A Novel Mouse Model of Acute-on-Chronic Cholestatic Alcoholic Liver Disease: A Systems Biology Comparison With Human Alcoholic Hepatitis

Alcohol Clin Exp Res. 2020 Jan;44(1):87-101. doi: 10.1111/acer.14234. Epub 2019 Nov 28.


Background: Alcohol-related liver disease is the main cause of liver-related mortality worldwide. The development of novel targeted therapies for patients with advanced forms (i.e., alcoholic hepatitis, AH) is hampered by the lack of suitable animal models. Here, we developed a novel mouse model of acute-on-chronic alcohol liver injury with cholestasis and fibrosis and performed an extensive molecular comparative analysis with human AH.

Methods: For the mouse model of acute-on-chronic liver injury, we used 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC, 0.05% w/w) diet for 8 weeks to establish cholestatic liver fibrosis. After 1-week washout period, male mice were fed intragastrically for 4 weeks with up to 24 g/kg of ethyl alcohol in a high-fat diet. This animal model was phenotyped using histopathology, clinical chemistry, microbiome, and gene expression approaches. Data were compared to the phenotypes of human alcohol-related liver disease, including AH.

Results: Mice with cholestatic liver fibrosis and subsequent alcohol exposure (DDC + EtOH) exhibited exacerbated liver fibrosis with a pericellular pattern, increased neutrophil infiltration, and ductular proliferation, all characteristics of human AH. DDC administration had no effect on urine alcohol concentration or liver steatosis. Importantly, DDC- and alcohol-treated mice showed a transcriptomic signature that resembled that of patients with AH. Finally, we show that mice in the DDC + EtOH group had an increased gut barrier dysfunction, mimicking an important pathophysiological mechanism of human AH.

Conclusions: We developed a novel mouse model of acute-on-chronic cholestatic alcoholic liver injury that has considerable translational potential and can be used to test novel therapeutic modalities for AH.

Keywords: Acute-on-Chronic; Alcoholic Hepatitis; Mouse Model.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Acute Disease
  • Animals
  • Cholestasis / etiology
  • Cholestasis / metabolism
  • Cholestasis / pathology*
  • Chronic Disease
  • Diet, High-Fat / adverse effects
  • Disease Models, Animal*
  • Ethanol / toxicity*
  • Hepatitis, Alcoholic / etiology
  • Hepatitis, Alcoholic / metabolism
  • Hepatitis, Alcoholic / pathology*
  • Humans
  • Liver Cirrhosis / etiology
  • Liver Cirrhosis / metabolism
  • Liver Cirrhosis / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Pyridines / toxicity
  • Systems Biology / methods*


  • 3,5-diethoxycarbonyl-1,4-dihydrocollidine
  • Pyridines
  • Ethanol