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Ezetimibe ameliorates steatohepatitis via AMP activated protein kinase-TFEB-mediated activation of autophagy and NLRP3 inflammasome inhibition

Authors
 Soo Hyun Kim  ;  Gyuri Kim  ;  Dai Hoon Han  ;  Milim Lee  ;  Irene Kim  ;  Bohkyung Kim  ;  Kook Hwan Kim  ;  Young-Mi Song  ;  Jeong Eun Yoo  ;  Hye Jin Wang  ;  Soo Han Bae  ;  Yong-Ho Lee : Byung-Wan Lee  ;  Eun Seok Kang  ;  Bong-Soo Cha  ;  Myung-Shik Lee 
Citation
 Autophagy, Vol.13(10) : 1767-1781, 2017 
Journal Title
 Autophagy 
ISSN
 1554-8627 
Issue Date
2017
Keywords
NASH ; autophagy ; exosome ; inflammasome ; inflammation
Abstract
Impairment in macroautophagy/autophagy flux and inflammasome activation are common characteristics of nonalcoholic steatohepatitis (NASH). Considering the lack of approved agents for treating NASH, drugs that can enhance autophagy and modulate inflammasome pathways may be beneficial. Here, we investigated the novel mechanism of ezetimibe, a widely prescribed drug for hypercholesterolemia, as a therapeutic option for ameliorating NASH. Human liver samples with steatosis and NASH were analyzed. For in vitro studies of autophagy and inflammasomes, primary mouse hepatocytes, human hepatoma cells, mouse embryonic fibroblasts with Ampk or Tsc2 knockout, and human or primary mouse macrophages were treated with ezetimibe and palmitate. Steatohepatitis and fibrosis were induced by feeding Atg7 wild-type, haploinsufficient, and knockout mice a methionine- and choline-deficient diet with ezetimibe (10 mg/kg) for 4 wk. Human livers with steatosis or NASH presented impaired autophagy with decreased nuclear TFEB and increased SQSTM1, MAP1LC3-II, and NLRP3 expression. Ezetimibe increased autophagy flux and concomitantly ameliorated lipid accumulation and apoptosis in palmitate-exposed hepatocytes. Ezetimibe induced AMPK phosphorylation and subsequent TFEB nuclear translocation, related to MAPK/ERK. In macrophages, ezetimibe blocked the NLRP3 inflammasome-IL1B pathway in an autophagy-dependent manner and modulated hepatocyte-macrophage interaction via extracellular vesicles. Ezetimibe attenuated lipid accumulation, inflammation, and fibrosis in liver-specific Atg7 wild-type and haploinsufficient mice, but not in knockout mice. Ezetimibe ameliorates steatohepatitis by autophagy induction through AMPK activation and TFEB nuclear translocation, related to an independent MTOR ameliorative effect and the MAPK/ERK pathway. Ezetimibe dampens NLRP3 inflammasome activation in macrophages by modulating autophagy and a hepatocyte-driven exosome pathway.
URI
http://ir.ymlib.yonsei.ac.kr/handle/22282913/161015
DOI
10.1080/15548627.2017.1356977
Appears in Collections:
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원)
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실)
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부)
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실)
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실)
Yonsei Authors
강은석(Kang, Eun Seok) ; 김국환(Kim, Kook Hwan) ; 김규리(Kim, Gyuri) ; 배수한(Bae, Soo Han) ; 왕혜진(Wang, Hye Jin) ; 유정은(Yoo, Jeong Eun) ; 이명식(Lee, Myung Shik) ; 이병완(Lee, Byung Wan) ; 이용호(Lee, Yong Ho) ; 차봉수(Cha, Bong Soo) ; 한대훈(Han, Dai Hoon)
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Full Text
https://www.tandfonline.com/doi/full/10.1080/15548627.2017.1356977
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