Oxidative stress in alcohol-related liver disease

Abstract

Alcohol consumption is one of the leading causes of the global burden of disease and results in high healthcare and economic costs. Heavy alcohol misuse leads to alcohol-related liver disease, which is responsible for a significant proportion of alcohol-attributable deaths globally. Other than reducing alcohol consumption, there are currently no effective treatments for alcohol-related liver disease. Oxidative stress refers to an imbalance in the production and elimination of reactive oxygen species and antioxidants. It plays important roles in several aspects of alcohol-related liver disease pathogenesis. Here, we review how chronic alcohol use results in oxidative stress through increased metabolism via the cytochrome P450 2E1 system producing reactive oxygen species, acetaldehyde and protein and DNA adducts. These trigger inflammatory signaling pathways within the liver leading to expression of pro-inflammatory mediators causing hepatocyte apoptosis and necrosis. Reactive oxygen species exposure also results in mitochondrial stress within hepatocytes causing structural and functional dysregulation of mitochondria and upregulating apoptotic signaling. There is also evidence that oxidative stress as well as the direct effect of alcohol influences epigenetic regulation. Increased global histone methylation and acetylation and specific histone acetylation inhibits antioxidant responses and promotes expression of key pro-inflammatory genes. This review highlights aspects of the role of oxidative stress in disease pathogenesis that warrant further study including mitochondrial stress and epigenetic regulation. Improved understanding of these processes may identify novel targets for therapy.

Keywords: Alcohol-related liver disease; Alcoholic hepatitis; Oxidative stress; Reactive oxygen species; Antioxidants; Epigenetics; Mitochondrial stress

Core tip: Alcohol is a global health problem with alcohol-related liver disease forming a significant proportion of alcohol-attributable deaths. However, there are no effective treatments for alcohol-related liver disease. Oxidative stress plays multiple roles in disease pathogenesis, which if better understood may yield new therapeutic targets. Here, we review the current literature on how alcohol consumption leads to oxidative stress and how this results in hepatocyte apoptosis and necrosis through its contribution to mitochondrial stress, dysregulation of cell signalling pathways and epigenetic regulation.