AMPK 通过重定向葡萄糖代谢调节滋养细胞侵袭和活力的稳态：对先兆子痫的影响,Cell Proliferation

当前位置： X-MOL 学术 › Cell Prolif. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

AMPK 通过重定向葡萄糖代谢调节滋养细胞侵袭和活力的稳态：对先兆子痫的影响
Cell Proliferation ( IF 5.9 ) Pub Date : 2022-12-08 , DOI: 10.1111/cpr.13358
Ping Xu _{1,

2,

3} , Yangxi Zheng _{1,

2,

4} , Jiujiang Liao _{1,

2} , Mingyu Hu _{1,

2} , Yike Yang ₅ , Baozhen Zhang ₆ , Mark D Kilby ₇ , Huijia Fu _{1,

2} , Yamin Liu ₈ , Fumei Zhang _{1,

2} , Liling Xiong _{1,

2} , Xiyao Liu _{1,

2} , Huili Jin _{1,

2} , Yue Wu _{1,

2} , Jiayu Huang _{1,

2} , Tingli Han ₂ , Li Wen _{1,

2} , Rufei Gao ₉ , Yong Fu _{1,

2} , Xiujun Fan ₆ , Hongbo Qi _{1,

2,

8} , Philip N Baker ₁₀ , Chao Tong _{1,

2}

Affiliation

State Key Laboratory of Maternal and Fetal Medicine of Chongqing Municipality, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Ministry of Education-International Collaborative Laboratory of Reproduction and Development, Chongqing Medical University, Chongqing, China.
Biochemistry and Molecular Biology, University of Texas McGovern Medical School, Houston, Texas, USA.
Department of Stem Cell Transplantation and Cell Therapy, MD Anderson Cancer Center, Houston, Texas, USA.
Department of Gynecology and Obstetrics, Peking University Third Hospital, Beijing, China.
Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China.
Institute of Metabolism and System Research, University of Birmingham, Edgbaston, UK.
Department of Obstetrics, Women and Children's Hospital of Chongqing Medical University, Chongqing, China.
Laboratory of Reproductive Biology, School of Public Health and Management, Chongqing Medical University, Chongqing, China.
College of Life Sciences, University of Leicester, Leicester, UK.

先兆子痫（pre-eclampsia, PE）被认为是由于胎盘形成过程中滋养层细胞的侵袭缺陷导致的胎盘缺血诱导的代谢紊乱；因此，代谢在 PE 发病机制中的驱动作用在很大程度上被忽略了。由于滋养细胞经历大量糖酵解，本研究旨在研究其在 PE 发育中的功能和 AMPK 的调节机制。PE 胎盘的代谢组学分析通过气相色谱-质谱法 (GC-MS) 进行。生成滋养层特异性AMPKα1 缺陷小鼠胎盘以评估形态。通过降低子宫灌注压建立小鼠 PE 模型，并通过纳米颗粒递送的 A769662 调节胎盘 AMPK。通过 2-NBDG 和 2-脱氧-d-[ 3 测量滋养细胞葡萄糖^摄取H] 葡萄糖摄取测定。通过 Seahorse 测定和 GC-MS 研究细胞代谢。PE 复杂的滋养细胞与 AMPK 过度激活有关，而不是由于能量缺乏。此后，胎盘形成过程中的 AMPK 激活加剧了 PE 表现，但减轻了胎盘中的细胞死亡。滋养细胞中的 AMPK 激活有助于 GLUT3 易位和随后的葡萄糖代谢，这些代谢被重新定向为糖异生，导致糖原沉积和磷酸烯醇丙酮酸积累；后者增强了生存能力，但损害了滋养细胞的入侵。然而，小鼠胎盘中 AMPK 的消融导致糖原沉积减少和结构畸形。这些数据揭示了滋养细胞侵袭性和生存力之间的一种新的稳态，

"点击查看英文标题和摘要"

AMPK regulates homeostasis of invasion and viability in trophoblasts by redirecting glucose metabolism: Implications for pre-eclampsia

Pre-eclampsia (PE) is deemed an ischemia-induced metabolic disorder of the placenta due to defective invasion of trophoblasts during placentation; thus, the driving role of metabolism in PE pathogenesis is largely ignored. Since trophoblasts undergo substantial glycolysis, this study aimed to investigate its function and regulatory mechanism by AMPK in PE development. Metabolomics analysis of PE placentas was performed by gas chromatography–mass spectrometry (GC–MS). Trophoblast-specific AMPKα1-deficient mouse placentas were generated to assess morphology. A mouse PE model was established by Reduced Uterine Perfusion Pressure, and placental AMPK was modulated by nanoparticle-delivered A769662. Trophoblast glucose uptake was measured by 2-NBDG and 2-deoxy-d-[³H] glucose uptake assays. Cellular metabolism was investigated by the Seahorse assay and GC–MS.PE complicated trophoblasts are associated with AMPK hyperactivation due not to energy deficiency. Thereafter, AMPK activation during placentation exacerbated PE manifestations but alleviated cell death in the placenta. AMPK activation in trophoblasts contributed to GLUT3 translocation and subsequent glucose metabolism, which were redirected into gluconeogenesis, resulting in deposition of glycogen and accumulation of phosphoenolpyruvate; the latter enhanced viability but compromised trophoblast invasion. However, ablation of AMPK in the mouse placenta resulted in decreased glycogen deposition and structural malformation. These data reveal a novel homeostasis between invasiveness and viability in trophoblasts, which is mechanistically relevant for switching between the ‘go’ and ‘grow’ cellular programs.

更新日期：2022-12-08

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南