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PERK prevents hepatic lipotoxicity by activating the p62-ULK1 axis-mediated noncanonical KEAP1-Nrf2 pathway

Authors
 Da Hyun Lee  ;  Jeong Su Park  ;  Yu Seol Lee  ;  Soo Han Bae 
Citation
 REDOX BIOLOGY, Vol.50 : 102235, 2022-04 
Journal Title
REDOX BIOLOGY
Issue Date
2022-04
MeSH
Autophagy ; Kelch-Like ECH-Associated Protein 1* / metabolism ; Liver* / metabolism ; NF-E2-Related Factor 2* / genetics ; NF-E2-Related Factor 2* / metabolism ; Oxidative Stress ; Protein Serine-Threonine Kinases* ; Sequestosome-1 Protein / genetics ; Sequestosome-1 Protein / metabolism ; eIF-2 Kinase* / metabolism
Keywords
KEAP1-Nrf2 pathway ; Lipotoxicity ; Nonalcoholic steatohepatitis ; PERK ; ULK1 ; p62
Abstract
Hepatic lipotoxicity is a crucial factor in nonalcoholic steatohepatitis resulting from excessive saturated fatty acid-induced reactive oxygen species (ROS)-mediated cell death, which is associated with the accumulation of endoplasmic reticulum (ER) stress in the liver. The unfolded protein response (UPR) alleviates ER stress by restoring ER protein folding homeostasis. However, whether UPR contributes ROS elimination under lipotoxicity remains unclear. The Kelch like ECH-associated protein 1 (KEAP1)-nuclear factor, erythroid 2 like 2 (Nrf2) pathway provides antioxidant defense against lipotoxic stress by eliminating ROS and can be activated by the p62-Unc-51 like autophagy activating kinase 1 (ULK1) axis. However, the upstream molecular regulator of the p62-ULK1 axis-induced KEAP1-Nrf2 pathway in the same context remains unidentified. Here, we demonstrated that PKR-like ER kinase (PERK), a UPR sensor, directly phosphorylates p62 and ULK1, thereby activating the noncanonical KEAP1-Nrf2 pathway. We also elucidated the molecular mechanism underlying the PERK-mediated p62-ULK1 axis-dependent noncanonical KEAP1-Nrf2 pathway, which could represent a promising therapeutic strategy against hepatic lipotoxicity.
Files in This Item:
T202201229.pdf Download
DOI
10.1016/j.redox.2022.102235
Appears in Collections:
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 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, Da Hyun(이다현) ORCID logo https://orcid.org/0000-0002-5412-6878
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/188123
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