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Background <p>Fetal hepatic glycogen is essential for intrauterine development and postnatal metabolic adaptation. This study aimed to explore the impact of intrauterine exposure to angiotensin II type 1 receptor autoantibodies (AT1-AA) on fetal hepatic glycogen homeostasis and underlying mechanisms.</p> Methods <p>AT1-AA-positive pregnant rat models were established by intravenous administration of AT1-AA on gestational days 13 and 15, with angiotensin II- and L-NAME-treated groups serving as controls. Serum levels of AT1-AA in pregnant rats were quantified using ELISA. Fetal hepatic glycogen content was evaluated through PAS staining and an anthrone-sulfuric acid assay kit. On gestational day 18, fetal livers were harvested for RNA sequencing. Alterations in signaling molecules in hepatocytes were analyzed by Western blot.</p> Results <p>Unlike the angiotensin II- and L-NAME-treated groups, which similarly induced placental ischemia and growth restriction, intrauterine exposure of AT1-AA uniquely reduced fetal hepatic glycogen content at gestational day 18. This reduction was attributed to impaired glycogen synthesis, as characterized by decreased GYS2 expression and glycogen synthase activity. Transcriptomic profiling revealed that suppression of the PI3K/AKT pathway was the predominant mechanism involved. Both in vivo and in vitro studies confirmed that AT1-AA-mediated PI3K/AKT inhibition occurs through AT1R activation. Either stimulation of the PI3K/AKT pathway or blockade of AT1R significantly restored glycogen synthesis.</p> Conclusions <p>Our study identifies AT1-AA as a unique maternal factor that selectively impairs fetal hepatic glycogen storage via AT1R-mediated suppression of PI3K/AKT pathway.</p>

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AT1R autoantibody impedes fetal hepatic glycogen synthesis by inhibiting PI3K/AKT signaling pathway during late gestation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月17日

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  • Jingwei Bian,
  • Wang Wang,
  • Pengli Wang,
  • Lina Bai,
  • Chunyu He,
  • Mingming Yue,
  • Xiang Cheng,
  • Huirong Liu,
  • Suli Zhang

摘要

Background

Fetal hepatic glycogen is essential for intrauterine development and postnatal metabolic adaptation. This study aimed to explore the impact of intrauterine exposure to angiotensin II type 1 receptor autoantibodies (AT1-AA) on fetal hepatic glycogen homeostasis and underlying mechanisms.

Methods

AT1-AA-positive pregnant rat models were established by intravenous administration of AT1-AA on gestational days 13 and 15, with angiotensin II- and L-NAME-treated groups serving as controls. Serum levels of AT1-AA in pregnant rats were quantified using ELISA. Fetal hepatic glycogen content was evaluated through PAS staining and an anthrone-sulfuric acid assay kit. On gestational day 18, fetal livers were harvested for RNA sequencing. Alterations in signaling molecules in hepatocytes were analyzed by Western blot.

Results

Unlike the angiotensin II- and L-NAME-treated groups, which similarly induced placental ischemia and growth restriction, intrauterine exposure of AT1-AA uniquely reduced fetal hepatic glycogen content at gestational day 18. This reduction was attributed to impaired glycogen synthesis, as characterized by decreased GYS2 expression and glycogen synthase activity. Transcriptomic profiling revealed that suppression of the PI3K/AKT pathway was the predominant mechanism involved. Both in vivo and in vitro studies confirmed that AT1-AA-mediated PI3K/AKT inhibition occurs through AT1R activation. Either stimulation of the PI3K/AKT pathway or blockade of AT1R significantly restored glycogen synthesis.

Conclusions

Our study identifies AT1-AA as a unique maternal factor that selectively impairs fetal hepatic glycogen storage via AT1R-mediated suppression of PI3K/AKT pathway.