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

 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 
 AUTOPHAGY, Vol.13(10) : 1767-1781, 2017 
Journal Title
Issue Date
NASH ; autophagy ; exosome ; inflammasome ; inflammation
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.
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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 Pharmacology (약리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
Yonsei Authors
Kang, Eun Seok(강은석) ORCID logo https://orcid.org/0000-0002-0364-4675
Kim, Kook Hwan(김국환)
Kim, Gyuri(김규리)
Bae, Soo Han(배수한) ORCID logo https://orcid.org/0000-0002-8007-2906
Wang, Hye Jin(왕혜진)
Yoo, Jeong Eun(유정은)
Lee, Myung Shik(이명식) ORCID logo https://orcid.org/0000-0003-3292-1720
Lee, Byung Wan(이병완) ORCID logo https://orcid.org/0000-0002-9899-4992
Lee, Yong Ho(이용호) ORCID logo https://orcid.org/0000-0002-6219-4942
Cha, Bong Soo(차봉수) ORCID logo https://orcid.org/0000-0003-0542-2854
Han, Dai Hoon(한대훈) ORCID logo https://orcid.org/0000-0003-2787-7876
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