神经氨酸酶1的非酶功能抑制了小鼠的肝胰高血糖素反应。
A non-enzymatic function of neuraminidase 1 restrains hepatic glucagon response in mice.
摘要(中文译文)
糖尿病中由胰高血糖素驱动的肝糖异生失调是高血糖的关键促成因素，然而限制该通路的分子机制仍不完全清楚。本研究发现神经氨酸酶1（NEU1）是糖尿病中肝脏胰高血糖素驱动糖异生的抑制因子。我们发现，胰高血糖素刺激下调肝脏NEU1表达，其与糖尿病患者空腹血糖水平呈负相关。在功能上，肝脏特异性NEU1过表达可拮抗胰高血糖素刺激小鼠和高脂饮食（HFD）喂养小鼠的肝糖异生，而NEU1敲除则增强胰高血糖素反应。此外，NEU1以非酶方式抑制肝糖异生。在机制上，NEU1与SAM68相互作用以激活GCN5启动子，导致PGC-1α乙酰化增加。在HFD喂养小鼠中，GCN5敲低可消除NEU1过表达对糖异生的抑制作用。一项靶向NEU1的筛选策略鉴定出α-常春藤皂苷和齐墩果酸可通过稳定NEU1和增强SAM68结合来协同抑制肝脏胰高血糖素反应。在此，我们展示了NEU1在肝脏胰高血糖素反应中的抑制作用，并提出了靶向NEU1治疗糖尿病的潜在途径。
Abstract
Dysregulated hepatic gluconeogenesis driven by glucagon is a key contributor to hyperglycemia in diabetes, yet the molecular mechanisms that restrain this pathway remain incompletely understood. This study reveals neuraminidase 1 (NEU1) as a suppressor of hepatic glucagon-driven gluconeogenesis in diabetes. We found that glucagon challenge downregulates hepatic NEU1 expression, inversely correlating with fasting blood glucose levels in individuals with diabetes. Functionally, liver-specific NEU1 overexpression antagonizes hepatic gluconeogenesis in glucagon-challenged mice and high fat diet (HFD)-fed mice, while NEU1 knockout augments glucagon response. Additionally, NEU1 inhibits hepatic gluconeogenesis in a non-enzymatic manner. Mechanistically, NEU1 interacts with SAM68 to activate GCN5 promoter, leading to increase of PGC-1α acetylation. The inhibitory effect of NEU1 overexpression on gluconeogenesis is abrogated by GCN5 knockdown in HFD-fed mice. A NEU1-targeted screening strategy identified α-hederin and oleanolic acid as synergistic inhibitors of hepatic glucagon response through NEU1 stabilization and SAM68 binding enhancement. Here we show an inhibitory role of NEU1 in the hepatic glucagon response and suggest a potential avenue for targeting NEU1 to treat diabetes.
如何引用
AMA
Xiao-Meng Sun, Li-Zeng Zhu, Guo-Dong Wu, Ting Wang, Xin-Yue Zhou, Xi-Hua Liu, et al. A non-enzymatic function of neuraminidase 1 restrains hepatic glucagon response in mice.. Nature communications. 2026; doi:10.1038/s41467-026-72630-2.
APA
Xiao-Meng Sun, Li-Zeng Zhu, Guo-Dong Wu, Ting Wang, Xin-Yue Zhou, Xi-Hua Liu, et al (2026). A non-enzymatic function of neuraminidase 1 restrains hepatic glucagon response in mice.. Nature communications. https://doi.org/10.1038/s41467-026-72630-2
GB/T 7714
Xiao-Meng Sun, Li-Zeng Zhu, Guo-Dong Wu, Ting Wang, Xin-Yue Zhou, Xi-Hua Liu, et al. A non-enzymatic function of neuraminidase 1 restrains hepatic glucagon response in mice.[J]. Nature communications, 2026 doi:10.1038/s41467-026-72630-2.
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