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 SeongDaehee Hwang, Jaewhan Song

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish
Article number3404
JournalNature Communications
Volume9
Issue number1
DOIs
Publication statusPublished - 2018 Dec 1

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adenosine monophosphate
diets
AMP-Activated Protein Kinases
Ubiquitin-Protein Ligases
Nutrition
Chemical activation
activation
Diet
proteins
rings
Liver
Degradation
Obese Mice
liver
Ubiquitination
mice
Therapeutic Uses
Ubiquitin
Makorin ring finger protein 1
Nutritional Status

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

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, Sehyun; Lee, Choong Sil; Kim, Sung Eun; Yoon, Seul Gi; Park, Jun Won; Kim, Jung Hoon; Shin, Soyeon; Jeong, Manhyung; Ko, Aram; Lee, Ho Young; Oh, Kyoung Jin; Lee, Yun Hee; Bae, Kwang Hee; Koo, Seung-Hoi; Kim, Jea woo; Seong, Je Kyung; Hwang, Daehee; Song, Jaewhan.

In: Nature Communications, Vol. 9, No. 1, 3404, 01.12.2018.

Research output: Contribution to journalArticle

Lee, MS, Han, HJ, Han, SY, Kim, IY, Chae, S, Lee, CS, Kim, SE, Yoon, SG, Park, JW, Kim, JH, Shin, S, Jeong, M, Ko, A, Lee, HY, Oh, KJ, Lee, YH, Bae, KH, Koo, S-H, Kim, JW, Seong, JK, Hwang, D & Song, J 2018, 'Loss of the E3 ubiquitin ligase MKRN1 represses diet-induced metabolic syndrome through AMPK activation', Nature Communications, vol. 9, no. 1, 3404. https://doi.org/10.1038/s41467-018-05721-4
Lee, Min Sik ; Han, Hyun Ji ; Han, Su Yeon ; Kim, Il Young ; Chae, Sehyun ; Lee, Choong Sil ; Kim, Sung Eun ; Yoon, Seul Gi ; Park, Jun Won ; Kim, Jung Hoon ; Shin, Soyeon ; Jeong, Manhyung ; Ko, Aram ; Lee, Ho Young ; Oh, Kyoung Jin ; Lee, Yun Hee ; Bae, Kwang Hee ; Koo, Seung-Hoi ; Kim, Jea woo ; Seong, Je Kyung ; Hwang, Daehee ; Song, Jaewhan. / Loss of the E3 ubiquitin ligase MKRN1 represses diet-induced metabolic syndrome through AMPK activation. In: Nature Communications. 2018 ; Vol. 9, No. 1.
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AU - Song, Jaewhan

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