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Mechanisms linking hypoxia to phosphorylation of insulin‐like growth factor binding protein‐1 in baboon fetuses with intrauterine growth restriction and in cell culture
Author(s) -
Kakadia Jenica,
Biggar Kyle,
Jain Bhawani,
Chen Allan W.,
Nygard Karen,
Li Cun,
Nathanielsz Peter W.,
Jansson Thomas,
Gupta Madhulika B.
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.202100397r
Subject(s) - mtorc1 , biology , pi3k/akt/mtor pathway , medicine , endocrinology , phosphorylation , ribosomal protein s6 , mechanistic target of rapamycin , vascular endothelial growth factor , p70 s6 kinase 1 , signal transduction , microbiology and biotechnology , cancer research , vegf receptors
Hypoxia increases fetal hepatic insulin‐like growth factor binding protein‐1 (IGFBP‐1) phosphorylation mediated by mechanistic target of rapamycin (mTOR) inhibition. Whether maternal nutrient restriction (MNR) causes fetal hypoxia remains unclear. We used fetal liver from a baboon ( Papio sp.) model of intrauterine growth restriction due to MNR (70% global diet of Control) and liver hepatocellular carcinoma (HepG2) cells as a model for human fetal hepatocytes and tested the hypothesis that mTOR‐mediated IGFBP‐1 hyperphosphorylation in response to hypoxia requires hypoxia‐inducible factor‐1α (HIF‐1α) and regulated in development and DNA‐damage responses‐1 (REDD‐1) signaling. Western blotting (n = 6) and immunohistochemistry (n = 3) using fetal liver indicated greater expression of HIF‐1α, REDD‐1 as well as erythropoietin and its receptor, and vascular endothelial growth factor at GD120 (GD185 term) in MNR versus Control. Moreover, treatment of HepG2 cells with hypoxia (1% pO 2 ) (n = 3) induced REDD‐1, inhibited mTOR complex‐1 (mTORC1) activity and increased IGFBP‐1 secretion/phosphorylation (Ser101/Ser119/Ser169). HIF‐1α inhibition by echinomycin or small interfering RNA silencing prevented the hypoxia‐mediated inhibition of mTORC1 and induction of IGFBP‐1 secretion/phosphorylation. dimethyloxaloylglycine (DMOG) induced HIF‐1α and also REDD‐1 expression, inhibited mTORC1 and increased IGFBP‐1 secretion/phosphorylation. Induction of HIF‐1α (DMOG) and REDD‐1 by Compound 3 inhibited mTORC1, increased IGFBP‐1 secretion/ phosphorylation and protein kinase PKCα expression. Together, our data demonstrate that HIF‐1α induction, increased REDD‐1 expression and mTORC1 inhibition represent the mechanistic link between hypoxia and increased IGFBP‐1 secretion/phosphorylation. We propose that maternal undernutrition limits fetal oxygen delivery, as demonstrated by increased fetal liver expression of hypoxia‐responsive proteins in baboon MNR. These findings have important implications for our understanding of the pathophysiology of restricted fetal growth.