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Loss of the E3 ubiquitin ligase MKRN1 represses diet-induced metabolic syndrome through AMPK activation

Title
Loss of the E3 ubiquitin ligase MKRN1 represses diet-induced metabolic syndrome through AMPK activation
Authors
Lee, Min SikHan, Hyun JiHan, Su YeonKim, Il YoungChae, Se HyunLee, Choong SilKim, Sung EunYoon, Seul GiPark, Jun WonKim, Jung HoonShin, So YeonJeong, Man HyungKo, A RamLee, Ho YoungOh, Kyoung JinLee, Yun HeeBae, Kwang HeeKoo, Seung HoiKim, Jea WooSeong, Je KyungHwang, DaeheeSong, Jae Whan
DGIST Authors
Hwang, Daehee
Issue Date
2018-08
Citation
Nature Communications, 9
Type
Article
Article Type
Article
Keywords
BROWN ADIPOSE-TISSUEPROTEIN-KINASEINSULIN-RESISTANCEENERGY SENSORRNA-SEQLIVERGENEHOMEOSTASISDEGRADATIONINTEGRATION
ISSN
2041-1723
Abstract
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).
URI
http://hdl.handle.net/20.500.11750/9300
DOI
10.1038/s41467-018-05721-4
Publisher
Nature Publishing Group
Files:
Collection:
Department of New BiologySystems Biology and Medicine Lab1. Journal Articles


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