Guigas Bruno, Sakamoto Kei, Taleux Nellie, Reyna Sara M, Musi Nicolas, Viollet Benoit, Hue Louis
Hormone and Metabolic Research Unit, Université catholique de Louvain and de Duve Institute, Brussels, Belgium.
IUBMB Life. 2009 Jan;61(1):18-26. doi: 10.1002/iub.135.
5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICA riboside) has been extensively used in vitro and in vivo to activate the AMP-activated protein kinase (AMPK), a metabolic sensor involved in both cellular and whole body energy homeostasis. However, it has been recently highlighted that AICA riboside also exerts AMPK-independent effects, mainly on AMP-regulated enzymes and mitochondrial oxidative phosphorylation (OXPHOS), leading to the conclusion that new compounds with reduced off target effects are needed to specifically activate AMPK. Here, we review recent findings on newly discovered AMPK activators, notably on A-769662, a nonnucleoside compound from the thienopyridone family. We also report that A-769662 is able to activate AMPK and stimulate glucose uptake in both L6 cells and primary myotubes derived from human satellite cells. In addition, A-769662 increases AMPK activity and phosphorylation of its main downstream targets in primary cultured rat hepatocytes but, by contrast with AICA riboside, does neither affect mitochondrial OXPHOS nor change cellular AMP:ATP ratio. We conclude that A-769662 could be one of the new promising chemical agents to activate AMPK with limited AMPK-independent side effects.
5-氨基咪唑-4-甲酰胺-1-β-D-呋喃核糖苷（AICA核苷）已在体外和体内被广泛用于激活AMP活化蛋白激酶（AMPK），AMPK是一种参与细胞和全身能量稳态的代谢传感器。然而，最近有研究强调，AICA核苷也发挥不依赖AMPK的作用，主要作用于AMP调节的酶和线粒体氧化磷酸化（OXPHOS），从而得出结论，需要新的具有降低脱靶效应的化合物来特异性激活AMPK。在此，我们综述了关于新发现的AMPK激活剂的最新研究结果，特别是关于A-769662，一种来自噻吩并吡啶酮家族的非核苷化合物。我们还报告了A-769662能够在L6细胞和源自人卫星细胞的原代肌管中激活AMPK并刺激葡萄糖摄取。此外，A-769662可增加原代培养大鼠肝细胞中AMPK的活性及其主要下游靶点的磷酸化，但与AICA核苷不同的是，它既不影响线粒体OXPHOS，也不改变细胞内AMP:ATP比值。我们得出结论，A-769662可能是一种新的有前景的化学试剂，可在有限的不依赖AMPK的副作用下激活AMPK。
