Rodent Models of Alcoholic Liver Disease: Role of Binge Ethanol Administration

Abstract

Both chronic and acute (binge) alcohol drinking are important health and economic concerns worldwide and prominent risk factors for the development of alcoholic liver disease (ALD). There are no FDA-approved medications to prevent or to treat any stage of ALD. Therefore, discovery of novel therapeutic strategies remains a critical need for patients with ALD. Relevant experimental animal models that simulate human drinking patterns and mimic the spectrum and severity of alcohol-induced liver pathology in humans are critical to our ability to identify new mechanisms and therapeutic targets. There are several animal models currently in use, including the most widely utilized chronic ad libitum ethanol (EtOH) feeding (Lieber-DeCarli liquid diet model), chronic intragastric EtOH administration (Tsukamoto-French model), and chronic-plus-binge EtOH challenge (Bin Gao-National Institute on Alcohol Abuse and Alcoholism (NIAAA) model). This review provides an overview of recent advances in rodent models of binge EtOH administration which help to recapitulate different features and etiologies of progressive ALD. These models include EtOH binge alone, and EtOH binge coupled with chronic EtOH intake, a high fat diet, or endotoxin challenge. We analyze the strengths, limitations, and translational relevance of these models, as well as summarize the liver injury outcomes and mechanistic insights. We further discuss the application(s) of binge EtOH models in examining alcohol-induced multi-organ pathology, sex- and age-related differences, as well as circadian rhythm disruption.

Keywords: EtOH-induced liver injury; alcoholic liver disease; animal models; binge drinking; blood alcohol concentration; high fat diet; lipopolysaccharide.

Figure 1

Paradigms of binge ethanol (EtOH) administration in rodent models. Approaches that have been used to model binge (acute) EtOH effects in rodents are shown. These include administration of single or multiple EtOH binge(s) alone, or in combination with short- or long-term exposure to chronic EtOH or high fat diet, or lipopolysaccharide (LPS) injection. Binge EtOH produces dose-, frequency-, and duration-dependent adverse effects on the liver and multiple organ systems. Factors that exacerbate binge alcohol-mediated toxicity in humans and rodent models are shown in the box.

Figure 2

Binge ethanol and multi-organ pathology. Acute (binge) ethanol intoxication contributes to tissue injury in several organ systems including the liver, gut [63,64,65,66], heart [58,67,68,69,70,71], adipose [72], pancreas [73,74], and brain [75,76,77]. The potential pathophysiological consequences of binge drinking and its impact on each organ system are shown. Abbreviations: EtOH, ethanol; ALT, alanine aminotransferase; and AST, aspartate aminotransferase.