Date: Saturday, June 1, 2019
Session Time: 5:30pm-7:30pm
Presentation Time: 5:30pm-7:30pm
Location: Hall C & D
*Purpose: The relationships among Farnesoid X receptor (FXR), nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain-containing 3 (NLRP3) inflammasome and pyroptosis are largely unknown in liver IRI. We aimed to investigate the mechanism by which the FXR/NLRP3 inflammasome/pyroptosis axis regulates inflammatory responses in a mouse hepatic ischemia reperfusion injury (IRI) model.
*Methods: A mouse partial (70%) liver warm ischemia (90 min) model was induced in the present study. The expression of FXR,GSDMD,NLRP3,IL-1β,cleaved caspase-1 in clinical liver transplantation samples and mouse IRI livers was detected by Western blot. Hepatic necrosis after IRI was detected by H&E staining. The lever of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were detected by a biochemical analyzer.
*Results: We showed that induction of pyroptosis in vivo in warm IRI mouse livers. Deletion of FXR exacerbated liver damage, as evidenced by increased levels of serum alanine aminotransferase and aspartate aminotransferase, hepatocellular necrosis, intrahepatic neutrophil trafficking, and the upregulation of pro-inflammatory cytokines. FXR deficiency activated the expression of gasdermin D (GSDMD), which has been identified the pyroptosis executioner. FXR silencing increased pyroptosis and liver IR injury. Blocking NLRP3 inflammasome in FXR knockout mice showed the reduced expression of GSDMD-N, cleaved caspase-1, IL-1β and decreased liver damage.
*Conclusions: These findings provide a novel mechanism that FXR regulates pyroptosis through inhibition of NLRP3 inflammasome, leading to ameliorate hepatic IRI.
To cite this abstract in AMA style:Zhu Z, Zhang Y, Tang Y, Huang S, Zhao Q, Ju W, Guo Z, He X. Loss of FXR Exacerbates Liver Damage by Activating NLRP3 Inflammasome Induced Pyroptosis in Liver Ischemia Reperfusion Injury [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/loss-of-fxr-exacerbates-liver-damage-by-activating-nlrp3-inflammasome-induced-pyroptosis-in-liver-ischemia-reperfusion-injury/. Accessed February 29, 2020.
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