Animal Models of Alcoholic Liver Disease

Abstract

The risk of alcohol-induced liver disease (ALD) increases dose- and time-dependently with consumption of alcohol. The progression of the disease is well characterized; however, although the progression of alcohol-induced liver injury is well characterized, there is no universally-accepted therapy available to halt or reverse this process in humans. With better understanding of the mechanism(s) and risk factors that mediate the initiation and progression of this disease, rational targeted therapy can be developed to treat or prevent it in the clinics. Several models for experimental ALD exist, including non-human primates, micropigs and rodents. However, most researchers employ rodent models of ALD. Furthermore, the advent of genetically modified strains of rodents (e.g. ‘knockout’ mice) has increased the specificity of the hypotheses that can be directly tested. Based on these models systems, several plausible hypotheses to explain the mechanism(s) by which alcohol leads to liver damage have been proposed, including consequences of alcohol metabolism, oxidative/nitrosative stress, altered inflammatory responses, and increased sensitivity to cytotoxic stimuli. These studies have also identified candidate genes for polymorphism studies to explain potential increased genetic risk in some individuals. However, despite significant advances in our understanding of the mechanisms by which ALD develops based on studies with these models, this work has yet to translate to a viable therapy for ALD in the clinics. This talk will also discuss potential reasons for these limitations to date and suggest future prospects to improve the translational utility of modeling ALD.

Betaine treatment decreased oxidative stress, inflammation, and stellate cell activation in rats with alcoholic liver fibrosis

“…In the present study, experimental alcoholic liver fibrosis was induced by ETH administration together with a low dose of CCl 4 treatment in rats. It has been reported that hepatic histopathologic changes in ETH + CCl 4 -induced fibrosis model were similar to those found in human fibrosis (Arteel, 2010;Su et al, 2014).…”

“…In the rodent model of ALD, ethanol alone fails to induce significant liver fibrosis regardless of the duration of ethanol consumption (Arteel, 2010). Therefore, some rodent models of ALD have been developed in which a secondary agent such as CCl 4 has been used concomitantly with chronic ETH treatment (Arteel, 2010;Erman et al, 2004;Safer et al, 2015).…”

“…Therefore, some rodent models of ALD have been developed in which a secondary agent such as CCl 4 has been used concomitantly with chronic ETH treatment (Arteel, 2010;Erman et al, 2004;Safer et al, 2015). The ETH plus CCl 4 model is in accordance with the "two-hit" theory of ALD.…”

Susceptibility of L-FABP−/− mice to oxidative stress in early-stage alcoholic liver

“…Animal models of early-stage ALD are often used to elucidate mechanisms of alcohol toxicity and disease progression ( 40,41 ). Whereas the animal model used for this current investigation does replicate early ALD, encompassing steatosis and oxidative stress ( 12,13,20 ), it does not encompass progression from the steatosis to steatohepatitis, which would occur using more prolonged ethanol administration paradigms ( 42 ).…”

Animals Models of Gastrointestinal and Liver Diseases. Animal models of alcohol-induced liver disease: pathophysiology, translational relevance, and challenges

“…There are no FDA-approved therapies for the treatment of ALD, and management of the disease is achieved through therapies targeted at disease-associated conditions (i.e., nutritional support to combat malnutrition and corticosteroids to manage inflammation). To date, there are no experimental models that recapitulate the full progression of ALD; however, over the past 40 years, animal models have proven to be valuable tools for understanding the underlying mechanisms of the various stages of ALD (3,5,7,29). These animal models have broadened our understanding of the signaling pathways that drive alcohol-induced liver injury and regeneration and have allowed for the identification of novel therapeutic targets for disease management.…”