Title :

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

Author(s) :

Furuya, Shinji [Auteur]
Texas A&M University [College Station]
Argemi, Josepmaria [Auteur]
University of Pittsburgh [PITT]
Uehara, Takeki [Auteur]
Osaka Prefecture University
Katou, Yuuki [Auteur]
Osaka Prefecture University
Fouts, Derrick E [Auteur]
J. Craig Venter Institute
Schnabl, Bernd [Auteur]
University of California [San Diego] [UC San Diego]
Dubuquoy, Laurent [Auteur]
Lille Inflammation Research International Center - U 995 [LIRIC]
Belorkar, Abha [Auteur]
Jefferson University Hospitals
Vadigepalli, Rajanikanth [Auteur]
Jefferson University Hospitals
Kono, Hiroshi [Auteur]
Yamanashi University
Bataller, Ramon [Auteur]
University of Pittsburgh [PITT]
Rusyn, Ivan [Auteur]
Texas A&M University [College Station]

Journal title :

Alcoholism, clinical and experimental research

Abbreviated title :

Alcohol Clin Exp Res

Volume number :

44

Pages :

87-101

Publication date :

2020-01

ISSN :

1530-0277

English keyword(s) :

Acute-on-Chronic
Alcoholic Hepatitis
Mouse Model

HAL domain(s) :

Sciences du Vivant [q-bio]

English abstract : [en]

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 ...
Show more >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. 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. 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. 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.Show less >

Language :

Anglais

Peer reviewed article :

Oui

Audience :

Non spécifiée

Administrative institution(s) :

Université de Lille
Inserm
CHU Lille

Collections :

• Institut de Recherche Translationnelle sur l'Inflammation (INFINITE) - U1286

Submission date :

2021-01-13T13:24:12Z
2021-01-18T09:35:31Z
2021-01-18T09:41:32Z
2021-04-23T12:47:55Z