Liu Xiaomei, Guo Yanyan, Wang Jun, Zhu Liangliang, Gao Linlin
Key Laboratory of Maternal-Fetal Medicine of Liaoning Province, Department of Obstetrics and Gynecology, Shengjing Hospital, China Medical University, Shenyang 110004, China.
Department of Obstetrics and Gynecology, Benxi Central Hospital of China Medical University, Benxi 117022, China.
Int J Endocrinol. 2020 Jan 20;2020:5759182. doi: 10.1155/2020/5759182. eCollection 2020.
Accumulating evidence suggests that fetal growth restriction (FGR) leads to the development of diabetes mellitus in adults. The aim of this study was to investigate the effect of protein malnutrition on the pancreatic unfolded protein response (UPR) pathway in FGR offspring. An FGR model was developed by feeding a low-protein diet to pregnant rats throughout gestation. Eighty-four UPR pathway components in the pancreas were investigated by quantitative PCR arrays and confirmed by qPCR and western blotting. Activating transcription factor (Atf4 and Atf6), herpud1, protein kinase R-like endoplasmic reticulum kinase (Perk), X-box binding protein 1 (Xbp1), and the phosphorylation of eIF2 were upregulated, while cyclic AMP-responsive element-binding protein 3-like protein was markedly downregulated in FGR fetuses compared with controls. Investigation in adult offspring revealed temporal changes, for most UPR factors restored to normal, except that dysregulation of Atf6 and Creb3l3 maintained until adulthood. Moreover, autophagy was suppressed in FGR fetal pancreas and may be associated with decreased activation of AMP-activated protein kinase (Ampk). Apoptosis regulators Bax and cleaved-caspase 3 and 9 were upregulated in FGR fetal pancreas. Given that islet size and number were decreased in FGR fetus, we speculated that the aberrant intrauterine milieu impaired UPR signaling in fetal pancreas development. Whether these alterations early in life contribute to the predisposition of FGR fetuses to adult metabolic disorders invites further exploration.
越来越多的证据表明，胎儿生长受限（FGR）会导致成年人患糖尿病。本研究的目的是调查蛋白质营养不良对FGR后代胰腺未折叠蛋白反应（UPR）途径的影响。通过在整个妊娠期给怀孕大鼠喂食低蛋白饮食建立FGR模型。通过定量PCR阵列研究胰腺中的84种UPR途径成分，并通过qPCR和蛋白质印迹法进行确认。与对照组相比，FGR胎儿中激活转录因子（Atf4和Atf6）、herpud1、蛋白激酶R样内质网激酶（Perk）、X盒结合蛋白1（Xbp1）和eIF2的磷酸化上调，而环磷酸腺苷反应元件结合蛋白3样蛋白明显下调。对成年后代的研究揭示了时间变化，大多数UPR因子恢复正常，但Atf6和Creb3l3的失调一直持续到成年。此外，FGR胎儿胰腺中的自噬受到抑制，可能与AMP激活的蛋白激酶（Ampk）的激活降低有关。FGR胎儿胰腺中凋亡调节因子Bax以及裂解的半胱天冬酶3和9上调。鉴于FGR胎儿的胰岛大小和数量减少，我们推测异常的子宫内环境在胎儿胰腺发育中损害了UPR信号传导。生命早期的这些改变是否导致FGR胎儿易患成人代谢紊乱有待进一步探索。
