法卡灵 A 通过激活 SIK1 增加 PDE4 活性并抑制 cAMP 信号通路来抑制肝糖异生。
Activation of SIK1 by phanginin A inhibits hepatic gluconeogenesis by increasing PDE4 activity and suppressing the cAMP signaling pathway.
机构信息
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; University of Chinese Academy of Sciences, Beijing, 100049, PR China.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China.
出版信息
Mol Metab. 2020 Nov;41:101045. doi: 10.1016/j.molmet.2020.101045. Epub 2020 Jun 26.
OBJECTIVE
Salt-induced kinase 1 (SIK1) acts as a key modulator in many physiological processes. However, the effects of SIK1 on gluconeogenesis and the underlying mechanisms have not been fully elucidated. In this study, we found that a natural compound phanginin A could activate SIK1 and further inhibit gluconeogenesis. The mechanisms by which phanginin A activates SIK1 and inhibits gluconeogenesis were explored in primary mouse hepatocytes, and the effects of phanginin A on glucose homeostasis were investigated in ob/ob mice.
METHODS
The effects of phanginin A on gluconeogenesis and SIK1 phosphorylation were examined in primary mouse hepatocytes. Pan-SIK inhibitor and siRNA-mediated knockdown were used to elucidate the involvement of SIK1 activation in phanginin A-reduced gluconeogenesis. LKB1 knockdown was used to explore how phanginin A activated SIK1. SIK1 overexpression was used to evaluate its effect on gluconeogenesis, PDE4 activity, and the cAMP pathway. The acute and chronic effects of phanginin A on metabolic abnormalities were observed in ob/ob mice.
RESULTS
Phanginin A significantly increased SIK1 phosphorylation through LKB1 and further suppressed gluconeogenesis by increasing PDE4 activity and inhibiting the cAMP/PKA/CREB pathway in primary mouse hepatocytes, and this effect was blocked by pan-SIK inhibitor HG-9-91-01 or siRNA-mediated knockdown of SIK1. Overexpression of SIK1 in hepatocytes increased PDE4 activity, reduced cAMP accumulation, and thereby inhibited gluconeogenesis. Acute treatment with phanginin A reduced gluconeogenesis in vivo, accompanied by increased SIK1 phosphorylation and PDE4 activity in the liver. Long-term treatment of phanginin A profoundly reduced blood glucose levels and improved glucose tolerance and dyslipidemia in ob/ob mice.
CONCLUSION
We discovered an unrecognized effect of phanginin A in suppressing hepatic gluconeogenesis and revealed a novel mechanism that activation of SIK1 by phanginin A could inhibit gluconeogenesis by increasing PDE4 activity and suppressing the cAMP/PKA/CREB pathway in the liver. We also highlighted the potential value of phanginin A as a lead compound for treating type 2 diabetes.
目的
盐诱导激酶 1（SIK1）在许多生理过程中充当关键调节剂。然而，SIK1 对糖异生的影响及其潜在机制尚未完全阐明。在本研究中，我们发现天然化合物 phanginin A 可以激活 SIK1 并进一步抑制糖异生。在原代小鼠肝细胞中探索了 phanginin A 激活 SIK1 和抑制糖异生的机制，并在 ob/ob 小鼠中研究了 phanginin A 对葡萄糖稳态的影响。
方法
在原代小鼠肝细胞中检测了 phanginin A 对糖异生和 SIK1 磷酸化的影响。使用泛 SIK 抑制剂和 siRNA 介导的敲低来阐明 SIK1 激活在 phanginin A 减少糖异生中的作用。使用 LKB1 敲低来探索 phanginin A 如何激活 SIK1。使用 SIK1 过表达来评估其对糖异生、PDE4 活性和 cAMP 途径的影响。在 ob/ob 小鼠中观察了 phanginin A 对代谢异常的急性和慢性影响。
结果
phanginin A 通过 LKB1 显著增加 SIK1 磷酸化，进一步通过增加 PDE4 活性和抑制 cAMP/PKA/CREB 途径抑制原代小鼠肝细胞中的糖异生，该作用被泛 SIK 抑制剂 HG-9-91-01 或 SIK1 的 siRNA 介导的敲低阻断。在肝细胞中过表达 SIK1 增加了 PDE4 活性，减少了 cAMP 积累，从而抑制了糖异生。phanginin A 的急性治疗降低了体内的糖异生，同时增加了肝脏中 SIK1 的磷酸化和 PDE4 活性。长期治疗 phanginin A 可显著降低 ob/ob 小鼠的血糖水平，并改善葡萄糖耐量和血脂异常。
结论
我们发现了 phanginin A 抑制肝糖异生的未被认识的作用，并揭示了一种新的机制，即 phanginin A 通过激活 SIK1 增加 PDE4 活性并抑制 cAMP/PKA/CREB 途径在肝脏中抑制糖异生。我们还强调了 phanginin A 作为治疗 2 型糖尿病的潜在价值。
Zotero 插件