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

Fingerprint

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

All Science Journal Classification (ASJC) codes

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

Cite this

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.
@article{b29fa186d8cc4949bedf2a11a5a20ba5,
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 Yun-Hee Lee and Bae, {Kwang Hee} and Koo, {Seung Hoi} and Kim, {Jea woo} and Seong, {Je Kyung} and Daehee Hwang and Jaewhan Song",
year = "2018",
month = "12",
day = "1",
doi = "10.1038/s41467-018-05721-4",
language = "English",
volume = "9",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",

}

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, Y-H, 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

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

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.

UR - http://www.scopus.com/inward/record.url?scp=85052150170&partnerID=8YFLogxK

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 -