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. 2018 Jun 13;13(6):e0198490.
doi: 10.1371/journal.pone.0198490. eCollection 2018.

The exposure to uteroplacental insufficiency is associated with activation of unfolded protein response in postnatal life

Annalisa Deodati  1 , Josepmaría Argemí  2 , Daniela Germani  3 , Antonella Puglianiello  1 , Anna Alisi  4 , Cristiano De Stefanis  4 , Roberto Ferrero  2 , Valerio Nobili  4 , Tomás Aragón  2 , Stefano Cianfarani  1   5
Affiliations

The exposure to uteroplacental insufficiency is associated with activation of unfolded protein response in postnatal life

Annalisa Deodati et al. PLoS One. .

Abstract

Early life events are associated with the susceptibility to chronic diseases in adult life. Perturbations of endoplasmic reticulum (ER) homeostasis activate the unfolded protein response (UPR), which contributes to the development of metabolic alterations. Our aim was to evaluate liver UPR in an animal model of intrauterine growth restriction (IUGR). A significantly increased expression of X-box binding protein-1 spliced (XBP1s) mRNA (p<0.01), Endoplasmic Reticulum-localized DnaJ homologue (Erdj4) mRNA (p<0.05) and Bip/GRP78-glucose-regulated protein 78 (Bip) mRNA (p<0.05) was observed in the liver of IUGR rats at birth. Furthermore, the expression of gluconeogenesis genes and lipogenesis genes were significantly upregulated (p<0.05) in IUGR pups. At 105 d, IUGR male rats showed significantly reduced glucose tolerance (p<0.01). A significant decreased expression of XBP1s mRNA (p<0.01) and increased expression of double-stranded RNA-dependent protein kinase-like ER kinase (PERK) and Asparagine synthetase (ASNS) (p<0.05) was observed in the liver of IUGR male adult rats. Liver focal steatosis and periportal fibrosis were observed in IUGR rats. These findings show for the first time that fetal exposure to uteroplacental insufficiency is associated with the activation of hepatic UPR and suggest that UPR signaling may play a role in the metabolic risk.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1
A. Birth weights of SHAM (n = 14) and IUGR (n = 14) animals (mean weight + SD, *p<0.001). B. Plasma concentrations of metabolic parameters in 14 SHAM and 14 IUGR (mean ± SD, *p<0.001). C. Expression of target genes from three branches of UPR (IRE1alpha, ATF6 and PERK). D. Expression of main lipogenesis and gluconeogenesis genes in liver. Values are expressed as fold change (mean + SD, *p<0.01, ** p<0.005).
Fig 2
Fig 2
A. Weights of SHAM (n = 11) and IUGR (n = 11) at PND 105. B Plasma concentrations of metabolic parameters in 11 SHAM and 11 IUGR adult animals (mean + SD, **p<0.005).
Fig 3
Fig 3
A. OGTT in male and in female rats at PND105 (mean ± SD, **p<0.005. B. Histology of SHAM and IUGR animals at PND105 (staining with H&E). C. WIB of insulin signaling in IUGR and SHAM adult animals. D. Protein and mRNA level of IR beta. E. Evaluation liver tissues of fibrosis pattern in IUGR and SHAM adult males rats, using Picro-Sirius Red Stain. Values are expressed as fold change (mean + SD, * p<0.01).
Fig 4
Fig 4
A. Expression of target genes from the three branches of UPR (IRE1 alpha, ATF6 and PERK) at PND105. Values are expressed as fold change (mean + SD, ** p<0.005). B. WIB of UPR activation (IRE1 alpha, ATF6 and PERK) at PND105. C. Relationship between mRNA Xbp1s and pAkt protein level (r = 0.86, p < 0.002) in IUGR animals. D. Relationship between liver fibrosis score (F1 and F2) and mRNA levels of UPR (IRE1 alpha and PERK), *p<0.05.
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