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 | |
| Publication status | Published - 2018 Dec 1 |
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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 journal › Article
}
TY - JOUR
T1 - Loss of the E3 ubiquitin ligase MKRN1 represses diet-induced metabolic syndrome through AMPK activation
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
PY - 2018/12/1
Y1 - 2018/12/1
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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UR - http://www.scopus.com/inward/citedby.url?scp=85052150170&partnerID=8YFLogxK
U2 - 10.1038/s41467-018-05721-4
DO - 10.1038/s41467-018-05721-4
M3 - Article
C2 - 30143610
AN - SCOPUS:85052150170
VL - 9
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 3404
ER -