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Hexosamine pathway regulates StarD7 expression in JEG-3 cells

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Abstract

StarD7 is a lipid binding protein involved in the delivery of phosphatidylcholine to the mitochondria whose promoter is activated by Wnt/β-catenin signaling. Although the majority of glucose enters glycolysis, ~ 2–5% of it can be metabolized via the hexosamine biosynthetic pathway (HBP). Considering that HBP has been implicated in the regulation of β-catenin we explored if changes in glucose levels modulate StarD7 expression by the HBP in trophoblast cells. We found an increase in StarD7 as well as in β-catenin expression following high-glucose (25 mM) treatment in JEG-3 cells; these effects were abolished in the presence of HBP inhibitors. Moreover, since HBP is able to promote unfolded protein response (UPR) the protein levels of GRP78, Ire1α, calnexin, p-eIF2α and total eIF2α as well as XBP1 mRNA was measured. Our results indicate that a diminution in glucose concentration leads to a decrease in StarD7 expression and an increase in the UPR markers: GRP78 and Ire1α. Conversely, an increase in glucose is associated to high StarD7 levels and low GRP78 expression, phospho-eIF2α and XBP1 splicing, although Ire1α remains high when cells are restored to high glucose. Taken together these findings indicate that glucose modulates StarD7 and β-catenin expression through the HBP associated to UPR, suggesting the existence of a link between UPR and HBP in trophoblast cells. This is the first study reporting the effects of glucose on StarD7 in trophoblast cells. These data highlight the importance to explore the role of StarD7 in placenta disorders related to nutrient availability.

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Abbreviations

AZA:

O-Diazoacetyl-l-serine

DON:

6-Diazo-5-oxo-l-norleucine

eIF2α:

Eukaryotic translation initiation factor 2 subunit 1α

ER:

Endoplasmic reticulum

FBS:

Fetal bovine serum

GFAT:

Glutamine fructose-6-phosphate amidotransferase

GlcNAc:

N-acetylglucosamine

GRP78:

Glucose regulated protein 78

HBP:

Hexosamine biosynthetic pathway

IRE1α:

Inositol-requiring enzyme 1

O-GlcNAc:

O-GlcNAcylation

OGT:

O-GlcNAc transferase

siRNA:

Small interfering RNA

StarD7:

StAR-related lipid transfer (START) domain containing 7

TBS:

Tris buffered saline

UDP-GlcNAc:

Uridine diphosphate N-acetylglucosamine

UPR:

Unfolding protein response.

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Acknowledgements

This work was funded by the Agencia Nacional de Promoción Ciencia y Técnica (FONCYT) PICT 2014-0806 and 2015-1781, and the Secretaría de Ciencia y Técnica de la Universidad Nacional de Córdoba (SECyT-UNC). S.G-R. and G.M.P-D. are Career Investigators of the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET). J F-M, L-R, M-CDP and ML-R thank FONCYT and CONICET for her fellowships.

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Authors and Affiliations

  1. Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Ciudad Universitaria, X5000HUA, Córdoba, Argentina

    Jésica Flores-Martín, Luciana Reyna, Mariano Cruz Del Puerto, María L. Rojas, Graciela M. Panzetta-Dutari & Susana Genti-Raimondi

  2. Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Ciudad Universitaria, X5000HUA, Córdoba, Argentina

    Jésica Flores-Martín, Luciana Reyna, Mariano Cruz Del Puerto, María L. Rojas, Graciela M. Panzetta-Dutari & Susana Genti-Raimondi

  3. Departamento de Bioquímica Clínica, CIBICI-CONICET, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende, X5000HUA, Córdoba, Argentina

    Susana Genti-Raimondi

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  1. Jésica Flores-Martín
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Correspondence to Susana Genti-Raimondi.

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Flores-Martín, J., Reyna, L., Cruz Del Puerto, M. et al. Hexosamine pathway regulates StarD7 expression in JEG-3 cells. Mol Biol Rep 45, 2593–2600 (2018). https://doi.org/10.1007/s11033-018-4428-9

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  • DOI: https://doi.org/10.1007/s11033-018-4428-9

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