Berberine promotes glucose uptake and inhibits gluconeogenesis by inhibiting deacetylase SIRT3
Berberine promotes glucose uptake and inhibits gluconeogenesis by inhibiting deacetylase SIRT3
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小檗碱通过抑制脱乙酰酶 SIRT3 促进葡萄糖摄取并抑制糖异生
DOI：
10.1007/s12020-018-1689-y
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发表时间：
2018-08
期刊：
影响因子：
3.7
通讯作者：
Mingming Zhang
中科院分区：
文献类型：
--
作者：
Bingjie Zhang;Yida Pan;Lei Xu;Dehua Tang;Robert Gregory Dorfman;Qian Zhou;Yuyao Yin;Yang Li;Lixing Zhou;Shimin Zhao;Xiaoping Zou;Lei Wang;Mingming Zhang
目的多项研究证实小檗碱对2型糖尿病患者具有降糖作用。尽管小檗碱的作用机制涉及改善胰岛素敏感性，但其降血糖机制仍不清楚。在此我们展示了小檗碱拮抗胰高血糖素信号传导的新机制，并发现SIRT3参与了小檗碱的降血糖作用。方法采用基因敲除和过表达的方法评估小檗碱对SIRT3的抑制作用。通过免疫印迹和代谢监测评估SIRT3的下游信号通路和降血糖作用。结果我们发现小檗碱通过抑制去乙酰酶SIRT3导致线粒体功能障碍和AMP积累。我们证实AMP的积累激活了AMPK信号通路并进一步促进了葡萄糖的摄取。同时，AMP 积累降低了环 AMP (cAMP) 水平，并消除了蛋白激酶 A (PKA) 关键蛋白靶标的磷酸化。此外，我们发现磷酸烯醇丙酮酸羧激酶 1 (PEPCK1) 是一种关键的糖异生酶，可以被胰高血糖素稳定。小檗碱通过拮抗胰高血糖素引起显着的 PEPCK1 泛素化和降解，并伴有高水平的 PEPCK1 乙酰化。有趣的是，小檗碱诱导的胰高血糖素抑制与 AMPK 激活无关。体外实验进一步证实了sirt3基因敲除小鼠的体内数据。结论小檗碱通过抑制SIRT3促进葡萄糖摄取并抑制糖异生，调节线粒体相关通路可能为抗糖尿病药物的开发提供新的途径。
ObjectiveMany studies have confirmed the glucose-lowering effect of berberine in type 2 diabetes patients. Although the mechanism of action of berberine involves the improvement of insulin sensitivity, its hypoglycemic mechanism remains elusive. Here we show a new mechanism by which berberine antagonizes glucagon signaling and find that SIRT3 is involved in the hypoglycemic effect of berberine.MethodsGene knockout and overexpression were used to assess the inhibitory effect of berberine on SIRT3. Downstream signaling pathways and the hypoglycemic effect of SIRT3 were evaluated by immunoblotting and metabolic monitoring.ResultsWe found that berberine led to mitochondrial dysfunction and AMP accumulation by inhibiting deacetylase SIRT3. We confirmed that AMP accumulation activated the AMPK signaling pathway and further promoted glucose uptake. Simultaneously, AMP accumulation reduced cyclic AMP (cAMP) levels and abrogated the phosphorylation of critical protein targets of protein kinase A (PKA). Furthermore, we found that phosphoenolpyruvate carboxykinase 1 (PEPCK1) is a key gluconeogenesis enzyme that can be stabilized by glucagon. Berberine caused significant PEPCK1 ubiquitination and degradation by antagonizing glucagon and was accompanied by high levels of PEPCK1 acetylation. Interestingly, berberine-induced glucagon inhibition is independent of AMPK activation. The in vivo data fromsirt3knockout mice were further confirmed by the in vitro experiments.ConclusionsBerberine promotes glucose uptake and inhibits gluconeogenesis by inhibiting SIRT3, and regulating mitochondria-related pathways may provide a novel approach to the development of antidiabetic drugs.
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