A Novel Mouse Model of Acute-on-Chronic Cholestatic Alcoholic Liver Disease: A Systems Biology Comparison With Human Alcoholic Hepatitis
Shinji Furuya (1), Josepmaria Argemi (2), Takeki Uehara (3), Yuuki Katou (3), Derrick E Fouts (4), Bernd Schnabl (5), Laurent Dubuquoy (6), Abha Belorkar (7), Rajanikanth Vadigepalli (7), Hiroshi Kono (8), Ramon Bataller (2), Ivan Rusyn (1)
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.
CITA DEL ARTÍCULO Alcohol Clin Exp Res . 2020 Jan;44(1):87-101.
doi: 10.1111/acer.14234. Epub 2019 Nov 28