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

作者全名："Xu, Ping; Zheng, Yangxi; Liao, Jiujiang; Hu, Mingyu; Yang, Yike; Zhang, Baozhen; Kilby, Mark D.; Fu, Huijia; Liu, Yamin; Zhang, Fumei; Xiong, Liling; Liu, Xiyao; Jin, Huili; Wu, Yue; Huang, Jiayu; Han, Tingli; Wen, Li; Gao, Rufei; Fu, Yong; Fan, Xiujun; Qi, Hongbo; Baker, Philip N.; Tong, Chao"

作者地址："[Xu, Ping; Zheng, Yangxi; Liao, Jiujiang; Hu, Mingyu; Fu, Huijia; Zhang, Fumei; Xiong, Liling; Liu, Xiyao; Jin, Huili; Wu, Yue; Huang, Jiayu; Wen, Li; Fu, Yong; Qi, Hongbo; Tong, Chao] Chongqing Med Univ, State Key Lab Maternal & Fetal Med Chongqing Muni, Affiliated Hosp 1, 1 Youyi Rd, Chongqing 400016, Peoples R China; [Xu, Ping; Zheng, Yangxi; Liao, Jiujiang; Hu, Mingyu; Fu, Huijia; Zhang, Fumei; Xiong, Liling; Liu, Xiyao; Jin, Huili; Wu, Yue; Huang, Jiayu; Han, Tingli; Wen, Li; Fu, Yong; Qi, Hongbo; Tong, Chao] Chongqing Med Univ, Minist Educ, Int Collaborat Lab Reprod & Dev, Chongqing, Peoples R China; [Xu, Ping] Univ Texas Houston, Houston, Biochem & Mol Biol, Houston, TX USA; [Zheng, Yangxi] MD Anderson Canc Ctr, Dept Stem Cell Transplantat & Cell Therapy, Houston, TX USA; [Yang, Yike] Peking Univ, Dept Gynecol & Obstet, Hosp 3, Beijing, Peoples R China; [Zhang, Baozhen; Fan, Xiujun] Chinese Acad Sci, Shenzhen Inst Adv Technol, Shenzhen, Guangdong, Peoples R China; [Kilby, Mark D.] Univ Birmingham, Inst Metab & Syst Res, Edgbaston, England; [Liu, Yamin; Qi, Hongbo] Chongqing Med Univ, Dept Obstet, Women & Childrens Hosp, Chongqing, Peoples R China; [Gao, Rufei] Chongqing Med Univ, Sch Publ Hlth & Management, Lab Reprod Biol, Chongqing, Peoples R China; [Baker, Philip N.] Univ Leicester, Coll Life Sci, Leicester, Leics, England"

通信作者："Qi, HB; Tong, C (通讯作者)，Chongqing Med Univ, State Key Lab Maternal & Fetal Med Chongqing Muni, Affiliated Hosp 1, 1 Youyi Rd, Chongqing 400016, Peoples R China."

来源：CELL PROLIFERATION

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:000894239100001

JCR分区：Q2

影响因子：8.5

年份：2023

卷号：56

期号：2

开始页：　

结束页：　

文献类型：Article

关键词：　

摘要："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 AMPK alpha 1-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-[H-3] 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."

基金机构："National Natural Science Foundation of China [81671488, 81871189, 82071675, U21A20346, 82171662]; Strategic Collaborative Research Program of the Ferring Institute of Reproductive Medicine; National Key R&D Program of China [2022YFC2702400]"

基金资助正文："National Natural Science Foundation of China, Grant/Award Numbers: 81671488, 81871189, 82071675, U21A20346, 82171662; Strategic Collaborative Research Program of the Ferring Institute of Reproductive Medicine; National Key R&D Program of China, Grant/Award Number: 2022YFC2702400"