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

Nature Communications
Min-Sik LeeJaewhan Song

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.

References

Mar 10, 2001·Cell·B M Spiegelman, J S Flier
Oct 17, 2001·The Journal of Clinical Investigation·G ZhouD E Moller
Jan 10, 2003·Nucleic Acids Research·Gary D BaderChristopher W V Hogue
Dec 19, 2003·Nucleic Acids Research·Suraj PeriAkhilesh Pandey
Nov 23, 2005·Proceedings of the National Academy of Sciences of the United States of America·Daehee HwangHamid Bolouri
Dec 31, 2005·Nucleic Acids Research·Chris StarkMike Tyers
Apr 4, 2006·Nature Reviews. Drug Discovery·Scott M Grundy
Aug 3, 2006·Proceedings of the National Academy of Sciences of the United States of America·Todd A GrayRobert D Nicholls
Dec 1, 2006·Nucleic Acids Research·Andrew Chatr-aryamontriGianni Cesareni
Oct 20, 2007·Nature Protocols·Melissa S ClineGary D Bader
Apr 29, 2008·Molecular Cell·Dana M GwinnReuben J Shaw
Jan 10, 2009·Nature Protocols·Da Wei HuangRichard A Lempicki
Mar 18, 2009·Bioinformatics·Cole TrapnellSteven L Salzberg
May 7, 2009·Cell Metabolism·Bei B ZhangCai Li
Jun 16, 2009·Methods : a Companion to Methods in Enzymology·S JudexC T Rubin
Jul 9, 2009·Physiological Reviews·Gregory R Steinberg, Bruce E Kemp
Jan 28, 2010·American Journal of Physiology. Endocrinology and Metabolism·Neil B RudermanYasuo Ido
Mar 4, 2010·Genome Biology·Mark D Robinson, Alicia Oshlack
May 7, 2010·Cell Metabolism·Adem KalenderGeorge Thomas
Jun 2, 2010·Nature Reviews. Drug Discovery·Yu-Hua TsengC Ronald Kahn
Jun 5, 2010·Critical Reviews in Biochemistry and Molecular Biology·Benoit ViolletFabrizio Andreelli
Mar 11, 2011·PloS One·Guy H E J VijgenWouter D van Marken Lichtenbelt
Jun 7, 2011·Cell Metabolism·Maryam AhmadianHei Sook Sul
Nov 15, 2011·Nucleic Acids Research·Minoru KanehisaMao Tanabe
Mar 23, 2012·Nature Reviews. Molecular Cell Biology·D Grahame HardieSimon A Hawley
Jul 4, 2012·Molecular and Cellular Endocrinology·R B Ceddia
Aug 4, 2012·Nature Reviews. Drug Discovery·Marcelo O Dietrich, Tamas L Horvath
Sep 4, 2012·Journal of Physiology and Biochemistry·Christopher R LindholmKurt W Saupe
Sep 27, 2012·BMB Reports·Eun-Woo LeeJaewhan Song
Oct 30, 2012·Journal of the National Cancer Institute·Aram KoJaewhan Song
Dec 12, 2012·The Journal of Clinical Investigation·Kristin I StanfordLaurie J Goodyear
Feb 28, 2013·Science Signaling·Sehyun ChaeKyong Soo Park

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Citations

Aug 12, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Meichan YangXin Tong
Dec 25, 2019·Scientific Reports·Jong-Chan ParkKang-Yell Choi
Jun 17, 2020·PloS One·Lena K HanssonJan Nygaard Jensen
Jan 31, 2021·International Journal of Molecular Sciences·Ashley J OvensWilliam J Smiles
Apr 8, 2021·The FEBS Journal·Claudia RodríguezDolores Prieto
Apr 17, 2021·Seminars in Cancer Biology·Che-Chia HsuHui-Kuan Lin
May 27, 2021·Trends in Endocrinology and Metabolism : TEM·Jia Liang Sun-WangAntonio Zorzano
Jul 15, 2021·Oncology Letters·Bin ShiWenzheng Fang
Apr 26, 2020·Biochimica Et Biophysica Acta. Molecular Cell Research·Seung-Joo YangKwang Min Lee
Apr 25, 2021·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Xia YangZhi-Gang She
Oct 13, 2020·Life Sciences·Rogério Oliveira BatistaRonaldo Carvalho Araújo

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Datasets Mentioned

BETA
GSE115012

Methods Mentioned

BETA
transfection
PCR
co-immunoprecipitation
ubiquitination
genotyping
transfect
X-ray
flow cytometry
Assay
ubiquitination assay

Software Mentioned

GlucoDr
GraphPad
Cytoscape
- Elements F
NIS
XF
ImageJ
edgeR
GraphPad Prism
DAVID

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