In cultured fetal liver cells, IGFBP-1 hyperphosphorylation in response to hypoxia and amino acid deprivation is mediated by inhibition of mechanistic target of rapamycin (mTOR) and activation of amino acid response (AAR) signalling and casein kinase CK2. We hypothesized that fetal liver mTOR inhibition, activation of AAR and CK2, and IGFBP-1 hyperphosphorylation occur prior to development of intrauterine growth restriction (IUGR). Pregnant baboons were fed a Control (C) or a Maternal Nutrient Restriction (MNR; 70% calories of Control) diet starting at gestational day (GD) 30 (Term GD185). Umbilical blood and fetal liver tissue were obtained at GD120 (C, n=7; MNR, n=10) and GD165 (C, n=7; MNR, n=8). Fetal weights were unchanged at GD120 but decreased at GD165 in the MNR group (-13%, p=0.03). IGFBP-1 phosphorylation, as determined by PRM-MS, immunohistochemistry and/or western blot, was enhanced in MNR fetal liver and umbilical plasma at GD120 and GD165. IGF-1 receptor autophosphorylation^Tyr1135 (-64%, p=0.05) was reduced in MNR fetal liver at GD120. Furthermore, fetal liver CK2 (α/α'/β) expression CK2β colocalization, proximity with IGFBP-1 and CK2 autophosphorylation^Tyr182 were greater at GD120 and GD165 in the MNR vs. Control. Additionally, mTORC1 (p-P70S6K^Thr389, -52%, p=0.05) and mTORC2 (p-Akt^Ser473, -56%, p<0.001) activity was decreased, and AAR was activated ((p-GCN2^Thr898, +117%, p=0.02), (p-eIF2α^Ser51, +294%, p=0.002), (p-ERK^Thr202, +111%, p=0.03)) in MNR liver at GD120. Our data suggest that fetal liver IGFBP-1 hyperphosphorylation, mediated by mTOR inhibition and both AAR and CK2 activation, is a key link between restricted nutrient and oxygen availability and the development of IUGR.

中文翻译：

---

在营养受限的狒狒中，胎儿肝脏 IGFBP-1 的过度磷酸化先于胎儿生长减慢，这可能是 IUGR 的潜在机制。

在培养的胎肝细胞中，响应于缺氧和氨基酸剥夺的 IGFBP-1 过度磷酸化是通过抑制雷帕霉素 (mTOR) 的机械靶点和激活氨基酸反应 (AAR) 信号和酪蛋白激酶 CK2 来介导的。我们假设胎肝 mTOR 抑制、AAR 和 CK2 的激活以及 IGFBP-1 过度磷酸化发生在宫内生长受限 (IUGR) 之前。从妊娠第 30 天（GD185）开始，对怀孕狒狒喂食对照（C）或母体营养限制（MNR；对照的 70% 卡路里）饮食。在 GD120（C，n=7；MNR，n=10）和 GD165（C，n=7；MNR，n=8）下获得脐血和胎肝组织。MNR 组的胎儿体重在 GD120 时没有变化，但在 GD165 时下降（-13%，p=0.03）。IGFBP-1 磷酸化，由 PRM-MS 确定，免疫组织化学和/或蛋白质印迹，在 GD120 和 GD165 的 MNR 胎肝和脐带血浆中得到增强。IGF-1受体自磷酸化^Tyr1135 (-64%, p=0.05) 在 GD120 时 MNR 胎肝中减少。此外，胎肝CK2（α/α'/β）的表达CK2β共定位，接近与IGFBP-1和CK2自磷酸化^Tyr182在MNR与控制在GD120和GD165是更大的。此外，mTORC1 (p-P70S6K ^Thr389 , -52%, p=0.05) 和 mTORC2 (p-Akt ^Ser473 , -56%, p<0.001) 活性降低，AAR 被激活 ((p- ^{GCN2 Thr898} , +117 %, p=0.02), (p-eIF2α ^Ser51 , +294%, p=0.002), (p-ERK ^Thr202, +111%, p=0.03)) 在 GD120 的 MNR 肝脏中。我们的数据表明，由 mTOR 抑制以及 AAR 和 CK2 激活介导的胎肝 IGFBP-1 过度磷酸化是营养和氧气供应受限与 IUGR 发展之间的关键联系。