Chalcone Derivative L6H21 Reduces EtOH + LPS-Induced Liver Injury Through Inhibition of NLRP3 Inflammasome Activation

Alcohol Clin Exp Res. 2019 Aug;43(8):1662-1671. doi: 10.1111/acer.14120. Epub 2019 Jun 30.

Abstract

Background: Chronic alcohol intake increases circulating endotoxin levels causing excessive inflammation that aggravates the liver injury. (E)-2,3-dimethoxy-4'-methoxychalcone (L6H21), a derivative of chalcone, has been found to inhibit inflammation in cardiac diseases and nonalcoholic fatty liver disease. However, the use of L6H21 in alcoholic liver disease 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.

Methods: C57BL6 mice were treated with 5% EtOH for 10 days, and LPS was given to the mice 6 hours before sacrificing. One group of mice was supplemented with L6H21 with EtOH and LPS. RAW264.7 cells were used to analyze the effects of L6H21 on macrophage activation.

Results: EtOH + LPS treatment significantly increased hepatic steatosis and serum levels of alanine transaminase (ALT) and aspartate transaminase (AST), which were reduced by L6H21 treatment. EtOH + LPS treatment increased hepatic inflammation, as shown by the increased hepatic protein levels of Toll-like receptor-4, p65, and p-IκB, and increased oxidative stress, as shown by protein carbonyl levels and reactive oxygen species formation, which were reduced by L6H21 treatment. In addition, L6H21 treatment markedly inhibited EtOH + LPS-elevated hepatic protein levels of NLRP3, cleaved caspase-1, cleaved IL-1β, and caspase-1-associated apoptosis.

Conclusions: Our results demonstrate that L6H21 treatment inhibits EtOH + LPS-induced liver steatosis and injury through suppression of NLRP3 inflammasome activation. L6H21 may be used as an alternative strategy for ALD prevention/treatment.

Keywords: Alcoholic Liver Disease; L6H21; Lipopolysaccharide; NLRP3 Inflammasome.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine Transaminase
  • Animals
  • Apoptosis / drug effects
  • Aspartate Aminotransferases / blood
  • Caspases / metabolism
  • Cells, Cultured
  • Chalcones / pharmacology*
  • Ethanol / adverse effects*
  • Fatty Liver
  • Inflammasomes / metabolism*
  • Inflammation / metabolism
  • Interleukin-1beta / metabolism
  • Lipopolysaccharides
  • Liver Diseases, Alcoholic / blood
  • Liver Diseases, Alcoholic / metabolism
  • Liver Diseases, Alcoholic / prevention & control*
  • Male
  • Mice
  • Microfilament Proteins / metabolism
  • NF-KappaB Inhibitor alpha / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • Oxidative Stress / drug effects
  • Toll-Like Receptor 4 / metabolism

Substances

  • 2,3-dimethoxy-4'-ethoxychalcone
  • Chalcones
  • IL1B protein, mouse
  • Inflammasomes
  • Interleukin-1beta
  • Lipopolysaccharides
  • Microfilament Proteins
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Toll-Like Receptor 4
  • Lcp1 protein, mouse
  • NF-KappaB Inhibitor alpha
  • Ethanol
  • Aspartate Aminotransferases
  • Alanine Transaminase
  • Caspases