Ginsenoside Rg1 Inhibits Glucagon-Induced Hepatic Gluconeogenesis through Akt-FoxO1 Interaction.
Ginsenoside Rg1 Inhibits Glucagon-Induced Hepatic Gluconeogenesis through Akt-FoxO1 Interaction.
复制标题
人参皂苷 Rg1 通过 Akt-FoxO1 相互作用抑制胰高血糖素诱导的肝糖异生
作者：
Liu Q;Zhang FG;Zhang WS;Pan A;Yang YL;Liu JF;Li P;Liu BL;Qi LW
理由胰高血糖素参与肝糖原生成，在 2 型糖尿病中起着关键作用。据报道，人参皂甙具有抗糖尿病活性。人参皂苷 Rg1 是人参中一种主要的丙三醇型皂苷。本研究旨在探讨 Rg1 对胰高血糖素诱导的肝糖生成的调节作用。
方法：在高脂饮食（HFD）喂养的小鼠和胰高血糖素诱导的 C57BL/6J 小鼠中研究 Rg1 的作用。葡萄糖代谢通过口服葡萄糖耐量试验和丙酮酸耐量试验进行评估。采用免疫荧光、免疫沉淀、siRNA 沉默、药物抑制剂和活性位点突变体等方法在原代肝细胞或 HepG2 细胞中研究了 Rg1 对 Akt-FoxO1 相互作用的调控作用。
结果显示在高密度脂蛋白胆固醇喂养的小鼠中观察到空腹胰高血糖素水平异常升高，这在很大程度上导致了空腹血浆葡萄糖水平的升高。不适当的空腹胰高血糖素分泌会使 Akt 失活，并通过上调 FoxO1 的活性促进肝糖生成。Rg1 部分通过与 Ser473 位点的 Akt 结合，维持了胰高血糖素受损的 Akt 激活。Rg1 还能促进 Akt 与 FoxO1 结合，并通过磷酸化使 FoxO1 失活。因此，Rg1 通过减少磷酸烯醇丙酮酸羧激酶（PEPCK）和葡萄糖 6-磷酸酶（G6Pase）的转录，降低了肝糖的产生。siRNA 沉默 Akt 和 Akt 抑制剂三尖杉酯碱都削弱了 Rg1 对空腹激素胰高血糖素反应的影响。
结论人参皂苷 Rg1 将 Akt 在 Ser473 处磷酸化是其降低糖元生成作用的关键，这表明人参皂苷 Rg1 具有对空腹激素胰高血糖素进行药物干预的潜力。
Rationale: Glucagon is involved in hepatic gluconeogenesis, playing a key role in type 2 diabetes. Ginsenosides are reported to have antidiabetic activities. Ginsenoside Rg1 is a major propanaxatriol-type saponin in ginseng. This study aims to investigate the regulatory effects of Rg1 on glucagon-induced hepatic glucose production. Methods: The effects of Rg1 were investigated in high-fat-diet (HFD)-fed mice and glucagon-challenged C57BL/6J mice. Glucose metabolism was evaluated by oral glucose tolerance test and pyruvate tolerance test. The role of Rg1 on the regulation of Akt-FoxO1 interaction was performed using immunofluorescence, immunoprecipitation, siRNA silencing, pharmacological inhibitor and active-site mutant in primary hepatocytes or HepG2 cells. Results: Abnormally elevated fasting glucagon levels were observed in HFD-fed mice, contributing significantly to increased fasting plasma glucose levels. Inappropriate fasting glucagon secretion inactivated Akt and promoted hepatic glucose production via upregulation of FoxO1 activity. Rg1 preserved glucagon-impaired Akt activation partly by binding to Akt at Ser473 site. Rg1 also promoted Akt binding to FoxO1 and inactivated FoxO1 by phosphorylation. Consequently, Rg1 decreased the hepatic glucose production through a decrease in transcription of phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase). Both siRNA silencing of Akt and Akt inhibitor triciribine attenuated the effects of Rg1 in response to fasting hormone glucagon. Conclusion: Akt phosphorylation at Ser473 by ginsenoside Rg1 is critical for its gluconeogenesis-lowering effect, suggesting a potential for pharmaceutical intervention in response to fasting hormone glucagon.
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