Niclosamide activates the AMP-activated protein kinase complex containing the β2 subunit independently of AMP
Niclosamide activates the AMP-activated protein kinase complex containing the β2 subunit independently of AMP
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氯硝柳胺独立于 AMP 激活含有 β2 亚基的 AMP 激活蛋白激酶复合物
DOI：
10.1016/j.bbrc.2020.09.071
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Yuji Yamamoto
中科院分区：
文献类型：
--
作者：
Tsukasa Suzuki;Momoko Kojima;Yu Matsumoto;Ken-Ichi Kobayashi;Jun Inoue;Yuji Yamamoto
AMP激活蛋白激酶（AMPK）通过抑制合成代谢过程和激活分解代谢过程来调节细胞能量稳态。由于AMPK激活对代谢的有利生理作用，AMPK激活剂是代谢综合征的重要治疗靶点。最近的研究表明，氯硝柳胺是一种FDA批准的驱虫药，对寄生虫的线粒体发挥解偶联作用，可以通过激活AMPK来改善小鼠的血糖水平并减少肝脏脂肪变性。氯硝柳胺被认为通过线粒体解偶联增加AMP/ATP比率来激活AMPK，但其作用的细节仍不清楚。在这项研究中，我们发现氯硝柳胺也激活AMPK复合物，该复合物含有AMP不敏感的γ亚基。此外，氯硝柳胺对含有β2亚基而非β1亚基的AMPK复合物显示出更大的AMPK活化。将β2亚基的Ser 108残基替换为丙氨酸可抑制这种效应。氯硝柳胺显示了一种新的AMPK激活机制，独立于AMP/ATP比值的增加。
AMP-activated protein kinase (AMPK) regulates cellular energy homeostasis by suppressing anabolic processes and activating catabolic processes. AMPK activators are an important therapeutic target for metabolic syndrome due to favorable physiological effects of AMPK activation on metabolism. Recent studies show that niclosamide, an FDA-approved anthelmintic drug that exerts an uncoupling effect on the mitochondria of the parasite, improves blood glucose levels and reduces hepatic steatosis in mice via AMPK activation. Niclosamide is thought to activate AMPK by increasing AMP/ATP ratio through mitochondrial uncoupling, but details of its action remain unclear. In this study, we found that niclosamide also activates the AMPK complex, which contains the AMP-insensitive γ subunit. Further, niclosamide shows greater AMPK activation for the AMPK complex containing β2 subunit, but not the β1 subunit. This effect was inhibited by substituting the Ser108 residue of the β2 subunit to alanine. Niclosamide displays a novel AMPK activation mechanism independent of the increase in AMP/ATP ratio.