Perturbation of placental protein glycosylation by endoplasmic reticulum stress promotes maladaptation of maternal hepatic glucose metabolism
Hong Wa Yung,
Xiaohui Zhao,
Luke Glover,
Charlotte Burrin,
Poh-Choo Pang,
Carolyn J.P. Jones,
Carolyn Gill,
Kate Duhig,
Matts Olovsson,
Lucy C. Chappell,
Stuart M. Haslam,
Anne Dell,
Graham J. Burton,
D. Stephen Charnock-Jones
Affiliations
Hong Wa Yung
Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 3EG, UK; Corresponding author
Xiaohui Zhao
Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 3EG, UK
Luke Glover
Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 3EG, UK
Charlotte Burrin
Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 3EG, UK
Poh-Choo Pang
Department of Life Sciences, Imperial College London, London, UK
Carolyn J.P. Jones
Maternal and Fetal Health Centre, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK
Carolyn Gill
Department of Women and Children’s Health, King’s College London, London, UK
Kate Duhig
Maternal and Fetal Health Centre, University of Manchester, Manchester Academic Health Sciences Centre, Manchester, UK; Department of Women and Children’s Health, King’s College London, London, UK
Matts Olovsson
Department of Women’s and Children’s Health, Uppsala University, Uppsala, Sweden
Lucy C. Chappell
Department of Women and Children’s Health, King’s College London, London, UK
Stuart M. Haslam
Department of Life Sciences, Imperial College London, London, UK
Anne Dell
Department of Life Sciences, Imperial College London, London, UK
Graham J. Burton
Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 3EG, UK
D. Stephen Charnock-Jones
Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 3EG, UK; Department of Obstetrics and Gynaecology, University of Cambridge, Cambridge CB2 0SW, UK; Corresponding author
Summary: 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.
