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.
Highlights
Life events play a critical role in the long-term susceptibility to chronic diseases [1]
Biochemistry revealed no significant differences in blood glucose (63.9±13 vs 62.9±21.5 mg/dl) and insulin (0.34±0.15 vs 0.36±0.16 ng/ml) levels among intrauterine growth restriction (IUGR) and SHAM animals
Our results show that fetal exposure to uteroplacental insufficiency is associated with activation of hepatic unfolded protein response (UPR)
Summary
Life events play a critical role in the long-term susceptibility to chronic diseases [1]. To explain this association the thrifty phenotype hypothesis was proposed [4] According to this hypothesis, when the fetus is exposed to malnutrition the organism diverts the limited nutrient supply to favor the survival of vital organs, such as brain, at the expense of growth and other organs, such as liver and pancreas. This fetal adaptation to in utero undernourishment leads to permanent endocrine and metabolic changes through postnatal life, eventually predisposing to cardiometabolic risk [5]. The aim of this study was to investigate the UPR activation in an animal model of intrauterine growth restriction (IUGR) induced by uteroplacental insufficiency, from birth to adulthood
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