Chalcone derivative L6H21 reduces EtOH‐LPS‐induced liver injury through inhibition of NLRP3 inflammasome activation

Abstract

Chronic alcohol intake increases circulating endotoxin levels causing excessive inflammation that aggravates the liver injury. L6H21, a derivative of chalcone, has been found to inhibit inflammation in cardiac diseases and non‐alcoholic fatty liver disease. However, use of L6H21 in alcoholic liver disease (ALD) to inhibit exotoxin‐associated inflammation has not been explored. In this study, we examined the effects of L6H21 on EtOH‐LPS‐induced hepatic inflammation, steatosis and liver injury, and investigated the underlying mechanisms. C57BL6 mice were treated with 5% ethanol for ten days, and LPS was applied on the last day. L6H21 was given with alcohol. EtOH‐LPS treatment significantly increased hepatic steatosis and serum ALT and AST levels, which were reduced by L6H21 treatment. L6H21 treatment significantly reduced hepatic protein levels of TLR4, p‐P65 and p‐IκB, and inhibited p65 translocation into the nucleus. In addition, L6H21 treatment markedly reduced hepatic protein levels of NLRP3, cleaved caspase‐1 and cleaved‐IL‐1β, which were increased by EtOH‐LPS exposure. Moreover, L6H21 treatment effectively inhibited caspase‐1 associate apoptosis. In vitro study using Raw264.7 cells confirmed the effects of L6H21 on macrophage activation. Taken together, our results demonstrate that L6H21 suppresses the LPS/TLR4/NF‐κB‐mediated inflammation and NLRP3 inflammasome activation in ethanol and LPS‐induced liver injury. L6H21 might be used an alternative strategy for ALD prevention/treatment.Support or Funding InformationNIHThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.