Nutrient Sensing Pathways Mediating IGFBP1 Phosphorylation in FGR
Abstract
Impairment of fetal oxygen levels and nutrient delivery contributes to fetal growth restriction (FGR), which affects 20% of pregnancies. Such cellular stress induces hepatic Insulin-like Growth Factor Binding Protein 1 (IGFBP1) phosphorylation, which sequesters Insulin-like Growth Factor 1 (IGF-I) and markedly reduces fetal growth signaling. IGFBP1 hyperphosphoryaltion in hypoxia is mediated through the mTOR signaling pathway and through the Amino Acid Response (AAR) pathway during amino acid deprivation. Hypoxia stimulates upstream mTORC1 regulators, AMPK and REDD1 which are well-established upstream regulators of one of the two mTOR complexes, mTORC1. The molecular mechanisms by which upstream mTORC1-driven processes regulate IGFBP1 phosphorylation in hypoxia are unknown. We hypothesized that AMPK impacts IGFBP1 phosphorylation by modulating mTORC1 signaling due to hypoxia – a key factor in the development of reduced fetal growth in utero. Our results indicated that upregulation of AMPK phosphorylation at Thr172 via chemical activators leads to greater IGFBP1 phosphorylation. Additionally, we investigated the effects of combined hypoxia and amino acid deprivation (specifically leucine) on pIGFBP1 levels. We hypothesized that combined hypoxia and leucine deprivation results in greater IGFBP1 phosphorylation than either treatment alone, however we found that the combined conditions lead to IGFBP1 phosphorylation similar to leucine deprivation alone. The investigations in this study of nutrient sensing proteins (AMPK-MTORC1) and multiple cellular stressors (nutrient deprivation and hypoxia) mediating IGFBP1 hyperphosphorylation help provide greater insight of the underlying mechanisms regulating FGR.