Shi Yu, Wu Xing-de, Liu Yanli, Shen Yu, Qu Hui, Zhao Qin-Shi, Leng Ying, Huang Suling
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
University of Chinese Academy of Sciences, Beijing, 100049, China.
Nat Prod Bioprospect. 2025 Apr 7;15(1):24. doi: 10.1007/s13659-025-00504-z.
Salt-inducible kinase 1 (SIK1) participates in various physiological processes, yet its involvement in regulating skeletal muscle glucose uptake remains unclear. Previously, we showed that phanginin A, a natural compound isolated from Caesalpinia sappan Linn, activated SIK1 to suppress gluconeogenesis in hepatocytes. Here, we aimed to elucidate the effects of SIK1 on skeletal muscle glucose uptake by using phanginin A. The C2C12 myotubes were incubated with phanginin A and then glucose uptake, mRNA levels, membrane GLUT4 content, phosphorylation levels of proteins in SIK1/HDACs and Akt/AS160 signaling pathways were determined. Phanginin A significantly promoted glucose uptake, while the pan-SIK inhibitor or knocking down SIK1 expression abolished the promotion. Further exploration showed that phanginin A enhanced GLUT4 mRNA levels by increasing histone deacetylase (HDAC) 4/5 phosphorylation and MEF2a mRNA and protein level, and knocking down SIK1 blocked these effects. Additionally, phanginin A induced HDAC7 phosphorylation, upregulated the junction plakoglobin (JUP) expression and Akt/AS160 phosphorylation. Knocking down JUP or SIK1 both attenuated the phanginin A-induced Akt/AS160 signaling and glucose uptake, suggesting that activation of SIK1 by phanginin A inactivated HDAC7 to increase JUP expression and Akt/AS160 phosphorylation, led to upregulation of GLUT4 translocation and glucose uptake. In vivo study showed that phanginin A increased phosphorylation levels of SIK1, HDAC4/5/7, Akt/AS160, and gene expression of MEF2a, GLUT4 and JUP, accompanied by elevated membrane GLUT4 and glycogen content in gastrocnemius muscle of C57BL/6 J mice, indicating enhanced glucose utilization. These findings reveal a novel mechanism that SIK1 activation by phanginin A stimulates skeletal muscle glucose uptake through phosphorylating HADC4/5/7 and the subsequent enhancement of GLUT4 expression and translocation.
盐诱导激酶1（SIK1）参与多种生理过程，但其在调节骨骼肌葡萄糖摄取中的作用仍不清楚。此前，我们发现从苏木中分离出的天然化合物番荔枝宁A可激活SIK1以抑制肝细胞中的糖异生。在此，我们旨在利用番荔枝宁A阐明SIK1对骨骼肌葡萄糖摄取的影响。将C2C12肌管与番荔枝宁A孵育，然后测定葡萄糖摄取、mRNA水平、膜GLUT4含量、SIK1/HDACs和Akt/AS160信号通路中蛋白质的磷酸化水平。番荔枝宁A显著促进葡萄糖摄取，而泛SIK抑制剂或敲低SIK1表达则消除了这种促进作用。进一步研究表明，番荔枝宁A通过增加组蛋白去乙酰化酶（HDAC）4/5磷酸化以及MEF2a mRNA和蛋白水平来提高GLUT4 mRNA水平，敲低SIK1可阻断这些作用。此外，番荔枝宁A诱导HDAC7磷酸化，上调桥粒斑珠蛋白（JUP）表达以及Akt/AS160磷酸化。敲低JUP或SIK1均减弱了番荔枝宁A诱导的Akt/AS160信号传导和葡萄糖摄取，这表明番荔枝宁A激活SIK1使HDAC7失活以增加JUP表达和Akt/AS160磷酸化，导致GLUT4转位和葡萄糖摄取上调。体内研究表明，番荔枝宁A增加了SIK1、HDAC4/5/7、Akt/AS160的磷酸化水平以及MEF2a、GLUT4和JUP的基因表达，同时伴有C57BL/6 J小鼠腓肠肌中膜GLUT4和糖原含量升高，表明葡萄糖利用率提高。这些发现揭示了一种新机制，即番荔枝宁A激活SIK1通过磷酸化HADC4/5/7以及随后增强GLUT4表达和转位来刺激骨骼肌葡萄糖摄取。
