Animal models of alcoholic liver disease.

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.