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SQSTM1/p62 activates NFE2L2/NRF2 via ULK1-mediated autophagic KEAP1 degradation and protects mouse liver from lipotoxicity

Authors
 Da Hyun Lee  ;  Jeong Su Park  ;  Yu Seol Lee  ;  Jisu Han  ;  Dong-Kyu Lee  ;  Sung Won Kwon  ;  Dai Hoon Han  ;  Yong-Ho Lee  ;  Soo Han Bae 
Citation
 AUTOPHAGY, Vol.16(11) : 1949-1973, 2020-11 
Journal Title
 AUTOPHAGY 
ISSN
 1554-8627 
Issue Date
2020-11
Keywords
KEAP1-NFE2L2 pathway ; NAFLD ; SQSTM1 ; ULK1 ; lipotoxicity
Abstract
Lipotoxicity, induced by saturated fatty acid (SFA)-mediated cell death, plays an important role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). The KEAP1 (kelch like ECH associated protein 1)-NFE2L2/NRF2 (nuclear factor, erythroid 2 like 2) pathway is a pivotal defense mechanism against lipotoxicity. We previously reported that SQSTM1/p62 has a cytoprotective role against lipotoxicity through activation of the noncanonical KEAP1- NFE2L2 pathway in hepatocytes. However, the underlying mechanisms and physiological relevance of this pathway have not been clearly defined. Here, we demonstrate that NFE2L2-mediated induction of SQSTM1 activates the noncanonical KEAP1-NFE2L2 pathway under lipotoxic conditions. Furthermore, we identified that SQSTM1 induces ULK1 (unc-51 like autophagy activating kinase 1) phosphorylation by facilitating the interaction between AMPK (AMP-activated protein kinase) and ULK1, leading to macroautophagy/autophagy induction, followed by KEAP1 degradation and NFE2L2 activation. Accordingly, the activity of this SQSTM1-mediated noncanonical KEAP1-NFE2L2 pathway conferred hepatoprotection against lipotoxicity in the livers of conventional sqstm1- and liver-specific sqstm1-knockout mice. Moreover, this pathway activity was evident in the livers of patients with nonalcoholic fatty liver. This axis could thus represent a novel target for NAFLD treatment.
Full Text
https://www.tandfonline.com/doi/full/10.1080/15548627.2020.1712108
DOI
10.1080/15548627.2020.1712108
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Park, Jeong Su(박정수) ORCID logo https://orcid.org/0000-0003-4551-4294
Bae, Soo Han(배수한) ORCID logo https://orcid.org/0000-0002-8007-2906
Lee, Yong Ho(이용호) ORCID logo https://orcid.org/0000-0002-6219-4942
Han, Dai Hoon(한대훈) ORCID logo https://orcid.org/0000-0003-2787-7876
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/180391
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