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

DC FieldValueLanguage
dc.contributor.author박정수-
dc.contributor.author배수한-
dc.contributor.author이용호-
dc.contributor.author한대훈-
dc.date.accessioned2020-12-01T17:41:44Z-
dc.date.available2020-12-01T17:41:44Z-
dc.date.issued2020-11-
dc.identifier.issn1554-8627-
dc.identifier.urihttps://ir.ymlib.yonsei.ac.kr/handle/22282913/180391-
dc.description.abstractLipotoxicity, 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.-
dc.description.statementOfResponsibilityrestriction-
dc.languageEnglish-
dc.publisherTaylor & Francis-
dc.relation.isPartOfAUTOPHAGY-
dc.rightsCC BY-NC-ND 2.0 KR-
dc.titleSQSTM1/p62 activates NFE2L2/NRF2 via ULK1-mediated autophagic KEAP1 degradation and protects mouse liver from lipotoxicity-
dc.typeArticle-
dc.contributor.collegeCollege of Medicine (의과대학)-
dc.contributor.departmentBioMedical Science Institute (의생명과학부)-
dc.contributor.googleauthorDa Hyun Lee-
dc.contributor.googleauthorJeong Su Park-
dc.contributor.googleauthorYu Seol Lee-
dc.contributor.googleauthorJisu Han-
dc.contributor.googleauthorDong-Kyu Lee-
dc.contributor.googleauthorSung Won Kwon-
dc.contributor.googleauthorDai Hoon Han-
dc.contributor.googleauthorYong-Ho Lee-
dc.contributor.googleauthorSoo Han Bae-
dc.identifier.doi10.1080/15548627.2020.1712108-
dc.contributor.localIdA01645-
dc.contributor.localIdA01798-
dc.contributor.localIdA01798-
dc.contributor.localIdA02989-
dc.contributor.localIdA02989-
dc.contributor.localIdA04273-
dc.contributor.localIdA04273-
dc.relation.journalcodeJ00269-
dc.identifier.eissn1554-8635-
dc.identifier.pmid31913745-
dc.identifier.urlhttps://www.tandfonline.com/doi/full/10.1080/15548627.2020.1712108-
dc.subject.keywordKEAP1-NFE2L2 pathway-
dc.subject.keywordNAFLD-
dc.subject.keywordSQSTM1-
dc.subject.keywordULK1-
dc.subject.keywordlipotoxicity-
dc.contributor.alternativeNamePark, Jeong Su-
dc.contributor.affiliatedAuthor박정수-
dc.contributor.affiliatedAuthor배수한-
dc.contributor.affiliatedAuthor배수한-
dc.contributor.affiliatedAuthor이용호-
dc.contributor.affiliatedAuthor이용호-
dc.contributor.affiliatedAuthor한대훈-
dc.contributor.affiliatedAuthor한대훈-
dc.citation.volume16-
dc.citation.number11-
dc.citation.startPage1949-
dc.citation.endPage1973-
dc.identifier.bibliographicCitationAUTOPHAGY, Vol.16(11) : 1949-1973, 2020-11-
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

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