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Review
. 2017 Jul 7;17(3):173-186.
doi: 10.3727/105221617X695519. Epub 2017 Apr 14.

Animal Models of Alcoholic Liver Disease: Pathogenesis and Clinical Relevance

Bin Gao, Ming-Jiang Xu, Adeline Bertola, Hua Wang, Zhou Zhou, Suthat Liangpunsakul
Review

Animal Models of Alcoholic Liver Disease: Pathogenesis and Clinical Relevance

Bin Gao et al. Gene Expr. .

Abstract

Alcoholic liver disease (ALD), a leading cause of chronic liver injury worldwide, comprises a range of disorders including simple steatosis, steatohepatitis, cirrhosis, and hepatocellular carcinoma. Over the last five decades, many animal models for the study of ALD pathogenesis have been developed. Recently, a chronic-plus-binge ethanol feeding model was reported. This model induces significant steatosis, hepatic neutrophil infiltration, and liver injury. A clinically relevant model of high-fat diet feeding plus binge ethanol was also developed, which highlights the risk of excessive binge drinking in obese/overweight individuals. All of these models recapitulate some features of the different stages of ALD and have been widely used by many investigators to study the pathogenesis of ALD and to test for therapeutic drugs/components. However, these models are somewhat variable, depending on mouse genetic background, ethanol dose, and animal facility environment. This review focuses on these models and discusses these variations and some methods to improve the feeding protocol. The pathogenesis, clinical relevance, and translational studies of these models are also discussed.

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Figures

Figure 1
Figure 1
(A) Mortality rate of male C57BL/6J and C57BL/6N mice subjected to chronic ethanol feeding. Eight- to 12-week-old male mice were fed the Lieber–Decali diet containing 5% ethanol at room temperature of 72 ± 3°F. (B) Mortality of male C57BL/6J mice subjected to chronic ethanol feeding under different room temperatures. Eight- to 12-week old male C57BL/6J mice were fed the Lieber–Decali diet containing 5% ethanol at different room temperatures (72 ± 3°F, 74 ± 3°F, and 76 ± 3°F). (C) Mortality of male C57BL/6N mice subjected to chronic-plus-binge ethanol. Eight- to 12-week-old male C57BL/6N mice were fed the Lieber–Decali diet containing 5% ethanol up to 12 weeks, followed by one binge of ethanol (5 g/kg). Mice were fed at room temperature of 72 ± 3°F. The percentage numbers on top of each bar indicate the corresponding survival rate.
Figure 2
Figure 2
(A) Mortality rate of male C57BL/6J mice subjected to HFD-plus-multiple binges. Eight- to 12-week-old male mice were fed an HFD diet for 3 months. Then mice were continued to be fed with HFD for 4 weeks, plus binge ethanol (5 g/kg) twice a week for 4 weeks. The survival rate of the mice was determined at 24 h after the gavage. (B) Survival rate of male C57BL/6J and C57BL/6N mice subjected to HFD-plus-single ethanol binge. Eight- to 12-week-old male C57BL/6J and C57BL/6N mice were fed an HFD diet for 3 months and then subjected to one binge of ethanol (5 g/kg). The survival rate was determined 24 h after the gavage, and the percentage of survival is shown on the top of the bars. (C) Body weight change of male C57BL/6J mice subjected to HFD-plus-multiple binges. The mice (n = 27) were treated as described in (A), and the body weight at the time of each gavage was examined and analyzed.
Figure 3
Figure 3
Multiple mechanisms underlying alcoholic steatohepatitis. Chronic-plus-binge or HFD-plus-binge ethanol consumption induces ER stress, followed by activation of the cyclic AMP-responsive element-binding protein H (CREBH) and nuclear translocation of nCREBH, and subsequent upregulation of the predominant form of FSP27β. FSP27 interacts with lipid droplet (LD) membrane proteins and subsequently promotes LD formation and steatosis. In addition, ethanol promotes FSP27 translocation into the mitochondria and subsequent mitochondrial injury and hepatocyte death. Ethanol also induces ER stress and subsequently produces proinflammatory mediators and danger-associated molecular patterns (DAMPs). Ethanol feeding activates natural killer T (NKT) cells to release proinflammatory mediators. Ethanol alters gut bacteria and elevates pathogen-associated molecular patterns (PAMPs). All of these factors lead to hepatic neutrophil infiltration and liver inflammation.
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