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Loss of the E3 ubiquitin ligase MKRN1 represses diet-induced metabolic syndrome through AMPK activation
- Loss of the E3 ubiquitin ligase MKRN1 represses diet-induced metabolic syndrome through AMPK activation
- Lee, Min Sik; Han, Hyun Ji; Han, Su Yeon; Kim, Il Young; Chae, Se Hyun; Lee, Choong Sil; Kim, Sung Eun; Yoon, Seul Gi; Park, Jun Won; Kim, Jung Hoon; Shin, So Yeon; Jeong, Man Hyung; Ko, A Ram; Lee, Ho Young; Oh, Kyoung Jin; Lee, Yun Hee; Bae, Kwang Hee; Koo, Seung Hoi; Kim, Jea Woo; Seong, Je Kyung; Hwang, Daehee; Song, Jae Whan
- DGIST Authors
- Hwang, Daehee
- Issue Date
- Nature Communications, 9
- Article Type
- BROWN ADIPOSE-TISSUE; PROTEIN-KINASE; INSULIN-RESISTANCE; ENERGY SENSOR; RNA-SEQ; LIVER; GENE; HOMEOSTASIS; DEGRADATION; INTEGRATION
- 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. © 2018, The Author(s).
- Nature Publishing Group
- Department of New BiologySystems Biology and Medicine Lab1. Journal Articles
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