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

Min Sik Lee ,Sung Eun Kim,Su Yeon Han,Il Young Kim,Aram Ko,Kyoung-Jin Oh,Daehee Hwang,Ho‐Young Lee ,Kwang‐Hee Bae ,Jea Woo Kim ,Seul Gi Yoon,Seung Hoi Koo ,Sehyun Chae,Yun Hee Lee ,Choong Sil Lee ,Soyeon Shin,Hyun Ju Han ,Min-Ji Jeong ,Jung Won Park ,Je Kyung Seong,Jung Hoon Kim ,Jaewhan Song

doi:10.1038/s41467-018-05721-4

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.

Highlights

AMP-activated protein kinase (AMPK) plays a key role in controlling energy metabolism in response to physiological and nutritional status
Metabolic syndrome is associated with the risk of developing a number of disorders, including type 2 diabetes (T2D), non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease, and has become a common pathological condition due to the increased prevalence of obesity associated with the western lifestyle[1,2,3]
Increased glucose uptake was observed in mouse embryonic fibroblasts (MEFs) lacking makorin ring finger protein 1 (MKRN1) or HepG2 cells depleted of MKRN1 (Fig. 1a, f and Supplementary Fig. 1a)

Summary

Introduction

AMP-activated protein kinase (AMPK) plays a key role in controlling energy metabolism in response to physiological and nutritional status. MKRN1-null mice show chronic AMPK activation in both liver and adipose tissue, resulting in significant suppression of diet-induced metabolic syndrome. Metabolic syndrome is associated with the risk of developing a number of disorders, including type 2 diabetes (T2D), non-alcoholic fatty liver disease (NAFLD) and cardiovascular disease, and has become a common pathological condition due to the increased prevalence of obesity associated with the western lifestyle[1,2,3]. The molecular mechanisms implicated in regulating the energy-wasting process in brown fat and skeletal muscle have been identified, new and effective drugs for the treatment of obesity that stimulate cellular EE remain to be developed[2]. The identification of a tissue-specific AMPK regulatory mechanism would be an alternative strategy for the development of potent and selective AMPK activators[25,26]

Methods

Results

Conclusion