Molecular Mechanisms Linking Amino Acid (Leucine) Deprivation to IGFBP-1 Hyperphosphorylation in Fetal Growth Restriction
Abstract
In this study, we explore the molecular mechanisms linking amino acid (leucine) deprivation to IGFBP-1 hyperphosphorylation in vitro. During pregnancy, a maladaptive fetal response to in utero amino acid deprivation leads to Fetal Growth Restriction (FGR). FGR infants display elevated phosphorylated IGFBP-1, which is associated with decreased IGF-I bioavailability. Leucine deprivation inhibits mechanistic target of rapamycin (mTOR) signaling and stimulates the amino acid response (AAR). Using HepG2 cells, a model for fetal hepatocytes, we demonstrate that in leucine deprivation, the AAR modulates total and phosphorylated IGFBP-1 while mTOR mediates total IGFBP-1 secretion only. We also reveal that protein kinases CK2 and PKC mediate IGFBP-1 phosphorylation and subsequent IGF-I bioactivity in leucine deprivation. Together, our findings implicate fetal hepatic AAR and CK2 activation as key mechanistic links between amino acid deprivation and decreased IGF-I bioavailability in FGR and suggest a novel role for PKC in modulating IGFBP-1 phosphorylation in vitro.