FXR Inhibits Endoplasmic Reticulum Stress-Induced NLRP3 Inflammasome in Hepatocytes and Ameliorates Liver Injury

Chang Yeob Han, Hyun Soo Rho, Ayoung Kim, Tae Hyun Kim, Kiseok Jang, Dae Won Jun, Jong Won Kim, Bumseok Kim, Sang Geon Kim

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Endoplasmic reticulum (ER) stress is associated with liver injury and fibrosis, and yet the hepatic factors that regulate ER stress-mediated inflammasome activation remain unknown. Here, we report that farnesoid X receptor (FXR) activation inhibits ER stress-induced NACHT, LRR, and PYD domains-containing protein 3 (NLRP3) inflammasome in hepatocytes. In patients with hepatitis B virus (HBV)-associated hepatic failure or non-alcoholic fatty liver disease, and in mice with liver injury, FXR levels in the liver inversely correlated with the extent of NLRP3 inflammasome activation. Fxr deficiency in mice augmented the ability of ER stress to induce NLRP3 and thioredoxin-interacting protein (TXNIP), whereas FXR ligand activation prevented it, ameliorating liver injury. FXR attenuates CCAAT-enhancer-binding protein homologous protein (CHOP)-dependent NLRP3 overexpression by inhibiting ER stress-mediated protein kinase RNA-like endoplasmic reticulum kinase (PERK) activation. Our findings implicate miR-186 and its target, non-catalytic region of tyrosine kinase adaptor protein 1 (NCK1), in mediating the inhibition of ER stress by FXR. This study provides the insights on how FXR regulation of ER stress ameliorates hepatocyte death and liver injury and on the molecular basis of NLRP3 inflammasome activation. Han et al. demonstrate that FXR inhibits ER stress-induced NLRP3 inflammasome activation in hepatocytes. FXR activation ameliorates ER stress-dependent hepatocyte death and liver injury. These findings provide insight into ER stress-mediated inflammasome activation and liver disease progression.

Original languageEnglish
Pages (from-to)2985-2999
Number of pages15
JournalCell Reports
Volume24
Issue number11
DOIs
StatePublished - 2018 Sep 11

Keywords

  • CHOP
  • ER stress
  • FXR
  • NLRP3
  • PERK
  • TXNIP
  • inflammasome

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