Host homeostatic responses to alcohol-induced cellular stress in animal models of alcoholic liver disease

Abstract

Humans develop various clinical phenotypes of severe alcoholic liver disease, including alcoholic hepatitis and cirrhosis, generally after decades of heavy drinking. In such individuals, following each episode of drinking, their livers experience heightened intracellular and extracellular stresses that are closely associated with alcohol consumption and alcohol metabolism. This article focuses on the latest advances made in animal models on evolutionarily conserved homeostatic mechanisms for coping with and resolving these stress conditions. The mechanisms discussed include the stress-activated protein kinase JNK, energy regulator AMPK, autophagy and the inflammatory response. Over time, the host may respond variably to stress with protective mechanisms that are critical in determining an individual’s vulnerability to developing severe alcoholic liver disease. A systematic review of these mechanisms and their temporal changes in animal models provides the basis for general conclusions, and raises questions for future studies. The relevance of these data to human conditions is also discussed.

Keywords:

• alcohol metabolism
• alcoholic liver disease
• AMP protein kinase
• animal models
• autophagy
• cellular stress
• c-Jun N-terminal kinases
• homeostatic response
• macrophage polarity
• oxidative stress

Financial & competing interests disclosure

JH Wang, MK Jung and GJ Murray are affiliated with the National Institutes of Health and the US Department of Health and Human Services. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending or royalties. The authors wish to thank B Gao (NIAAA) for his critical reading of the manuscript and helpful comments.

Key issues

• Severe alcoholic liver disease, alcoholic hepatitis and cirrhosis, are significant medical problems with a high mortality rate but few effective treatments.

• Rodent models of alcoholic liver disease have, until recently, been successful in generating pathology mimicking only the mild form of human disease, namely fatty liver, mild steatohepatitis and fibrosis. Nevertheless, research on these models has led to abundant evidence on the intermediate steps from alcohol metabolism to tissue damage.

• In animal models, as in most conditions in humans, mild tissue damage caused by alcohol exposure can be readily repaired through the action of host protective systems.

• Much of the host repair capacity is regulated through evolutionarily conserved homeostatic response mechanisms. A better understanding of these responses to alcohol-induced stress conditions, both intracellular and extracellular, and changes to these responses over time could have significant translational value.

• Alcohol feeding protocols and diets vary widely among different laboratories, making generalization of data from animal models difficult. Improvement in this area is needed.

• Recently, the development of binge on chronic alcohol feeding protocols offers an opportunity for research into later stages in the progression of alcoholic liver disease: steatohepatitis and fibrosis. In addition, comparative study of different lab strains holds the promise of revealing pathogenic mechanisms from animal models that are more generalizable to a heterogeneous human population.