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FXR Inhibits NLRP3 Inflammasome Activation by ER Stress
Author(s) -
Kim Ayoung,
Han Chang Yeob,
Rho Hyun Soo,
Kim Tae Hyun,
Kim Sang Geon
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.533.2
Subject(s) - inflammasome , unfolded protein response , endoplasmic reticulum , txnip , farnesoid x receptor , chemistry , endocrinology , microbiology and biotechnology , signal transduction , chop , medicine , cancer research , receptor , biology , oxidative stress , nuclear receptor , biochemistry , transcription factor , gene , thioredoxin
Chronic endoplasmic reticulum (ER) stress is closely associated with hepatic inflammation, which may contribute to liver injury and fibrosis. However, the potential regulators that act against ER stress‐mediated inflammasome activation in hepatocytes is largely unknown. This study investigated the role of farnesoid X receptor (FXR) in the regulation of NLRP3 inflammasome activation by ER stress. The degree of NLRP3 inflammasome activation was inversely correlated with hepatic FXR level in patients with HBV‐associated hepatic failure or non‐alcoholic fatty liver disease. The inverse relationship between FXR and NLRP3 was confirmed in animal models with liver injury. In mice, FXR deficiency exacerbated the effect of ER stress inducer on NLRP3 and TXNIP expression levels. Consistently, FXR agonist treatment had an opposite effect, alleviating liver injury. In addition, FXR activation specifically inhibited PERK pathway among canonical UPR pathways in hepatocytes, and CHOP was necessary for NLRP3 and TXNIP induction by ER stress. Moreover, FXR activation abolished the ability of ER stress to decrease the expression of Nck1, leading to the inhibition of inflammasome activation and cell death. MiR‐186 was identified as a repressor of Nck1 and involved in ER stress‐mediated NLRP3 inflammasome activation. Overall, our results demonstrate that FXR acts as a novel regulator of hepatic ER stress and consequential NLRP3 inflammasome activation through PERK‐CHOP signaling pathway, which may depend on miR‐186 regulation of Nck1. Support or Funding Information NRF‐2015R1A2A1A10052663, 2017R1D1A1B03028272 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .