5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside and metformin inhibit hepatic glucose phosphorylation by an AMP-activated protein kinase-independent effect on glucokinase translocation
5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside and metformin inhibit hepatic glucose phosphorylation by an AMP-activated protein kinase-independent effect on glucokinase translocation
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DOI：
10.2337/diabetes.55.04.06.db05-1178
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发表时间：
2006-04-01
期刊：
影响因子：
7.7
通讯作者：
Hue, L
中科院分区：
文献类型：
--
作者：
Guigas, B;Bertrand, L;Hue, L
amp活化蛋白激酶（AMPK）控制肌肉中的葡萄糖摄取和糖酵解。它在肝脏葡萄糖摄取中的作用知之甚少，葡萄糖摄取是由葡萄糖激酶控制的。我们在这里报道了5-氨基咪唑-4-羧酰胺-1- β - d -核呋喃苷（AICAR）、二甲双胍和寡霉素激活AMPK并抑制大鼠肝细胞中的葡萄糖磷酸化和糖酵解。体外实验表明，这种抑制不是由于AMPK对葡萄糖激酶或其调节蛋白的直接磷酸化。相比之下，AMPK磷酸化肝脏6-磷酸果糖-2-激酶-/果糖-2,6-双磷酸酶而不影响活性。内皮型一氧化氮合酶、应激激酶和磷脂酰肌醇3激酶途径的抑制剂不能抵消AICAR、二甲双胍或寡霉素的作用，这表明这些信号通路没有参与。有趣的是，在缺乏肝脏α(1)和α (2) AMPK催化亚基的新工程小鼠的原代培养肝细胞中，这些众所周知的AMPK激活剂对葡萄糖磷酸化的抑制作用持续存在，这表明这种作用显然不是由AMPK介导的。最后，AICAR、二甲双胍和寡霉素被发现抑制葡萄糖诱导的葡萄糖激酶从细胞核到胞浆的易位，其机制可能与在这些条件下观察到的细胞内ATP浓度下降有关。
AMP-activated protein kinase (AMPK) controls glucose uptake and glycolysis in muscle. Little is known about its role in liver glucose uptake, which is controlled by glucokinase. We report here that 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR), metformin, and oligomycin activated AMPK and inhibited glucose phosphorylation and glycolysis in rat hepatocytes. In vitro experiments demonstrated that this inhibition was not due to direct phosphorylation of glucokinase or its regulatory protein by AMPK. By contrast, AMPK phosphorylated liver 6-phosphofructo-2-kinase-/fructose-2,6-bisphosphatase without affecting activity. Inhibitors of the endothelial nitric oxide synthase, stress kinases, and phosphatidylinositol 3-kinase pathways did not counteract the effects of AICAR, metformin, or oligomycin, suggesting that these signaling pathways were not involved. Interestingly, the inhibitory effect on glucose phosphorylation of these well-known AMPK activators persisted in primary cultured hepatocytes from newly engineered mice lacking both liver alpha(1) and alpha(2) AMPK catalytic subunits, demonstrating that this effect was clearly not mediated by AMPK. Finally, AICAR, metformin, and oligomycin were found to inhibit the glucose-induced translocation of glucokinase from the nucleus to the cytosol by a mechanism that could be related to the decrease in intracellular ATP concentrations observed in these conditions.