Acrolein, a New Villain in the Development of Alcoholic Liver Disease

lcoholic liver disease (ALD) is a consequence of Achronic alcohol abuse. Alcoholic hepatitis (AH) and alcoholic cirrhosis are 2 major disease forms that worsen morbidity and mortality in patients with ALD. Approximately 35% of heavy alcohol drinkers develop AH and 40% of severe AH patients die within 6 months; AH patients who survive may progress to alcoholic cirrhosis. The treatment for severe AH still largely is dependent on glucocorticoids and pentoxifylline, as it has been for the past 40 years. In the United States, approximately 45% of cirrhosis-related deaths are caused by ALD and there are currently no therapeutic agents for cirrhosis approved by the Food and Drug Administration. Therefore, a better understanding of the underlying molecular mechanisms of ALD and the development of effective therapies would be highly clinically relevant. Liver is the major organ to metabolize alcohol. Alcohol is converted by alcohol dehydrogenase to acetaldehyde, followed by a breakdown to acetate through acetaldehyde dehydrogenase. However, when alcohol intake exceeds the capacity of alcohol dehydrogenase, excessive amounts of alcohol are metabolized by cytochrome p4502E1, and this alternative pathway generates reactive oxygen species (ROS) in addition to acetaldehyde. Both ROS and acetaldehyde are highly hepatotoxic byproducts. ROS further induces lipid peroxidation, which damages the liver. Previous studies have shown that levels of dietary linoleic acid are associated with the degree of liver injury in animal models of alcoholic liver disease. Simultaneous treatment with ethanol and corn oil enriched in linoleic acids results in induction of high levels of hepatic cytochrome p4502E1, increased lipid peroxidation, and resulting enhanced liver injury. In addition to 4-hydroxynonenal and malondialdehyde, lipid peroxidation of polyunsaturated fatty acids such as linoleic acids generates acrolein, a highly toxic byproduct. In the current issue of Cellular and Molecular Gastroenterology and Hepatology, Chen et al provide new evidence that acrolein, an unsaturated aldehyde, is generated and accumulated in ALD and plays a significant role in promoting ALD through endoplasmic reticulum (ER) stress. This study showed that acrolein and acrolein adducts accumulate highly in the livers from alcohol-fed animals in vivo and in hepatocytes exposed to ethanol and acetaldehyde in vitro. One of the key mechanisms of acrolein accumulation the study proposes is through downregulation of glutathione-s-transferase-Pi, which normally eliminates acrolein through glutathione conjugation. The second important finding in this study was that hepatic ER stress is associated with acrolein-mediated liver pathophysiology in ALD. Heavy in vivo alcohol significantly