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

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15 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

All Science Journal Classification (ASJC) codes

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

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    Lee, M. S., Han, H. J., Han, S. Y., Kim, I. Y., Chae, S., Lee, C. S., Kim, S. E., Yoon, S. G., Park, J. W., Kim, J. H., Shin, S., Jeong, M., Ko, A., Lee, H. Y., Oh, K. J., Lee, Y. H., Bae, K. H., Koo, S. H., Kim, J. W., ... Song, J. (2018). Loss of the E3 ubiquitin ligase MKRN1 represses diet-induced metabolic syndrome through AMPK activation. Nature communications, 9(1), [3404]. https://doi.org/10.1038/s41467-018-05721-4