FXR Inhibits Endoplasmic Reticulum Stress-Induced NLRP3 Inflammasome in Hepatocytes and Ameliorates Liver Injury
- Title
- FXR Inhibits Endoplasmic Reticulum Stress-Induced NLRP3 Inflammasome in Hepatocytes and Ameliorates Liver Injury
- Author
- 장기석
- Keywords
- THIOREDOXIN-INTERACTING PROTEIN; FARNESOID X RECEPTOR; ER STRESS; CELL-DEATH; NONALCOHOLIC STEATOHEPATITIS; HEPATIC STEATOSIS; OXIDATIVE STRESS; DOWN-REGULATION; ACTIVATION; SURVIVAL
- Issue Date
- 2018-09
- Publisher
- CELL PRESS
- Citation
- CELL REPORTS, v. 24, no. 11, page. 2985-2999
- 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 CCAA-Tenhancer-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, noncatalytic 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.
- URI
- https://www.cell.com/cell-reports/fulltext/S2211-1247(18)31186-0?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2211124718311860%3Fshowall%3Dtruehttps://repository.hanyang.ac.kr/handle/20.500.11754/120022
- ISSN
- 2211-1247
- DOI
- 10.1016/j.celrep.2018.07.068
- Appears in Collections:
- COLLEGE OF MEDICINE[S](의과대학) > MEDICINE(의학과) > Articles
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