安普克
AMP活化蛋白激酶
自噬
泛素连接酶
蛋白激酶A
化学
细胞生物学
胰岛素抵抗
磷酸化
信号转导
胰岛素
泛素
药理学
生物
内分泌学
生物化学
细胞凋亡
基因
作者
Yuan Liu,Michael J. Jurczak,Travis Lear,Bo Lin,Mads Larsen,Jason R. Kennerdell,Yanwen Chen,Brydie R. Huckestein,Matthew K. Nguyen,Ferhan Tuncer,Yu Jiang,Satdarshan P. Monga,Christopher P. O’Donnell,Toren Finkel,Bill B. Chen,Rama K. Mallampalli
标识
DOI:10.1038/s41589-020-00723-0
摘要
The adenosine monophosphate (AMP)-activated protein kinase (Ampk) is a central regulator of metabolic pathways, and increasing Ampk activity has been considered to be an attractive therapeutic target. Here, we have identified an orphan ubiquitin E3 ligase subunit protein, Fbxo48, that targets the active, phosphorylated Ampkα (pAmpkα) for polyubiquitylation and proteasomal degradation. We have generated a novel Fbxo48 inhibitory compound, BC1618, whose potency in stimulating Ampk-dependent signaling greatly exceeds 5-aminoimidazole-4-carboxamide-1-β-ribofuranoside (AICAR) or metformin. This compound increases the biological activity of Ampk not by stimulating the activation of Ampk, but rather by preventing activated pAmpkα from Fbxo48-mediated degradation. We demonstrate that, consistent with augmenting Ampk activity, BC1618 promotes mitochondrial fission, facilitates autophagy and improves hepatic insulin sensitivity in high-fat-diet-induced obese mice. Hence, we provide a unique bioactive compound that inhibits pAmpkα disposal. Together, these results define a new pathway regulating Ampk biological activity and demonstrate the potential utility of modulating this pathway for therapeutic benefit.
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