Maternal Protein Restriction Induces Alterations in Hepatic Unfolded Protein Response-Related Molecules in Adult Rat Offspring.

Xiaomei Liu,Yisheng Jiao,Jun Wang,Linlin Gao,Caixia Liu

doi:10.3389/fendo.2018.00676

Abstract

Intrauterine growth restriction (IUGR) leads to the development of metabolic syndrome in adulthood. To explore the potential mechanisms of metabolic imprinting, we investigated the effect of malnutrition in utero on hepatic unfolded protein response (UPR)-related genes in IUGR offspring. An IUGR rat model was developed by feeding a low-protein diet to pregnant rats. The expression levels and activity of hepatic UPR genes were analysed by quantitative PCR (qPCR) arrays and western blotting. The hepatic UPR molecules heat-shock 70-kDa protein 4l (Hspa4l), mitogen-activated protein kinase 10 (Mapk10), and endoplasmic reticulum to nucleus signalling 2 (Ern2) were markedly downregulated in IUGR foetuses, but the expression of Mapk10 and Ern2 returned to normal levels at 3 weeks postnatal. In contrast, cAMP responsive element binding protein 3-like 3 (Creb3l3) was upregulated in hepatic tissues at embryo 20(E20), then restored to normal in adulthood (12 weeks). The protein levels of activating transcription factor 2 (Atf2) and Atf6, two key factors of the UPR pathway, were upregulated in the livers of IUGR foetuses, and the latter remained upregulated until 12 weeks. Combined with our previous findings showing an increase in hepatic gluconeogenesis enzymes in IUGR offspring, we speculated that aberrant intrauterine milieu impaired UPR signalling in hepatic tissues; these alterations early in life might contribute to the predisposition of IUGR foetuses to adult metabolic disorders.

Highlights

Intrauterine growth restriction (IUGR) occurs in about 3–10% of pregnancies, and is considered one of the biggest causes of prenatal morbidity and mortality [1, 2]
There was no difference in hepatic glycogen levels at E20; the concentrations of glycogen were remarkably lower in IUGR offspring at 12 weeks (12 W) (Figure 2D)
Stefano reported recently that IUGR induced by uteroplacenta insufficiency led to activation of hepatic unfolded protein response (UPR) in offspring rats, confirmed by upregulated expression of X-box binding protein 1 (XBP1) and PKR-like ER kinase (PERK), which indicated that UPR signalling may play a role in the metabolic risk [29]

Summary

Introduction

Intrauterine growth restriction (IUGR) occurs in about 3–10% of pregnancies, and is considered one of the biggest causes of prenatal morbidity and mortality [1, 2]. Concerns over the programming effects of IUGR in the liver have gained momentum in recent years. Studies in birth cohorts show that low birth weight followed by rapid postnatal weight gain is positively associated with subsequent obesity and NAFLD, the Hepatic UPR Molecules in IUGR Offspring latter is independent of insulin resistance [6,7,8]. Using a welldefined IUGR model in rats by maternal protein restriction, our group previously demonstrated that IUGR animals developed glucose intolerance and hyperglycaemia in adulthood [9]; this was closely related to disorders in cholesterol metabolism and glucogenesis [10], similar with other experimental model report [11]. Despite the clearly demonstrated hepatic dysfunction in IUGR offspring, the underlying mechanisms of the programming effects on foetal livers remain unknown

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