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Induction of SIRT1 by melatonin improves alcohol-mediated oxidative liver injury by disrupting the CRBN-YY1-CYP2E1 signaling pathway

Authors
 Sung-Eun Lee  ;  Hong Koh  ;  Dong Jin Joo  ;  Balachandar Nedumaran  ;  Hwang-Ju Jeon  ;  Chul-Seung Park  ;  Robert A Harris  ;  Yong Deuk Kim 
Citation
 JOURNAL OF PINEAL RESEARCH, Vol.68(3) : e12638, 2020-04 
Journal Title
 JOURNAL OF PINEAL RESEARCH 
ISSN
 0742-3098 
Issue Date
2020-04
Keywords
Sirt1 ; alcoholic liver disease ; cytochrome P450 2E1 ; melatonin ; metabolism ; oxidative liver injury ; reactive oxygen species
Abstract
Alcoholic liver disease is the most prevalent chronic liver disease. Melatonin is known to control many vital processes. Here, we explored a novel molecular mechanism by which melatonin-induced SIRT1 signaling protects against alcohol-mediated oxidative stress and liver injury. Gene expression profiles and metabolic changes were measured in liver specimens of mice and human subjects. Expression levels of Cb1r, Crbn, Btg2, Yy1, pro-inflammatory cytokines, and Cyp2e1 were significantly enhanced in chronic alcohol-challenged mice and human subjects. Levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), hepatic CYP2E1 protein, and reactive oxygen species (ROS) were elevated in alcohol-fed WT mice but not in Cb1r antagonist-treated, Crbn null, or Yy1-silenced mice. Importantly, alcohol-induced Yy1 and Cyp2e1 expression, ROS amount, and liver injury were markedly diminished by melatonin treatment and the transduction of Sirt1 in mice, whereas this phenomenon was prominently ablated by silencing of Sirt1. Notably, SIRT1 physically interacted with YY1 and attenuated YY1 occupancy on the Cyp2e1 gene promoter. Melatonin-SIRT1 signaling ameliorates alcohol-induced oxidative liver injury by disrupting the CRBN-YY1-CYP2E1 signaling pathway. The manipulation of CRBN-YY1-CYP2E1 signaling network by the melatonin-SIRT1 pathway highlights a novel entry point for treating alcoholic liver disease.
Full Text
https://onlinelibrary.wiley.com/doi/full/10.1111/jpi.12638
DOI
10.1111/jpi.12638
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Pediatrics (소아과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Koh, Hong(고홍) ORCID logo https://orcid.org/0000-0002-3660-7483
Joo, Dong Jin(주동진) ORCID logo https://orcid.org/0000-0001-8405-1531
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/179165
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