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; Jaewhan Song

doi:10.1038/s41467-018-05721-4

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 journal › Article › peer-review

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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 language	English
Article number	3404
Journal	Nature communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-05721-4
Publication status	Published - 2018 Dec 1

Bibliographical note

Funding Information:
We thank I.Y.K. and J.K.S. for the productive discussions and K.-J.O., S.-H.K. and J.-W.K. for providing technical support. We specifically thank Deyu Feng (Northwestern University) and T. A. Gray (David Axelrod Institute) for their support in providing MKRN1-null mice. This research was supported by grants from the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (NCC-1420300) and the Ministry of Science, ICT and Future Planning (NRF-2015R1A3A2066581). Additionally, this research was partially supported by the BK21 Plus project of the National Research Foundation of Korea Grant) and by grants from the Korea Mouse Phenotyping Project (2013M3A9D5072550 and 2013M3A9 D507256) and the Institute for Basic Science (IBS-R013-A1) of the Ministry of Science, ICT and Future Planning through the National Research Foundation of Korea.

Publisher Copyright:
© 2018, The Author(s).

ASJC Scopus subject areas

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-018-05721-4

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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), Article 3404. https://doi.org/10.1038/s41467-018-05721-4

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, SH, 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

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

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.",

author = "Lee, {Min Sik} and Han, {Hyun Ji} and Han, {Su Yeon} and Kim, {Il Young} and Sehyun Chae and Lee, {Choong Sil} and Kim, {Sung Eun} and Yoon, {Seul Gi} and Park, {Jun Won} and Kim, {Jung Hoon} and Soyeon Shin and Manhyung Jeong and Aram Ko and Lee, {Ho Young} and Oh, {Kyoung Jin} and Lee, {Yun Hee} and Bae, {Kwang Hee} and Koo, {Seung Hoi} and Kim, {Jea woo} and Seong, {Je Kyung} and Daehee Hwang and Jaewhan Song",

note = "Funding Information: We thank I.Y.K. and J.K.S. for the productive discussions and K.-J.O., S.-H.K. and J.-W.K. for providing technical support. We specifically thank Deyu Feng (Northwestern University) and T. A. Gray (David Axelrod Institute) for their support in providing MKRN1-null mice. This research was supported by grants from the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (NCC-1420300) and the Ministry of Science, ICT and Future Planning (NRF-2015R1A3A2066581). Additionally, this research was partially supported by the BK21 Plus project of the National Research Foundation of Korea Grant) and by grants from the Korea Mouse Phenotyping Project (2013M3A9D5072550 and 2013M3A9 D507256) and the Institute for Basic Science (IBS-R013-A1) of the Ministry of Science, ICT and Future Planning through the National Research Foundation of Korea. Publisher Copyright: {\textcopyright} 2018, The Author(s).",

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AU - Lee, Min Sik

AU - Han, Hyun Ji

AU - Han, Su Yeon

AU - Kim, Il Young

AU - Chae, Sehyun

AU - Lee, Choong Sil

AU - Kim, Sung Eun

AU - Yoon, Seul Gi

AU - Park, Jun Won

AU - Kim, Jung Hoon

AU - Shin, Soyeon

AU - Jeong, Manhyung

AU - Ko, Aram

AU - Lee, Ho Young

AU - Oh, Kyoung Jin

AU - Lee, Yun Hee

AU - Bae, Kwang Hee

AU - Koo, Seung Hoi

AU - Kim, Jea woo

AU - Seong, Je Kyung

AU - Hwang, Daehee

AU - Song, Jaewhan

N1 - Funding Information: We thank I.Y.K. and J.K.S. for the productive discussions and K.-J.O., S.-H.K. and J.-W.K. for providing technical support. We specifically thank Deyu Feng (Northwestern University) and T. A. Gray (David Axelrod Institute) for their support in providing MKRN1-null mice. This research was supported by grants from the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (NCC-1420300) and the Ministry of Science, ICT and Future Planning (NRF-2015R1A3A2066581). Additionally, this research was partially supported by the BK21 Plus project of the National Research Foundation of Korea Grant) and by grants from the Korea Mouse Phenotyping Project (2013M3A9D5072550 and 2013M3A9 D507256) and the Institute for Basic Science (IBS-R013-A1) of the Ministry of Science, ICT and Future Planning through the National Research Foundation of Korea. Publisher Copyright: © 2018, The Author(s).

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N2 - 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.

AB - 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.

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

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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