Abstract
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 InformationNRF‐2015R1A2A1A10052663, 2017R1D1A1B03028272This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.