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The N-degron pathway mediates lipophagy: The chemical modulation of lipophagy in obesity and NAFLD

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Author(s)
Eui Jung JungKi Woon SungTae Hyun BaeHee-Yeon KimHa Rim ChoiSung Hyun KimChan Hoon JungSu Ran MunYeon Sung SonShin KimYoung Ho SuhAnna KashinaJoo-Won ParkYong Tae Kwon
Keimyung Author(s)
Kim, Shin
Department
Dept. of Immunology (면역학)
Journal Title
Metabolism
Issued Date
2023
Volume
146
Keyword
HepatosteatosisLipid dropletN-terminal arginylationObesityThe autophagy-lysosome systemp62/SQSTM1/Sequestosome-1
Abstract
Background and aims:
Central to the pathogenesis of nonalcoholic fatty liver disease (NAFLD) is the accumulation of lipids in the liver and various fat tissues. We aimed to elucidate the mechanisms by which lipid droplets (LDs) in the liver and adipocytes are degraded by the autophagy-lysosome system and develop therapeutic means to modulate lipophagy, i.e., autophagic degradation of LDs.

Methods:
We monitored the process in which LDs are pinched off by autophagic membranes and degraded by lysosomal hydrolases in cultured cells and mice. The autophagic receptor p62/SQSTM-1/Sequestosome-1 was identified as a key regulator and used as a target to develop drugs to induce lipophagy. The efficacy of p62 agonists was validated in mice to treat hepatosteatosis and obesity.

Results:
We found that the N-degron pathway modulates lipophagy. This autophagic degradation initiates when the molecular chaperones including BiP/GRP78, retro-translocated from the endoplasmic reticulum, is N-terminally (Nt-) arginylated by ATE1 R-transferase. The resulting Nt-arginine (Nt-Arg) binds the ZZ domain of p62 associated with LDs. Upon binding to Nt-Arg, p62 undergoes self-polymerization and recruits LC3+ phagophores to the site of lipophagy, leading to lysosomal degradation. Liver-specific Ate1 conditional knockout mice under high fat diet developed severe NAFLD. The Nt-Arg was modified into small molecule agonists to p62 that facilitate lipophagy in mice and exerted therapeutic efficacy in obesity and hepatosteatosis of wild-type but not p62 knockout mice.

Conclusions:
Our results show that the N-degron pathway modulates lipophagy and provide p62 as a drug target to treat NAFLD and other diseases related with metabolic syndrome.
Keimyung Author(s)(Kor)
김신
Publisher
School of Medicine (의과대학)
Type
Article
ISSN
1532-8600
Source
https://www.clinicalkey.com/#!/content/playContent/1-s2.0-S0026049523002482
DOI
10.1016/j.metabol.2023.155644
URI
https://kumel.medlib.dsmc.or.kr/handle/2015.oak/45280
Appears in Collections:
1. School of Medicine (의과대학) > Dept. of Immunology (면역학)
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