Role of Nrf2 in chronic liver disease

Abstract

Nuclear erythroid 2-related factor 2 (Nrf2) is a central regulator of antioxidative response elements-mediated gene expression. It has a significant role in adaptive responses to oxidative stress by interacting with the antioxidant response element, which induces the expression of a variety of downstream targets aimed at cytoprotection. Previous studies suggested oxidative stress and associated damage could represent a common link between different forms of diseases. Oxidative stress has been implicated in various liver diseases, including viral hepatitis, nonalcoholic fatty liver disease/steatohepatitis, alcoholic liver disease and drug-induced liver injury. Nrf2 activation is initiated by oxidative or electrophilic stress, and aids in the detoxification and elimination of potentially harmful exogenous chemicals and their metabolites. The expression of Nrf2 has been observed throughout human tissue, with high expression in detoxification organs, especially the liver. Thus, Nrf2 may serve as a major regulator of several cellular defense associated pathways by which hepatic cells combat oxidative stress. We review the relevant literature concerning the crucial role of Nrf2 and its signaling pathways against oxidative stress to protect hepatic cell from oxidative damage during development of common chronic liver diseases. We also review the use of Nrf2 as a therapeutic target to prevent and treat liver diseases.

Keywords: Nuclear erythroid 2-related factor 2, Chronic liver disease, Oxidative stress, Reactive oxygen species, Hepatic injury, Hepatic protection

Core tip: Chronic liver disease is associated with an imbalance, comprising increased reactive oxygen species and decreased net antioxidant activity. Oxidative stress plays an important role in the pathophysiological changes of liver diseases. Nuclear erythroid 2-related factor 2 (Nrf2) can activate cytoprotective genes and has a crucial role against oxidative stress to protect hepatic cells from oxidative damage. This article focuses on the activation the Nrf2-mediated antioxidant response, which prevents the progression of chronic liver disease and presents new treatment opportunities. Accordingly, integrative therapeutic strategies including Nrf2 activators have great potential as therapeutic agents against oxidative stress during chronic liver injuries.