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Animal model of acute-on-chronic alcoholic liver injury

ABSTRACT: Background and aims: We aimed to study the pathogenesis of AH in an animal model of acute-on-chronic alcoholic liver disease which combines chronic hepatic fibrosis with intragastric alcohol administration. Methods: Adult male C57BL6/J mice were treated with CCl4 (0.2 ml/kg, 2×weekly by intraperitoneal injections for 6 weeks) to induce chronic liver fibrosis. Then, ethyl alcohol (EtOH) (up to 25 g/kg/day, for 3 weeks) was administered continuously to mice via a gastric feeding tube, with or without one-half dose of CCl4. Liver and serum markers were evaluated to characterize acute-on-chronic-alcoholic liver disease in our model. Results: CCl4 or EtOH treatment alone induced liver fibrosis or steatohepatitis, respectively, findings that were consistent with expected pathology. Combined treatment with CCl4 and EtOH resulted in a marked exacerbation of liver injury, as evident by the development of hepatic inflammation, marked steatosis, and pericellular fibrosis, and by increased serum transaminase levels, compared to mice treated with either treatment alone. Liver transcriptomic changes specific to combined treatment group demonstrated close concordance with pathways perturbed in human severe cases of AH. In addition to gene expression changes, E. coli and Candida species were also significantly more abundant in livers of mice co-treated with CCl4 and EtOH. Conclusions: Mice treated with CCl4 and EtOH displayed several key characteristics of human AH, including pericellular fibrosis, increased hepatic bacterial load, and dysregulation of the same molecular pathways. This model may be useful for developing therapeutics for AH.

ORGANISM(S): Mus musculus

PROVIDER: GSE119470 | GEO | 2018/09/05

REPOSITORIES: GEO

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Project description:Background and aims: Liver is a major target organ for alcohol-induced disease and the spectrum of pathological states elicited by alcohol in liver comprises steatosis, alcoholic steatohepatitis, progressive fibrosis and cirrhosis, conditions that may progress to hepatocellular carcinoma. Many experimental animal models of alcoholic steatohepatitis exist that vary in duration, mode of alcohol administration and the degree and types of liver injury produced. While most of these models, regardless whether alcohol is administered through liquid diet or intragastrically, produce steatohepatitis and mild fibrosis, it is widely acknowledged that these models fail to fully recapitulate key characteristics of severe forms of alcoholic liver disease, such as alcoholic hepatitis. Recent studies attempted to combine alcohol and fibrosis and achieved promising results in mouse models that achieve some of the key features of alcoholic liver disease accompanied by exacerbated fibrosis and acute renal injury. This study combined a chronic cholestatic liver fibrosis model induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) with a mouse model of intragastric alcohol feeding. Methods: Adult male C57BL6/J mice were treated with 3,5-diethoxycarbonyl-1,4-dihydrocolidine (DDC) containing diet (0.05% w/w) to induce chronic liver fibrosis. Following DDC-induced fibrogenesis, ethyl alcohol (EtOH) (up to 27 g/ kg/day, up to 28 days) was administered continuously to mice via a gastric feeding tube (Tsukamoto-Frenchmodel of alcoholic liver disease). Results: Exposure to DDC or EtOH alone resulted in liver fibrosis or steatosis, respectively. Combined treatment with DDC and EtOH lead to an additive effect on liver injury, as evident by the development of hepatic inflammation, steatosis, and pericellular fibrosis, and by increased serum transaminase levels, compared to mice treated with either agent alone. Liver transcriptomic changes specific to combined treatment group included pathways involved in the cell cycle and DNA damage. Analyses of feces from these mice revealed alcohol-associated changes to the bile acid profile and gut microbiome. Conclusions: Mice treated with DDC and EtOH displayed several key characteristics of human alcoholic hepatitis, including pericellular fibrosis, increased hepatic bacterial load with dysbiosis, reduced capacity of the microbiome to synthesize secondary bile acids.

Project description:BACKGROUND: Alcohol-related liver disease ranges from silent alcoholic steatohepatitis (sASH), an asymptomatic and compensated phenotype, to life- threatening alcoholic hepatitis (AH). A systematic comparative study of the clinical, histological and molecular features of these subtypes is lacking. METHODS : Two large cohorts of patients were recruited in an international, observational multi-center study: a retrospective cohort of patients with sASH (n=110) and a prospective cohort of patients with AH (two subgroups with n=121 and 104). sASH and AH were compared by doing clinical, analytical, immunohistochemistry and hepatic RNA microarray analysis. FINDINGS: Age and mean alcohol intake were similar in patients with sASH vs AH. AH showed lower mean arterial pressure than sASH. AH patients had greater aspartate amino transferase/alanine amino transferase ratio and lower gamma- glutamyl transferase levels than AH. Individuals with AH demonstrated profound liver failure, lower blood pressure and increased mortality. Histologically, the grade of steatosis, ballooning and pericellular fibrosis were similar in both groups, while advanced fibrosis, Mallory-Denk bodies, bilirubinostasis, severe neutrophil infiltration and progenitor cell expansion were more frequent among AH patients. One-year mortality was 10% in sASH and 50% in AH. Transcriptome analysis revealed a profound gene dysregulation within both phenotypes when compare to controls. Globally, AH patients exhibited changes in 4,921 genes, while the number of dysregulated genes in sASH patients was less pronounced -1,327-. While sASH was characterized by deregulated expression of genes involved in matrisome and immune response, the development of AH resulted in a marked deregulation of genes involved in hepatocyte reprogramming and bile acid metabolism. INTERPRETATION: Despite comparable daily alcohol intake, AH patients presented with worse liver function and hemodynamic status compared to sASH. Bilirubinostasis, severe fibrosis and progenitor cell expansion were prominent features of AH. AH patients exhibited a more profound deregulation of gene expression compared to sASH.

Project description:Background & Aims: Rapid induction of beta-PDGF receptor (beta-PDGFR) is a core feature of hepatic stellate cell activation, the hallmark of liver fibrogenesis. However, biological consequences of the induction are not well characterized. We aimed to determine the involvement of beta-PDGFR-mediated molecular pathway activation on hepatic stellate cells in liver injury, fibrogenesis, and carcinogenesis in vivo. Methods: Loss and constitutive activation of beta-PDGFR were assessed in mouse models with either a stellate cell-specific beta-PDGFR knockout or the expression of an autoactivating mutation respectively. Liver injury and fibrosis were induced in two mechanistically distinct models: carbontetrachloride (CCl4) treatment and ligation of the common bile duct. Hepatocarcinogenesis with underlying liver injury/fibrosis was assessed by a single dose of diethylnitrosamine (DEN) followed by repeated injections of CCl4. Genome-wide expression profiling was performed isolated stellate cells from these models to determine deregulated pathways. Results: Depletion of beta-PDGFR in hepatic stellate cells led to decreased histological liver injury, serum transaminases, collagen alpha 1(I) and alpha smooth muscle actin expression, and collagen deposition. Stellate cell proliferation was significantly reduced after acute hepatic injury in vivo. In contrast, autoactivation of beta-PDGFR in stellate cells accelerated liver fibrosis, most prominently after 6 weeks of CCl4 induced injury. There was no difference in development of DEN-induced pre-neoplastic loci according to the status of beta-PDGFR. Conclusions: Depletion of beta-PDGFR in hepatic stellate cells attenuated the development of liver injury, fibrosis, and stellate cell proliferation in multiple animal models, whereas the constitutive activation of beta-PDGFR enhanced fibrosis. However, manipulation of beta-PDGFR alone did not reduce development of dysplastic nodules. These findings indicate that titration of receptor beta-PDGFR expression on stellate cells parallels fibrosis and injury, but may not impact the development of hepatic neoplasia alone. Hepatic stellate cells were isolated from liver of beta-PDGFR-wild-type or knockout mice, and treated with beta-PDGF ligand or vehicle control.

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Animal model of acute-on-chronic alcoholic liver injury

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