Alcoholic liver disease: Utility of animal models

Abstract

Alcoholic liver disease (ALD) is a major cause of acute and chronic liver injury. Extensive evidence has been accumulated on the pathological process of ALD during the past decades. However, effective treatment options for ALD are very limited due to the lack of suitable in vivo models that recapitulate the full spectrum of ALD. Experimental animal models of ALD, particularly rodents, have been used extensively to mimic human ALD. An ideal animal model should recapitulate all aspects of the ALD process, including significant steatosis, hepatic neutrophil infiltration, and liver injury. A better strategy against ALD depends on clear diagnostic biomarkers, accurate predictor(s) of its progression and new therapeutic approaches to modulate stop or even reverse the disease. Numerous models employing rodent animals have been established in the last decades to investigate the effects of acute and chronic alcohol exposure on the initiation and progression of ALD. Although significant progress has been made in gaining better knowledge on the mechanisms and pathology of ALD, many features of ALD are unknown, and require further investigation, ideally with improved animal models that more effectively mimic human ALD. Although differences in the degree and stages of alcoholic liver injury inevitably exist between animal models and human ALD, the acquisition and translational relevance will be greatly enhanced with the development of new and improved animal models of ALD.

Keywords: Alcoholic liver disease; Cirrhosis; Hepatocellular carcinoma; Reactive oxygen species; Steatohepatitis.

Figure 1

Alcohol metabolism in hepatocytes. Ethanol is oxidized to acetaldehyde through action of the enzyme alcohol dehydrogenase and cytochrome P450 isoenzyme 2E1 a major component of the microsomal enzyme oxidation system. Acetaldehyde is subsequently metabolized to acetate by acetaldehyde dehydrogenase. In this process coenzyme nicotinamide adenine dinucleotide is reduced to coenzyme nicotinamide adenine dinucleotide reduced. The metabolism of ethanol increases generation of reactive oxygen species, including hydroxyethyl, superoxide anion and hydroxyl radicals, which contribute to oxidative stress and also can react with other cellular molecules, forming adducts (proteins, lipids or DNA). ADH: Alcohol dehydrogenase; CYP2E1: Cytochrome P450 isoenzyme 2E1; MEOS: Microsomal enzyme oxidation system; ALDH: Acetaldehyde dehydrogenase; NAD⁺: Nicotinamide adenine dinucleotide; NADH: Nicotinamide adenine dinucleotide reduced; ROS: Reactive oxygen species.

Figure 2

Alcohol induces fatty liver disease. Alcohol causes the accumulation of fat droplets in hepatocytes increasing the lipogenesis and decreasing the fatty acid oxidation. CYP2E1: Cytochrome P450 isoenzyme 2E1; ROS: Reactive oxygen species.