Effect of alcohol on the interleukin 6-mediated inflammatory response in a new mouse model of acute-on-chronic liver injury

Biochim Biophys Acta Mol Basis Dis. 2019 Feb 1;1865(2):298-307. doi: 10.1016/j.bbadis.2018.11.008. Epub 2018 Nov 15.


Background and aims: ACLF is usually associated with a precipitant in the setting of a chronically damaged liver. We aim to combine a mouse model with a pre-injured liver (Abcb4/Mdr2-/-) with a recently standardized ethanol feeding model to dissect alcohol-related inflammatory responses in this model.

Method: Ten (n = 64) and 15 (n = 64) week old wild-type (WT) C57BL/6 J and Abcb4-/- knock-out (KO) mice were either fed control (WT/Cont and KO/Cont groups) or liquid ethanol diet (5% v/v) followed by an ethanol binge (4 mg/kg) (WT/EtOH and KO/EtOH groups). Hepatic mRNA levels of IL6, IFN-G, IL-1B, TGFB1, TNF-A, CCL2, HGF, CRP, RANTES, PNPLA3 and COL3A1 were evaluated using the 2-ΔΔCt method. IL6 and HGF plasma levels were quantified by ELISA.

Results: Older mice in KO/EtOH group displayed higher IL6 expressions compared to KO/Cont, WT/EtOH and WT/Cont groups of the same age, whereas HGF did not differ. Significant over-expression of CCL2 also corresponded to the same group. Males in KO/EtOH group exhibited higher IL6 expression than females. Lipid droplets were observed in about 80% of mice challenged with ethanol. There was a profound downregulation in PNPLA3 and RANTES levels after ethanol exposure. Mean size of the LDs was inversely correlated with hepatic PNPLA3 levels.

Conclusion: We propose a novel promising approach to model alcohol-related ACLI. Acute inflammatory IL6-driven response might help transition from a stable chronic state to a progressive liver damage in Abcb4-/- mice. Repression of PNPLA3 resulted in a notable expansion in size of lipid droplets, indicating lipid remodeling in this model.

Keywords: Abcb4 knock-out mouse; Acute-on-chronic liver failure (ACLF); Inflammation; alcoholic liver disease (ALD); liver fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute-On-Chronic Liver Failure / blood
  • Acute-On-Chronic Liver Failure / pathology*
  • Animals
  • Biomarkers / blood
  • Disease Models, Animal
  • Ethanol / blood
  • Ethanol / toxicity*
  • Female
  • Hepatocyte Growth Factor / blood
  • Inflammation / blood
  • Inflammation / pathology*
  • Inflammation Mediators / metabolism
  • Interleukin-6 / blood
  • Interleukin-6 / metabolism*
  • Lipid Droplets / metabolism
  • Liver / injuries*
  • Liver / metabolism
  • Liver / pathology
  • Liver Cirrhosis / blood
  • Liver Cirrhosis / pathology
  • Male
  • Mice, Inbred C57BL
  • Phospholipases A2, Calcium-Independent / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism


  • Biomarkers
  • Inflammation Mediators
  • Interleukin-6
  • RNA, Messenger
  • Ethanol
  • Hepatocyte Growth Factor
  • PNPLA3 protein, mouse
  • Phospholipases A2, Calcium-Independent