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Autophagy. 2017 Oct 3;13(10):1767-1781. doi: 10.1080/15548627.2017.1356977. Epub 2017 Sep 21.

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

Kim SH1, Kim G1,2,3, Han DH4, Lee M1, Kim I1, Kim B1, Kim KH5, Song YM6, Yoo JE7, Wang HJ8, Bae SH5, Lee YH1,3,9, Lee BW1,3,9, Kang ES1,3,9, Cha BS1,3,9, Lee MS1,5.

Author information

1
a Department of Internal Medicine , Yonsei University College of Medicine , Seoul , Korea.
2
b Department of Medicine, Samsung Medical Center , Sungkyunkwan University School of Medicine , Seoul , Korea.
3
c Graduate School , Yonsei University College of Medicine , Seoul , Korea.
4
d Department of Surgery , Yonsei University College of Medicine , Seoul , Korea.
5
e Severance Biomedical Science Institute, Yonsei Biomedical Research Institute , Yonsei University College of Medicine , Seoul , Korea.
6
f Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital , University of Toronto , Toronto , Canada.
7
g Department of Pathology , Yonsei University College of Medicine , Seoul , Korea.
8
h Department of Pharmacology , Yonsei University College of Medicine , Seoul , Korea.
9
i Institute of Endocrine Research , Yonsei University College of Medicine , Seoul , Korea.

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.

KEYWORDS:

NASH; autophagy; exosome; inflammasome; inflammation

PMID:
28933629
PMCID:
PMC5640190
DOI:
10.1080/15548627.2017.1356977
[Indexed for MEDLINE]
Free PMC Article

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