PMID- 37963715
OWN - NLM
STAT- Publisher
LR  - 20231114
IS  - 2542-5641 (Electronic)
IS  - 0366-6999 (Linking)
DP  - 2023 Oct 24
TI  - METTL3 regulates glucose transporter expression in placenta exposed to 
      hyperglycemia through the mTOR signaling pathway.
LID - 10.1097/CM9.0000000000002840 [doi]
AB  - BACKGROUND: Alterations in the placental expression of glucose transporters 
      (GLUTs), the crucial maternal-fetal nutrient transporters, have been found in 
      women with hyperglycemia in pregnancy (HIP). However, there is still uncertainty 
      about the underlying effect of the high-glucose environment on placental GLUTs 
      expression in HIP. METHODS: We quantitatively evaluated the activity of mammalian 
      target of rapamycin (mTOR) and expression of GLUTs (GLUT1, GLUT3, and GLUT4) in 
      the placenta of women with normal pregnancies (CTRL, n = 12) and pregnant women 
      complicated with poorly controlled type 2 diabetes mellitus (T2DM, n = 12) by 
      immunohistochemistry. In addition, BeWo cells were treated with different glucose 
      concentrations to verify the regulation of hyperglycemia. Then, changes in the 
      expression of GLUTs following the activation or suppression of the mTOR pathway 
      were also assessed using MHY1485/rapamycin (RAPA) treatment or small interfering 
      RNA (siRNA)-mediated silencing approaches. Moreover, we further explored the 
      alteration and potential upstream regulatory role of methyltransferase-like 3 
      (METTL3) when exposed to hyperglycemia. RESULTS: mTOR, phosphorylated mTOR 
      (p-mTOR), and GLUT1 protein levels were upregulated in the placenta of women with 
      T2DM compared with those CTRL. In BeWo cells, mTOR activity increased with 
      increasing glucose concentration, and the expression of GLUT1, GLUT3, and GLUT4 
      as well as GLUT1 cell membrane translocation were upregulated by hyperglycemia to 
      varying degrees. Both the drug-mediated and genetic depletion of mTOR signaling 
      in BeWo cells suppressed GLUTs expression, whereas MHY1485-induced mTOR 
      activation upregulated GLUTs expression. Additionally, high glucose levels 
      upregulated METTL3 expression and nuclear translocation, and decreasing METTL3 
      levels suppressed GLUTs expression and mTOR activity and vice versa. Furthermore, 
      in METTL3 knockdown BeWo cells, the inhibitory effect on GLUTs expression was 
      eliminated by activating the mTOR signaling pathway using MHY1485. CONCLUSION: 
      High-glucose environment-induced upregulation of METTL3 in trophoblasts regulates 
      the expression of GLUTs through mTOR signaling, contributing to disordered 
      nutrient transport in women with HIP.
CI  - Copyright (c) 2023 The Chinese Medical Association, produced by Wolters Kluwer, 
      Inc. under the CC-BY-NC-ND license.
FAU - Ning, Jie
AU  - Ning J
AD  - Department of Obstetrics and Gynaecology, Peking University First Hospital, 
      Beijing 100034, China.
AD  - Beijing Key Laboratory of Maternal Foetal Medicine of Gestational Diabetes 
      Mellitus, Beijing 100034, China.
AD  - Peking University, Beijing 100034, China.
FAU - Huai, Jing
AU  - Huai J
AD  - Department of Obstetrics and Gynaecology, Peking University First Hospital, 
      Beijing 100034, China.
AD  - Beijing Key Laboratory of Maternal Foetal Medicine of Gestational Diabetes 
      Mellitus, Beijing 100034, China.
AD  - Peking University, Beijing 100034, China.
FAU - Wang, Shuxian
AU  - Wang S
AD  - Department of Obstetrics and Gynaecology, Peking University First Hospital, 
      Beijing 100034, China.
AD  - Beijing Key Laboratory of Maternal Foetal Medicine of Gestational Diabetes 
      Mellitus, Beijing 100034, China.
AD  - Peking University, Beijing 100034, China.
FAU - Yan, Jie
AU  - Yan J
AD  - Department of Obstetrics and Gynaecology, Peking University First Hospital, 
      Beijing 100034, China.
AD  - Beijing Key Laboratory of Maternal Foetal Medicine of Gestational Diabetes 
      Mellitus, Beijing 100034, China.
FAU - Su, Rina
AU  - Su R
AD  - Department of Obstetrics and Gynaecology, Peking University First Hospital, 
      Beijing 100034, China.
AD  - Beijing Key Laboratory of Maternal Foetal Medicine of Gestational Diabetes 
      Mellitus, Beijing 100034, China.
FAU - Zhang, Muqiu
AU  - Zhang M
AD  - Department of Obstetrics and Gynaecology, Peking University First Hospital, 
      Beijing 100034, China.
AD  - Beijing Key Laboratory of Maternal Foetal Medicine of Gestational Diabetes 
      Mellitus, Beijing 100034, China.
AD  - Peking University, Beijing 100034, China.
FAU - Liu, Mengtong
AU  - Liu M
AD  - Department of Obstetrics and Gynaecology, Peking University First Hospital, 
      Beijing 100034, China.
AD  - Beijing Key Laboratory of Maternal Foetal Medicine of Gestational Diabetes 
      Mellitus, Beijing 100034, China.
AD  - Peking University, Beijing 100034, China.
FAU - Yang, Huixia
AU  - Yang H
AD  - Department of Obstetrics and Gynaecology, Peking University First Hospital, 
      Beijing 100034, China.
AD  - Beijing Key Laboratory of Maternal Foetal Medicine of Gestational Diabetes 
      Mellitus, Beijing 100034, China.
AD  - Peking University, Beijing 100034, China.
LA  - eng
PT  - Journal Article
DEP - 20231024
PL  - China
TA  - Chin Med J (Engl)
JT  - Chinese medical journal
JID - 7513795
SB  - IM
EDAT- 2023/11/15 00:41
MHDA- 2023/11/15 00:41
CRDT- 2023/11/14 21:12
PHST- 2023/02/10 00:00 [received]
PHST- 2023/11/15 00:41 [medline]
PHST- 2023/11/15 00:41 [pubmed]
PHST- 2023/11/14 21:12 [entrez]
AID - 00029330-990000000-00823 [pii]
AID - 10.1097/CM9.0000000000002840 [doi]
PST - aheadofprint
SO  - Chin Med J (Engl). 2023 Oct 24. doi: 10.1097/CM9.0000000000002840.