Maternal Protein Restriction Induces Alterations in Hepatic Unfolded Protein Response-Related Molecules in Adult Rat Offspring
Maternal Protein Restriction Induces Alterations in Hepatic Unfolded Protein Response-Related Molecules in Adult Rat Offspring
复制标题
母体蛋白质限制诱导成年大鼠后代肝脏未折叠蛋白质反应相关分子的改变
DOI：
10.3389/fendo.2018.00676
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发表时间：
2018-11-20
影响因子：
5.2
通讯作者：
Liu, Caixia
中科院分区：
文献类型：
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作者：
Liu, Xiaomei;Wang, Jun;Liu, Caixia
胎儿宫内发育迟缓(IUGR)会导致代谢综合征的发生。为了探讨代谢印迹的可能机制，我们研究了宫内营养不良对IUGR子代肝脏未折叠蛋白反应(UPR)相关基因的影响。用低蛋白饲料喂养孕鼠，建立IUGR大鼠模型。用定量聚合酶链式反应(QPCR)芯片和Western blotting分析肝脏UPR基因的表达水平和活性。IUGR胎儿肝脏UPR分子热休克蛋白41(Hspa41)、丝裂原活化蛋白激酶10(MAPK10)和内质网到核信号转导2(Ern2)的表达显著下调，而MAPK10和Ern2的表达在出生后3周恢复正常。相反，cAMP反应元件结合蛋白3样蛋白(Creb313)在胚胎20(E20)时在肝组织中表达上调，然后在成年期(12周)恢复正常。活化转录因子2(ATF2)和ATF6是UPR途径的两个关键因子，在IUGR胎儿肝脏中表达上调，直至12周。结合我们先前发现的IUGR子代肝脏糖异生酶的增加，我们推测异常的宫内环境损害了肝脏组织中的UPR信号；这些在生命早期的变化可能导致IUGR胎儿对成年代谢紊乱的易感性。
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 41 (Hspa41), 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 (Creb313) 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.