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

Author

Listed:
  • Min-Sik Lee

    (Boston Children’s Hospital)

  • Hyun-Ji Han

    (Yonsei University)

  • Su Yeon Han

    (Yonsei University)

  • Il Young Kim

    (Seoul National University
    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
    Seoul National University)

  • Daehee Hwang

    (Daegu Gyeongbuk Institute of Science and Technology (DGIST))

  • Jaewhan Song

    (Yonsei University)

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.

Suggested Citation

  • 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 L, 2018. "Loss of the E3 ubiquitin ligase MKRN1 represses diet-induced metabolic syndrome through AMPK activation," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05721-4
    DOI: 10.1038/s41467-018-05721-4
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    Cited by:

    1. Weiqin Yin & Praveen Kumar Rajvanshi & Heather M. Rogers & Teruhiko Yoshida & Jeffrey B. Kopp & Xiuli An & Max Gassmann & Constance T. Noguchi, 2024. "Erythropoietin regulates energy metabolism through EPO-EpoR-RUNX1 axis," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Yong Geun Jeon & Hahn Nahmgoong & Jiyoung Oh & Dabin Lee & Dong Wook Kim & Jane Eunsoo Kim & Ye Young Kim & Yul Ji & Ji Seul Han & Sung Min Kim & Jee Hyung Sohn & Won Taek Lee & Sun Won Kim & Jeu Park, 2024. "Ubiquitin ligase RNF20 coordinates sequential adipose thermogenesis with brown and beige fat-specific substrates," Nature Communications, Nature, vol. 15(1), pages 1-17, December.

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