophoblast cells

Owen Vaughn, Theresa Powell and Thomas Jansson

Journal of Molecular Endocrinology 2019. 63: 239-248.


Excess maternal glucocorticoids reduce placental amino acid transport and fetal growth, but whether these effects are mediated directly on the syncytiotrophoblast remains unknown. We hypothesised that glucocorticoids inhibit mechanistic target of rapamycin (mTOR) signaling and insulin-stimulated System A amino acid transport activity in primary human trophoblast (PHT) cells. Syncytialised PHTs, isolated from term placentas (n = 15), were treated with either cortisol (1 ?M) or dexamethasone (1 ?M), ± insulin (1 nM) for 24 h. Compared to vehicle, dexamethasone increased mRNA expression, but not protein abundance of the mTOR suppressor, regulated in development and DNA damage response 1 (REDD1). Dexamethasone enhanced insulin receptor abundance, activated mTOR complex 1 and 2 signaling and stimulated System A activity, measured by Na+-dependent14C-methylaminoisobutyric acid uptake. Cortisol also activated mTORC1 without significantly altering insulin receptor or mTORC2 read-outs or System A activity. Both glucocorticoids downregulated expression of the glucocorticoid receptor and the System A transporter genes SLC38A1, SLC38A2 and SLC38A4, without altering SNAT1 or SNAT4 protein abundance. Neither cortisol nor dexamethasone affected System L amino acid transport. Insulin further enhanced mTOR and System A activity, irrespective of glucocorticoid treatment and despite downregulating its own receptor. Contrary to our hypothesis, glucocorticoids do not inhibit mTOR signaling or cause insulin resistance in cultured PHT cells. We speculate that glucocorticoids stimulate System A activity in PHT cells by activating mTOR signaling, which regulates amino acid transporters post-translationally. We conclude that downregulation of placental nutrient transport in vivo following excess maternal glucocorticoids is not mediated by a direct effect on the placenta.

Our Thoughts on This Paper

The effects of glucocorticoids on macronutrient transport in the placenta are not well understood. The dose and length of maternal glucocorticoid use can have varying effects on fetal nutrient acquisition and placental anabolic signaling. In this paper, Vaughan et al. demonstrate that glucocorticoids promote placental anabolic signaling and System A amino acid transport in the presence of insulin in primary human trophoblasts.

To determine the effects of glucocorticoids on placental mechanistic target of rapamycin complex (mTORC) signaling and amino acid uptake, syncytialised primary human trophoblasts were cultured with cortisol or dexamethasone in the presence or absence of insulin. The authors observed insulin responsiveness in these cells with Akt and mTORC1 signaling regardless of glucocorticoid treatment. In fact, they found modest elevations of both signaling pathways after glucocorticoid treatment in the presence of insulin. This was concordant with elevated System A but not System L transporter activity. Despite increasing System A uptake, dexamethasone and cortisol caused reductions in gene expression of System A transporters with and without insulin and did not alter protein abundance, potentially suggesting post-translational mechanisms by which insulin and glucocorticoids promote amino acid transport. These findings highlight the short-term anabolic effects of glucocorticoids on placental amino acid transport and suggest that, similar to the brain, glucocorticoids may promote nutrient flux to those critical tissues during times of stress.

Written by Noura El Habbal on Jan. 28, 2020.


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