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Metab.-Clin. Exp., Available online 28 June 2023 | https://doi.org/10.1016/j.metabol.2023.155644 The N-degron pathway mediates lipophagy: The chemical modulation of lipophagy in obesity and NAFLD

Eui Jung Jung ^a,b,1, Ki Woon Sung ^a,b,c,1, Tae Hyun Bae ^a,b,1, Hee-Yeon Kim ^d, Ha Rim Choi ^b, Sung Hyun Kim ^c, Chan Hoon Jung ^a,b, Su Ran Mun ^a, Yeon Sung Son ^e, Shin Kim ^f, Young Ho Suh ^b,e, Anna Kashina ^g, Joo-Won Park ^d, Yong Tae Kwon^a,b,c,h,i

^aCellular Degradation Biology Center, College of Medicine, Seoul National University, Seoul, 03080, Republic of Korea
^bDepartment of Biomedical Sciences, College of Medicine, Seoul National University, Seoul, 03080, Republic of Korea
^cAUTOTAC Bio Inc., Changgyeonggung-Ro 254, Jongno-Gu, Seoul, 03077, Republic of Korea
^dDepartment of Biochemistry, College of Medicine, Ewha Womans University, Seoul, 07804, Republic of Korea
^eNeuroscience Research Institute, College of Medicine, Seoul National University, Seoul, 03080, Republic of Korea
^fDepartment of Immunology, School of Medicine, Keimyung University, Daegu, 42601, Republic of Korea
^gDepartment of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, United States
^hConvergence Research Center for Dementia, Seoul National University Medical Research Center, Seoul, 03080, Republic of Korea
ⁱIschemic/Hypoxic Disease Institute, College of Medicine, Seoul National University, Seoul, 03080, Republic of Korea

¹Equal contribution.
Corresponding authors : Joo-Won Park, Yong Tae Kwon

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.

논문정보

형식Research article
게재일2023년 06월 (BRIC 등록일 2023-07-14)
연구진국내(교신)+국외 연구진
분야 생명과학 > 분자생물학

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