Nrf2: a potential target for new therapeutics in liver disease

Abstract

Nuclear erythroid 2-related factor 2 (Nrf2) is an oxidative stress-mediated transcription factor with a variety of downstream targets aimed at cytoprotection. Nrf2 has recently been implicated as a new therapeutic target for the treatment of liver disease. Here, we focus on the most common liver diseases-nonalcoholic fatty liver disease/steatohepatitis, alcoholic liver disease, and drug-induced liver injury-and highlight areas in the development of these conditions where activation of Nrf2 may alleviate disease progression.

Figure 1

A schematic representation of the mechanism of action of Nrf2. Nrf2 is sequestered in the cytoplasm via physical attachment to Keap1, causing inhibition of Nrf2 activity due to proteosomal degradation. During an oxidative stress event, Nrf2 dissociates from Keap1, translocates to the nucleus, and dimerizes with a variety of different transcription factors. Here, Jun is used as an example of one of those transcription factors that binds Nrf2. The heterodimer then binds to the antioxidant response element (ARE) in the promoter region of a variety of genes and activates transcription. Some of the genes that are transcriptionally regulated by Nrf2 are heme oxygenase 1 (Ho-1), NAD(P)H quinone oxidoreductase 1 (Nqo1), glutathione-S-transferase (Gst), glutamate–cysteine ligase (Glc), cytochrome P450s (CYPs), and multidrug-resistant proteins (MRPs). Nrf2, nuclear erythroid 2–related factor 2.

Figure 2

A schematic representation of the changes that occur during the development of NAFLD/NASH (shown in yellow boxes) from the initial accumulation of triglycerides in the liver to the inflammation and fibrosis that would be seen in steatohepatitis. In addition, this schematic depicts the areas in which Nrf2 activation may positively affect this pathway and prevent the development and/or progression of this disease (shown in green circles). These deductions are based on many findings from the literature cited in the text of this review. NAFLD, nonalcoholic fatty liver disease; NASH, nonalcoholic steatohepatitis; Nrf2, nuclear erythroid 2–related factor 2; ROS, reactive oxygen species; SOD, superoxide dismutase.

Figure 3

Overview of ways in which Nrf2 activation may affect the progression of three common liver pathologies. This schematic outlines the various ways by which an Nrf2-enhancing therapeutic may help to alleviate nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH), alcoholic liver disease (ALD), and drug-induced liver injury (DILI), based on the current literature as cited in the text. GSH, glutathione; NF- B, nuclear factor- B; ROS, reactive oxygen species; SOD, superoxide dismutase; TGF-β, transforming growth factor-β.