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

Min-Sik Lee, Hyun-Ji Han, Su Yeon Han, Il Young Kim, Sehyun Chae, Choong-Sil Lee, Sung Eun Kim, Seul Gi Yoon, Jun-Won Park, Jung-Hoon Kim, Soyeon Shin, Manhyung Jeong, Aram Ko, Ho-Young Lee, Kyoung-Jin Oh, Yun-Hee Lee, Kwang-Hee Bae, Seung-Hoi Koo, Jea-woo Kim, Je Kyung Seong, Daehee Hwang and Jaewhan Song ()
Additional contact information
Min-Sik Lee: Boston Children’s Hospital
Hyun-Ji Han: Yonsei University
Su Yeon Han: Yonsei University
Il Young Kim: Seoul National University
Sehyun Chae: Daegu Gyeongbuk Institute of Science and Technology (DGIST)
Choong-Sil Lee: Yonsei University
Sung Eun Kim: Yonsei University
Seul Gi Yoon: Seoul National University
Jun-Won Park: Seoul National University
Jung-Hoon Kim: Yonsei University
Soyeon Shin: Yonsei University
Manhyung Jeong: Yonsei University
Aram Ko: Yonsei University
Ho-Young Lee: Seoul National University Bundang Hospital
Kyoung-Jin Oh: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Yun-Hee Lee: Yonsei University
Kwang-Hee Bae: Korea Research Institute of Bioscience and Biotechnology (KRIBB)
Seung-Hoi Koo: Korea University
Jea-woo Kim: Yonsei University College of Medicine
Je Kyung Seong: Seoul National University
Daehee Hwang: Daegu Gyeongbuk Institute of Science and Technology (DGIST)
Jaewhan Song: Yonsei University

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05721-4

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