SIRT1 alleviates hepatic ischemia-reperfusion injury via the miR-182-mediated XBP1/NLRP3 pathway

Abstract

The hepatoprotection of histone deacetylase sirtuin 1 (SIRT1) has been identified to attenuate ischemia-reperfusion (IR)-triggered inflammation and liver damage. This study was performed to characterize the function of SIRT1 in hepatic IR injury. In in vivo assays on liver-specific knockout mice of SIRT1, we first validated the effect of SIRT1 knockout on liver damage and XBP1/NLRP3 inflammasome activation. Next, we examined whether knockdown of XBP1/NLRP3 or miR-182 agomir could reverse the effect of SIRT1 knockout. In in vitro assays, NCTC1469 cells subjected to hypoxia/reoxygenation (H/R) were transduced with small interfering RNA (siRNA)/activator of SIRT1 or miR-182 agomir to confirm the effect of SIRT1 on NCTC1469 cell behaviors as well as the regulation of miR-182 and the XBP1/NLRP3 signaling pathway. Hepatic IR injury was appreciably aggravated in SIRT1 knockout mice, and SIRT1 knockdown abolished the inhibition of XBP1/NLRP3 inflammasome activation, which was reversed by NLRP3 knockdown, XBP1 knockdown, or miR-182 agomir. Mechanistically, miR-182 expression was positively regulated by SIRT1 in hepatic IR injury in mice, and miR-182 inhibited the expression of XBP1 by binding to the 3′ untranslated region (UTR) of XBP1. The histone deacetylase SIRT1 inhibits the downstream XBP1/NLRP3 inflammatory pathway by activating miR-182, thus alleviating hepatic IR injury in mice.

Propofol reduces renal ischemia/reperfusion-induced acute lung injury by stimulating sirtuin 1 and inhibiting pyroptosis

“…Notably, our study also revealed that SIRT1 was a crucial conveyer of the beneficial effects of propofol, as demonstrated by the results of inhibiting SIRT1 using nicotinamide. Propofol has been reported to activate SIRT1 in hepatic I/R tissues and human umbilical vein endothelial cells [ 28 , 29 ]. We found that propofol enhanced SIRT1 expression in NR8383 cells, suggesting that propofol could be used to inhibit pulmonary disorders by inducing SIRT1.…”

An Epigenetic Insight into NLRP3 Inflammasome Activation in Inflammation-Related Processes

“…It had been clearly stablished that the endoplasmic reticulum (ER) stress is involved in inflammatory processes by upregulating NLRP3 inflammasome [ 103 ]. SIRT1 regulates the transcriptional levels of XBP1, either by decreasing the acetylation levels of XBP1s or upregulating the miR-182 expression that binds to XBP1 to inhibit its expression and, therefore, the NLRP3 inflammasome activation and pyroptosis [ 104 , 105 ].…”

Non-Coding RNAs: Master Regulators of Inflammasomes in Inflammatory Diseases

“…Mechanistically, the expression of miR-182 was positively regulated by SIRT1 in a mouse model of hepatic IR injury; miR-182 inhibited the expression of XBP1 by binding to the 3′-UTR of XBP1, thus providing a new perspective on the hepatoprotective mechanisms of SIRT1 in hepatic IR injury. 163 In addition, AIM2 is known to act as a DNA sensor and can be activated by mtDNAs following the mitochondrial damage that occurs in many inflammatory diseases. Liang et al demonstrated that lncRNA MRG3 could regulate the AIM2 inflammasome in cerebral I/R injury.…”

“…ROS can cause differential expression of ncRNAs in a variety of diseases. 163 Whether these ncRNAs can regulate the activation of inflammasomes needs further research. In addition, several studies showed that ncRNAs could regulate inflammasomes activation by regulate ROS.…”