Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Furuya S

PROVIDER: S-EPMC6980964 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Publications

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

Furuya Shinji S Argemi Josepmaria J Uehara Takeki T Katou Yuuki Y Fouts Derrick E DE Schnabl Bernd B Dubuquoy Laurent L Belorkar Abha A Vadigepalli Rajanikanth R Kono Hiroshi H Bataller Ramon R Rusyn Ivan I

Alcoholism, clinical and experimental research 20191128 1

<h4>Background</h4>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.<h4>Methods</h4>For the mouse model of acute-on-chron ...[more]

PMID: 31710124

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Project description:The abnormal accumulation of fat in the liver is often related either to metabolic risk factors associated with metabolic syndrome in the absence of alcohol consumption (nonalcoholic fatty liver disease, NAFLD) or to chronic alcohol consumption (alcoholic fatty liver disease, AFLD). Clinical and histological studies suggest that NAFLD and AFLD share pathogenic mechanisms. Nevertheless, current data are still inconclusive as to whether the underlying biological process and disease pathways of NAFLD and AFLD are alike. Our primary aim was to integrate omics and physiological data to answer the question of whether NAFLD and AFLD share molecular processes that lead to disease development. We also explored the extent to which insulin resistance (IR) is a distinctive feature of NAFLD. To answer these questions, we used systems biology approaches, such as gene enrichment analysis, protein-protein interaction networks, and gene prioritization, based on multi-level data extracted by computational data mining. We observed that the leading disease pathways associated with NAFLD did not significantly differ from those of AFLD. However, systems biology revealed the importance of each molecular process behind each of the two diseases, and dissected distinctive molecular NAFLD and AFLD-signatures. Comparative co-analysis of NAFLD and AFLD clarified the participation of NAFLD, but not AFLD, in cardiovascular disease, and showed that insulin signaling is impaired in fatty liver regardless of the noxa, but the putative regulatory mechanisms associated with NAFLD seem to encompass a complex network of genes and proteins, plausible of epigenetic modifications. Gene prioritization showed a cancer-related functional map that suggests that the fatty transformation of the liver tissue is regardless of the cause, an emerging mechanism of ubiquitous oncogenic activation. In conclusion, similar underlying disease mechanisms lead to NAFLD and AFLD, but specific ones depict a particular disease signature that has a different impact on the systemic context.

Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

Similar Datasets

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