Placental Remote Control of Fetal Metabolism: Trophoblast mTOR Signaling Regulates Liver IGFBP-1 Phosphorylation and IGF-1 Bioavailability.
Placental Remote Control of Fetal Metabolism: Trophoblast mTOR Signaling Regulates Liver IGFBP-1 Phosphorylation and IGF-1 Bioavailability.
复制标题
DOI：
10.3390/ijms24087273
复制
发表时间：
2023-04-14
影响因子：
5.6
通讯作者：
Jansson, Thomas
中科院分区：
文献类型：
--
作者：
Rosario, Fredrick J.;Chopra, Anand;Biggar, Kyle;Powell, Theresa L.;Gupta, Madhulika B.;Jansson, Thomas
胎儿宫内生长受限（IUGR）的发病机制尚未完全阐明。雷帕霉素（mTOR）信号转导机制作为胎盘营养传感器发挥作用，通过调节胎盘功能间接影响胎儿生长。已知胎肝IGFBP-1的分泌增加和磷酸化显著降低IGF-1（一种主要的胎儿生长因子）的生物利用度。我们假设滋养层mTOR的抑制增加肝脏IGFBP-1的分泌和磷酸化。我们从培养的原代人滋养层（PHT）细胞收集条件培养基（CM），所述细胞具有沉默的RAPTOR（特异性抑制mTOR复合物1）、RICTOR（抑制mTOR复合物2）或DEPTOR（激活两种mTOR复合物）。随后，在来自PHT细胞的CM中培养HepG 2细胞（一种完善的人胎肝细胞模型），并测定IGFBP-1分泌和磷酸化。通过2D-免疫印迹测定，来自PHT细胞的具有mTORC 1或mTORC 2抑制的CM引起HepG 2细胞中IGFBP-1的显著过度磷酸化，而平行反应质谱（PRM-MS）鉴定出增加的双重磷酸化Ser 169 + Ser 174。此外，使用相同的样品，PRM-MS鉴定出与IGFBP-1共免疫沉淀的多种CK 2肽和更大的CK 2自磷酸化，表明CK 2的激活，这是介导IGFBP-1磷酸化的关键酶。增加IGFBP-1磷酸化抑制IGF-1功能，如通过减少IGF-1 R自身磷酸化所确定的。相反，来自具有mTOR活化的PHT细胞的CM降低IGFBP-1磷酸化。来自非滋养层细胞的CM与mTORC 1或mTORC 2抑制对HepG 2 IGFBP-1磷酸化没有影响。胎盘mTOR信号可能通过远程控制胎肝IGFBP-1磷酸化来调节胎儿生长。
The mechanisms mediating the restricted growth in intrauterine growth restriction (IUGR) remain to be fully established. Mechanistic target of rapamycin (mTOR) signaling functions as a placental nutrient sensor, indirectly influencing fetal growth by regulating placental function. Increased secretion and the phosphorylation of fetal liver IGFBP-1 are known to markedly decrease the bioavailability of IGF-1, a major fetal growth factor. We hypothesized that an inhibition of trophoblast mTOR increases liver IGFBP-1 secretion and phosphorylation. We collected conditioned media (CM) from cultured primary human trophoblast (PHT) cells with a silenced RAPTOR (specific inhibition of mTOR Complex 1), RICTOR (inhibition of mTOR Complex 2), or DEPTOR (activates both mTOR Complexes). Subsequently, HepG2 cells, a well-established model for human fetal hepatocytes, were cultured in CM from PHT cells, and IGFBP-1 secretion and phosphorylation were determined. CM from PHT cells with either mTORC1 or mTORC2 inhibition caused the marked hyperphosphorylation of IGFBP-1 in HepG2 cells as determined by 2D-immunoblotting while Parallel Reaction Monitoring-Mass Spectrometry (PRM-MS) identified increased dually phosphorylated Ser169 + Ser174. Furthermore, using the same samples, PRM-MS identified multiple CK2 peptides coimmunoprecipitated with IGFBP-1 and greater CK2 autophosphorylation, indicating the activation of CK2, a key enzyme mediating IGFBP-1 phosphorylation. Increased IGFBP-1 phosphorylation inhibited IGF-1 function, as determined by the reduced IGF-1R autophosphorylation. Conversely, CM from PHT cells with mTOR activation decreased IGFBP-1 phosphorylation. CM from non-trophoblast cells with mTORC1 or mTORC2 inhibition had no effect on HepG2 IGFBP-1 phosphorylation. Placental mTOR signaling may regulate fetal growth by the remote control of fetal liver IGFBP-1 phosphorylation.
登录
查看更多内容
影响因子：
4.4
作者：
Abu Shehab, Majida;Khosravi, Javad;Gupta, Madhulika B.
通讯作者：
Gupta, Madhulika B.
影响因子：
5.5
作者：
Nandi P;Jang CE;Biggar K;Halari CD;Jansson T;Gupta MB
通讯作者：
Gupta MB
DOI：
10.1073/pnas.1515484112
发表时间：
2015-10-13
影响因子：
11.1
作者：
Aye, Irving L. M. H.;Rosario, Fredrick J.;Janssona, Thomas
通讯作者：
Janssona, Thomas
影响因子：
13
作者：
Clemmons, David R.
通讯作者：
Clemmons, David R.
影响因子：
4.8
作者：
Abu Shehab, Majida;Damerill, Ian;Gupta, Madhulika B.
通讯作者：
Gupta, Madhulika B.