Perturbation of placental protein glycosylation by endoplasmic reticulum stress promotes maladaptation of maternal hepatic glucose metabolism.
Perturbation of placental protein glycosylation by endoplasmic reticulum stress promotes maladaptation of maternal hepatic glucose metabolism.
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DOI：
10.1016/j.isci.2022.105911
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发表时间：
2023-01-20
期刊：
影响因子：
5.8
通讯作者：
Charnock-Jones, D. Stephen
中科院分区：
文献类型：
--
作者：
Yung, Hong Wa;Zhao, Xiaohui;Glover, Luke;Burrin, Charlotte;Pang, Poh-Choo;Jones, Carolyn J. P.;Gill, Carolyn;Duhig, Kate;Olovsson, Matts;Chappell, Lucy C.;Haslam, Stuart M.;Dell, Anne;Burton, Graham J.;Charnock-Jones, D. Stephen
胎盘激素协调母亲的新陈代谢适应，以支持怀孕。我们假设胎盘内质网应激，其特征是早发性先兆子痫(EPE)，损害糖基化，降低激素生物活性，这些适应不良使母亲在以后的生活中容易患代谢性疾病。我们证明了内质网应激降低了滋养细胞蛋白N-糖基化的复杂性和唾液酸化，而血管内皮生长因子的异常糖基化降低了其生物活性。内质网应激改变了146个基因中的66个的表达，并降低了唾液酸基转移酶的表达。使用小鼠胎盘外植体，我们发现内质网应激促进错误糖基化糖蛋白的分泌。携带交界区特异性内质网应激的胎盘的怀孕小鼠血糖降低，肝脏葡萄糖代谢异常，细胞应激增加，DNA甲基转移酶3A升高。使用妊娠特异性糖蛋白作为读数，我们还证明了患有EPE的妇女胎盘蛋白的异常糖基化，从而提供了EPE和随后的母体代谢紊乱之间的机制联系。内质网应激促进错误糖化蛋白的分泌错误糖化蛋白失去正常生物活性胎盘特异性内质网应激导致母体糖代谢适应不良早发型子痫前期胎盘释放错误糖化蛋白妊娠；生物科学；人类代谢
Placental hormones orchestrate maternal metabolic adaptations to support pregnancy. We hypothesized that placental ER stress, which characterizes early-onset pre-eclampsia (ePE), compromises glycosylation, reducing hormone bioactivity and these maladaptations predispose the mother to metabolic disease in later life. We demonstrate ER stress reduces the complexity and sialylation of trophoblast protein N-glycosylation, while aberrant glycosylation of vascular endothelial growth factor reduced its bioactivity. ER stress alters the expression of 66 of the 146 genes annotated with “protein glycosylation” and reduces the expression of sialyltransferases. Using mouse placental explants, we show ER stress promotes the secretion of mis-glycosylated glycoproteins. Pregnant mice carrying placentas with junctional zone-specific ER stress have reduced blood glucose, anomalous hepatic glucose metabolism, increased cellular stress and elevated DNA methyltransferase 3A. Using pregnancy-specific glycoproteins as a readout, we also demonstrate aberrant glycosylation of placental proteins in women with ePE, thus providing a mechanistic link between ePE and subsequent maternal metabolic disorders. ER stress promotes the secretion of mis-glycosylated proteins Mis-glycosylated protein looses normal biological activity Placenta-specific ER stress causes mal-adaptation of maternal glucose metabolism The placenta in early-onset pre-eclampsia releases mis-glycosylated proteins Pregnancy; Biological sciences; Human metabolism
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影响因子：
5.8
作者：
Gu, Zuguang;Eils, Roland;Schlesner, Matthias
通讯作者：
Schlesner, Matthias
影响因子：
5.6
作者：
Costantine MM
通讯作者：
Costantine MM
影响因子：
3.1
作者：
Hague WM;Callaway L;Chambers J;Chappell L;Coat S;de Haan-Jebbink J;Dekker M;Dixon P;Dodd J;Fuller M;Gordijn S;Graham D;Heikinheimo O;Hennessy A;Kaaja R;Khong TY;Lampio L;Louise J;Makris A;Markus C;Marschall HU;Middleton P;Mol BW;Morris J;Newnham JP;Ovadia C;Peek M;Shand A;Stark M;Thornton J;Timonen S;Walker S;Warrilow D;Williamson C
通讯作者：
Williamson C
影响因子：
16
作者：
Harding, HP;Zhang, YH;Ron, D
通讯作者：
Ron, D
影响因子：
10.8
作者：
Cindrova-Davies T;Sanders DA;Burton GJ;Charnock-Jones DS
通讯作者：
Charnock-Jones DS