Zhang Qin, Yuan Xi, Luan Xiaojin, Lei Ting, Li Yiran, Chu Wei, Yao Qi, Baker Philip N, Qi Hongbo, Li Hui
Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
Chongqing Key Laboratory of Maternal and Fetal Medicine, Chongqing Medical University, Chongqing, 400016, China.
Mol Med. 2024 Dec 20;30(1):257. doi: 10.1186/s10020-024-01028-x.
Gestational diabetes mellitus (GDM) has been associated with several fetal complications, such as macrosomia and fetal growth restriction (FGR). Infants from GDM associated FGR are at increased risk for adult-onset obesity and associated metabolic disorders. However, the underlying mechanisms of GDM associated FGR remain to be explored.
We analyzed placentas from GDM patients with FGR for ferroptosis markers and GLUT1 expression. High glucose conditions were established by adding different concentrations of D-Glucose to the 1640 cell culture medium. RSL3 were used to test ferroptosis sensitivity in trophoblast cells. GLUT1 was inhibited using siRNA or its inhibitor WZB117 to assess its impact on ferroptosis inhibition in HTR8/SVneo cell line. Mechanistic studies explored the effects of GLUT1 on AMPK and ACC phosphorylation, which in turn impacted lipid metabolism and ferroptosis. In mouse models, streptozotocin (STZ)-induced GDM was treated with WZB117 and the ferroptosis inhibitor liproxstatin-1 (Lip-1). Finally, AMPK and ACC phosphorylation levels were evaluated in GDM patient samples.
In this study, placentas from GDM patients with FGR showed signs of ferroptosis and upregulation of GLUT1. In cell models, high glucose conditions sensitized trophoblast cells to ferroptosis and induced GLUT1 expression. Interestingly, GLUT1 inhibition significantly suppressed ferroptosis in trophoblast cells under high glucose conditions. Mechanistically, elevated GLUT1 inhibited AMPK phosphorylation and reduced ACC phosphorylation, thereby promoting lipid synthesis and facilitating ferroptosis. In pregnant mice, STZ-induced hyperglycemia led to FGR, and treatment with either the GLUT1 inhibitor WZB117 or the ferroptosis inhibitor Lip-1 alleviated the FGR phenotype. Moreover, in vivo elevation of GLUT1 increased ferroptosis markers, decreased AMPK/ACC phosphorylation, and resulted in altered lipid metabolism, which likely contributed to the observed phenotype. Finally, placental samples from GDM patients showed reduced AMPK and ACC phosphorylation.
Our findings suggest a potential role of ferroptosis in GDM associated FGR and indicate that the dysregulated GLUT1-AMPK-ACC axis may be involved in the pathogenesis of GDM associated FGR in clinicals.
妊娠期糖尿病（GDM）与多种胎儿并发症相关，如巨大儿和胎儿生长受限（FGR）。患有GDM相关FGR的婴儿患成人期肥胖及相关代谢紊乱的风险增加。然而，GDM相关FGR的潜在机制仍有待探索。
我们分析了患有FGR的GDM患者胎盘的铁死亡标志物和葡萄糖转运蛋白1（GLUT1）表达。通过向1640细胞培养基中添加不同浓度的D-葡萄糖来建立高糖条件。使用RSL3检测滋养层细胞中铁死亡敏感性。使用小干扰RNA（siRNA）或其抑制剂WZB117抑制GLUT1，以评估其对HTR8/SVneo细胞系中铁死亡抑制的影响。机制研究探讨了GLUT1对腺苷酸活化蛋白激酶（AMPK）和乙酰辅酶A羧化酶（ACC）磷酸化的影响，这反过来又影响脂质代谢和铁死亡。在小鼠模型中，用WZB117和铁死亡抑制剂liproxstatin-1（Lip-1）治疗链脲佐菌素（STZ）诱导的GDM。最后，评估GDM患者样本中AMPK和ACC的磷酸化水平。
在本研究中，患有FGR的GDM患者胎盘显示出铁死亡迹象和GLUT1上调。在细胞模型中，高糖条件使滋养层细胞对铁死亡敏感并诱导GLUT1表达。有趣的是，抑制GLUT1可显著抑制高糖条件下滋养层细胞的铁死亡。机制上，GLUT1升高抑制AMPK磷酸化并降低ACC磷酸化，从而促进脂质合成并促进铁死亡。在妊娠小鼠中，STZ诱导的高血糖导致FGR，用GLUT1抑制剂WZB117或铁死亡抑制剂Lip-1治疗可减轻FGR表型。此外，体内GLUT1升高会增加铁死亡标志物，降低AMPK/ACC磷酸化，并导致脂质代谢改变，这可能导致了观察到的表型。最后，GDM患者的胎盘样本显示AMPK和ACC磷酸化降低。
我们的研究结果表明铁死亡在GDM相关FGR中可能起作用，并表明失调的GLUT1-AMPK-ACC轴可能参与临床GDM相关FGR的发病机制。
