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

Research output: Contribution to journalArticle

33 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1767-1781
Number of pages15
JournalAutophagy
Volume13
Issue number10
DOIs
Publication statusPublished - 2017 Oct 3

    Fingerprint

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Cite this

Kim, S. H., Kim, G., Han, D. H., Lee, M., Kim, I., Kim, B., Kim, K. H., Song, Y. M., Yoo, J. E., Wang, H. J., Bae, S. H., Lee, Y. H., Lee, B. W., Kang, E. S., Cha, B. S., & Lee, M. S. (2017). Ezetimibe ameliorates steatohepatitis via AMP activated protein kinase-TFEB-mediated activation of autophagy and NLRP3 inflammasome inhibition. Autophagy, 13(10), 1767-1781. https://doi.org/10.1080/15548627.2017.1356977