Date Published: June 13, 2018
Publisher: Public Library of Science
Author(s): Annalisa Deodati, Josepmaría Argemí, Daniela Germani, Antonella Puglianiello, Anna Alisi, Cristiano De Stefanis, Roberto Ferrero, Valerio Nobili, Tomás Aragón, Stefano Cianfarani, Arun Rishi.
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.
Early life events play a critical role in the long-term susceptibility to chronic diseases . Epidemiological studies have shown an association between low-birth weight and cardiometabolic risk, including visceral adiposity, hypertension, dyslipidemia, insulin resistance, glucose intolerance, type 2 diabetes and cardiovascular disease [2,3].
In this study, we have investigated longitudinally the activation of hepatic ER stress in a rat model of intrauterine growth restriction and, at the same time, we have tested whether UPR activation is associated with metabolic dysregulation in adult animals. Our results provide the first evidence that “in utero” malnutrition stimulate UPR at birth and may lead to a dysfunctional UPR status in adulthood.
Our results show that fetal exposure to uteroplacental insufficiency is associated with activation of hepatic UPR. In parallel with IRE1α, ATF6 and PERK activation, adult male IUGR animals show an impairment of glucose tolerance and the development of hepatic steatosis with progression to fibrosis. These findings suggest that hepatic ER stress/UPR signaling may play a key role in the metabolic risk associated with intrauterine growth restriction.