AMP-activated protein kinase (AMPK) plays a key role in controlling energy metabolism in response to physiological and nutritional status. Although AMPK activation has been proposed as a promising molecular target for treating obesity and its related comorbidities, the use of pharmacological AMPK activators has been met with contradictory therapeutic challenges. Here we show a regulatory mechanism for AMPK through its ubiquitination and degradation by the E3 ubiquitin ligase makorin ring finger protein 1 (MKRN1). MKRN1 depletion promotes glucose consumption and suppresses lipid accumulation due to AMPK stabilisation and activation. Accordingly, MKRN1-null mice show chronic AMPK activation in both liver and adipose tissue, resulting in significant suppression of diet-induced metabolic syndrome. We demonstrate also its therapeutic effect by administering shRNA targeting MKRN1 into obese mice that reverses non-alcoholic fatty liver disease. We suggest that ubiquitin-dependent AMPK degradation represents a target therapeutic strategy for metabolic disorders.
Bibliographical noteFunding Information:
We thank I.Y.K. and J.K.S. for the productive discussions and K.-J.O., S.-H.K. and J.-W.K. for providing technical support. We specifically thank Deyu Feng (Northwestern University) and T. A. Gray (David Axelrod Institute) for their support in providing MKRN1-null mice. This research was supported by grants from the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (NCC-1420300) and the Ministry of Science, ICT and Future Planning (NRF-2015R1A3A2066581). Additionally, this research was partially supported by the BK21 Plus project of the National Research Foundation of Korea Grant) and by grants from the Korea Mouse Phenotyping Project (2013M3A9D5072550 and 2013M3A9 D507256) and the Institute for Basic Science (IBS-R013-A1) of the Ministry of Science, ICT and Future Planning through the National Research Foundation of Korea.
All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)