AMPK is one of the core molecules regulating bioenergy metabolism and an important target for the treatment of metabolic diseases. AMPK senses cell metabolism. Lack of glucose, ATP, etc. causes AMPK activation1, promotes energy production in cells, and inhibits various energy-consuming physiological processes, thereby maintaining cell metabolic homeostasis. However, people know very little about the negative regulation mechanism that inhibits AMPK activity, and lack a comprehensive understanding of AMPK signal pathway regulation. Studying how excess energy inhibits AMPK signaling pathway can not only help us fully understand the regulation of AMPK signaling pathway, but also has important significance for exploring the molecular mechanisms and treatment strategies of metabolic diseases such as obesity and type 2 diabetes.
On January 4, 2021, the Xiao Ruiping group of Future Technology College published an online article entitled”Negative Regulation of AMPK Signaling by High Glucose via E3 Ubiquitin Ligase MG53″ in Molecular Cell, reporting that high glucose inhibits AMPK activity The regulation mechanism of schizophrenia provides a new theory for metabolic disorders caused by excess energy, especially skeletal muscle metabolic disorders.
This study found that high sugar has a dual inhibitory effect on the protein level and kinase activity of AMPK’s catalytic subunit AMPKα. First of all, high glucose stimulation did not cause an increase in ATP levels, but a transient increase in the ratio of AMP/ATP and ADP/ATP, so ATP is not the cause of the inhibition of AMPK signal by high glucose. But high sugar promotes the production of reactive oxygen species (ROS) in cells. Elevated ROS activates AKT, so that the serine at position 485/491 of AMPKα (S485 in AMPKα1, S491 in AMPKα2) is phosphorylated by AKT. The phosphorylation of S485/491 site promotes AMPKα recruitment of the highly expressed E3 ubiquitination ligase MG53 in skeletal muscle. The previous research of Xiao Ruiping’s group showed that the expression level of MG53 increased in patients and animal models of metabolic syndrome, and interfered with the insulin signaling pathway2,3. In this study, it was further found that MG53 bound to AMPKα catalyzed the ubiquitination of lysine at position 470 of AMPKα, and caused the ubiquitination-dependent degradation of AMPKα, resulting in a decrease in AMPKα protein levels. In addition, ROS also caused the dissociation of AMPKα from its upstream kinase LKB1, resulting in a decrease in the phosphorylation level of threonine at position 172 of AMPKα, resulting in a decrease in AMPKα activity. In summary, this work reveals a new signaling pathway that ROS caused by high glucose inhibits AMPK, and the important role of this new pathway in maintaining the homeostasis of energy metabolism in skeletal muscle cells.
Figure 1. The negative regulatory mechanism of high sugar on AMPK
Jiang Peng, a PhD student at the Institute of Molecular Medicine, School of Future Technology, Peking University, and Ren Lejiao and Zhi Li, Ph.D. candidates at the Joint Center for Life Sciences, Frontier Interdisciplinary Research Institute, are the co-first authors of the paper. Professor Ruiping Xiao and Associate Researcher Hu Xinli serve as the paper Co-corresponding author. This work was supported by the Key R&D Program of the Ministry of Science and Technology, the National Natural Science Foundation of China, the Beijing Municipal Science and Technology Commission and the Beijing Municipal Natural Science Foundation of China.
1 Lin, S. C. & Hardie, D. G. AMPK:Sensing Glucose as well as Cellular Energy Status. Cell metabolism 27, 299-313, doi:10.1016/j.cmet.2017.10.009 (2018).
2 Song, R. et al. Central role of E3 ubiquitin ligase MG53 in insulin resistance and metabolic disorders. Nature 494, 375-379, doi:10.1038/nature11834 (2013).
3 Yi, J. S. et al. MG53-induced IRS-1 ubiquitination negatively regulates skeletal myogenesis and insulin signalling. Nature communications 4, 2354, doi:10.1038/ncomms3354 (2013).