SRM介导的亚精胺合成将脂质超载与AMPK通路联系起来，以调节肝脏胰岛素信号传导和葡萄糖生成
SRM-Mediated Spermidine Synthesis Links Lipid Overload With AMPK Pathway to Regulate Hepatic Insulin Signaling and Gluconeogenesis.
摘要(中文译文)
多胺代谢对细胞增殖和分化至关重要；然而，其在胰岛素信号调控中的具体作用仍知之甚少。在此，我们揭示了亚精胺合成酶（SRM）在将脂质过载与胰岛素抵抗相关联方面的一个意外作用。在硬骨鱼模型中，我们证明高脂饮食（HFD）通过X盒结合蛋白1（XBP1）依赖性转录抑制来抑制肝脏SRM表达。SRM的缺失，无论是通过药理学抑制还是siRNA介导的敲低，均会损害胰岛素信号传导，表现为AKT磷酸化降低和糖异生酶表达增加。相反，SRM的过表达增强胰岛素敏感性并抑制糖异生。在机制上，SRM介导的胰岛素信号通路调控依赖于其下游代谢产物亚精胺（SPD），后者通过AMP活化蛋白激酶（AMPK）通路发挥作用，因为SPD的有益效应可被AMPK抑制剂Compound C所消除。此外，膳食HFD使黄姑鱼肝脏SPD水平显著降低35%，并使p-AKT/AKT比值降低58%，同时使血糖水平升高39%。相反，与HFD组相比，SPD补充使p-AKT/AKT比值升高131%，并使血糖水平降低20%。综上所述，我们的研究结果确立了SRM-SPD轴作为营养应激与胰岛素抵抗之间的关键纽带，并突出表明SPD可作为对抗硬骨鱼胰岛素抵抗和葡萄糖不耐受的潜在营养保健品。
Abstract
Polyamine metabolism is essential for cell proliferation and differentiation; however, its specific role in insulin signaling regulation remains poorly understood. Here, we uncover an unexpected role for spermidine synthase (SRM) in linking lipid overload to insulin resistance. In a teleost fish model, we demonstrate high fat diet (HFD) suppresses hepatic SRM expression via X-box binding protein 1 (XBP1)-dependent transcriptional repression. Loss of SRM, either by pharmacological inhibition or siRNA-mediated knockdown, impairs insulin signaling, as evidenced by decreased AKT phosphorylation and increased expression of gluconeogenic enzymes. Conversely, overexpression of SRM enhances insulin sensitivity and suppresses gluconeogenesis. Mechanistically, SRM-mediated regulation of the insulin signaling pathway is dependent on its downstream metabolite spermidine (SPD), which functions through AMP-activated protein kinase (AMPK) pathway, as the beneficial effects of SPD are abolished by the AMPK inhibitor Compound C. In addition, dietary HFD significantly decreases hepatic SPD levels by 35% and reduces the p-AKT/AKT ratio by 58% in croaker, while it elevates blood glucose levels by 39%. Conversely, SPD supplementation increases the p-AKT/AKT ratio by 131% and lowers blood glucose levels by 20%, compared with the HFD group. Taken together, our findings establish the SRM-SPD axis as a critical link between nutritional stress and insulin resistance, and highlight SPD as a potential nutraceutical for combating insulin resistance and glucose intolerance in teleost fish.
如何引用
AMA
Zengqi Zhao, Geye Ding, Yanan Shen, Wencong Lai, Shanshan Yang, Xiaolu Zhang, et al. SRM-Mediated Spermidine Synthesis Links Lipid Overload With AMPK Pathway to Regulate Hepatic Insulin Signaling and Gluconeogenesis.. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2026; doi:10.1096/fj.202601021R.
APA
Zengqi Zhao, Geye Ding, Yanan Shen, Wencong Lai, Shanshan Yang, Xiaolu Zhang, et al (2026). SRM-Mediated Spermidine Synthesis Links Lipid Overload With AMPK Pathway to Regulate Hepatic Insulin Signaling and Gluconeogenesis.. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. https://doi.org/10.1096/fj.202601021R
GB/T 7714
Zengqi Zhao, Geye Ding, Yanan Shen, Wencong Lai, Shanshan Yang, Xiaolu Zhang, et al. SRM-Mediated Spermidine Synthesis Links Lipid Overload With AMPK Pathway to Regulate Hepatic Insulin Signaling and Gluconeogenesis.[J]. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2026 doi:10.1096/fj.202601021R.
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