Attenuating MKRN1 E3 ligase-mediated AMPKα suppression increases tolerance against metabolic stresses in mice
Authors:Hyunji Han1, Sehyun Chae2, Daehee Hwang2,3 and Jaewhan Song1
1 Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea.
2 Center for Plant Aging Research, Institute for Basic Science.
3 Department of New Biology, Daegu Gyeongbuk Institute of Science and Technology (DGIST), Daegu 42988, Republic of Korea.
Keywords:
AMPK, MKRN1, metabolic syndrome, obesity, diabetes.
Corresponding Author(s):
Conflict of interest statement:
The authors declare no conflict of interest.
Please cite this article as:
Hyunji Han, Sehyun Chae, Daehee Hwang and Jaewhan Song (2018). Attenuating MKRN1 E3 ligase-mediated AMPKα suppression increases tolerance against metabolic stresses in mice. Cell Stress 2(11): 325-328. doi: 10.15698/cst2018.11.164
© 2018 Han et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduction in any medium, provided the original author and source are acknowledged.
Abstract:
The 5′ adenosine monophosphate-activated protein kinase (AMPK) is an essential energy sensor in the cell, which, at low energy levels, instigates the cellular energy-generating systems along with suppression of the anabolic signaling pathways. The activation of AMPK through phosphorylation is a well-known process; however, activation alone is not sufficient, and knowledge about the other regulatory networks of post-translational modifications connecting the activities of AMPK to systemic metabolic syndromes is important, which is still lacking. The recent studies on Makorin Ring Finger Protein 1 (MKRN1) mediating the ubiquitination and proteasome-dependent degradation of AMPKa implicate that the post-translational modification of AMPK, regulating its protein homeostasis, could impose significant systemic metabolic effects (Lee et al. Nat Commun 9:3404). In this study, MKRN1 was identified as a novel E3 ligase for both AMPKα1 and α2. Mouse embryonic fibroblasts, genetically deleted for Mkrmn1, and Ampkα1 and α2, became stabilized with the suppression of lipogenesis pathways and an increase in nutrient consumption and mitochondria regeneration. Of note, the Mkrn1 knockout mice fed normal chow displayed no obvious phenotypic defects or abnormality, whereas the Mkrn1-null mice exhibited strong tolerance to metabolic stresses induced by high-fat diet (HFD). Thus, these mice, when compared with the HFD-induced wild type, were resistant to obesity, diabetes, and non-alcoholic fatty liver disease. Interestingly, in whole-body Mkrn1 knockout mouse, only the liver and white and brown adipose tissues displayed anincrease in the active phosphorylated AMPK levels, but no other organs, such as the hypothalamus, skeletal muscles, or pancreas, displayed such increases. Specific ablation of MKRN1 in the mouse liver using adenovirus prevented HFD-induced lipid accumulation in the liver and blood, implicating MKRN1 as a possible therapeutic target for metabolic syndromes, such as obesity, type II diabetes, and fat liver diseases. This study would provide a crucial perspective on the importance of post-translational regulation of AMPK in metabolic pathways and will help researchers develop novel therapeutic strategies that target not only AMPK but also its regulators.