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Repositioningofniclosamideethanolamine(NEN), ananthelminticdrug, for thetreatmentoflipotoxicity

Authors
 Jeong Su Park  ;  Yu Seol Lee  ;  Da Hyun Lee  ;  Soo HanBae 
Citation
 FREE RADICAL BIOLOGY AND MEDICINE, Vol.137 : 143-157, 2019 
Journal Title
FREE RADICAL BIOLOGY AND MEDICINE
ISSN
 0891-5849 
Issue Date
2019
Keywords
Lipotoxicity ; NASH ; NEN ; Nrf2 ; p62
Abstract
Nonalcoholic steatohepatitis (NASH) is a common liver disease associated with metabolic disorders, including obesity and type 2 diabetes (T2D). Despite its worldwide prevalence, there are no effective drugs for thetreatmentof NASH. The progression of NASH is mainly accelerated by reactive oxygen species (ROS)-inducedlipotoxicity. The transcription factor known as nuclear factor erythroid 2-related factor 2 (Nrf2) is pivotal for the elimination of ROS. Accordingly, activators of Nrf2 have been implicated as promising therapeutic targets for thetreatmentof NASH.Niclosamide(ethanolaminesalt;NEN), adrugapproved by the US Food andDrugAdministration (USFDA), is currently used as ananthelminticdrugfor thetreatmentof parasitic infections. Recently,NENwas shown to improve hepatic steatosis in high-fat diet (HFD)-fed mice. However, the underlying mechanism of its antioxidant function in NASH remains unknown. Here, we demonstrate thatNENinduces AMPK-mediated phosphorylation of p62 at S351 that can lead to noncanonical Nrf2 activation. We also demonstrate thatNENprotects cells and mouse liver from acute lipotoxic stress through activating p62-dependent Keap1-Nrf2 pathway. Taken together,NENcan be used for clinical applications and has the potential to provide a new therapeutic option for NASH.
Full Text
https://www.sciencedirect.com/science/article/pii/S0891584919302837
DOI
10.1016/j.freeradbiomed.2019.04.030
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/22282913/170212
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