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.

Nrf2 pathway activation contributes to anti-fibrosis effects of ginsenoside Rg1 in a rat model of alcohol- and CCl4-induced hepatic fibrosis

“…Nrf2 activation is generally considered to have a beneficial effect [68] , especially in liver disease [65,69] . In Nrf2 knockout mice, increased death and delayed proliferation of hepatocytes were observed [70] .…”

“…Some of the Nrf2 activators have progressed to clinical trials for treatment of conditions such as skin cancer, multiple sclerosis and chronic kidney disease [65] . Nrf2 is considered to be involved in protection against ethanol-induced oxidative stress [65][66][67] .…”

“…Nrf2 is considered to be involved in protection against ethanol-induced oxidative stress [65][66][67] . Evidence from studies in which Nrf2 has been knocked down in cells, and in studies that used Nrf2-null mice [66] , show that Nrf2 plays a protective role against ethanolinduced liver damage.…”

Hepatic and Intestinal Multidrug Resistance-Associated Protein 2: Transcriptional and Post-transcriptional Regulation by Xenobiotics

“…For instance, the Nrf2 activator N-acetylcysteine was described to ameliorate the rMrp2 down-regulation exerted by the pro-oxidant phytochemical timosaponin A3 [55]. Similarly, other Nrf2 activators are being tested in clinical trials for the treatment of hepatic and extrahepatic diseases [53].…”

“…Under homeostatic conditions, Nrf2 is sequestered in the cytosol by the Kelch-like ECH-associated protein 1 Keap1 which promotes Nrf2 ubiquitination and proteosomal degradation. Upon an oxidative stimulus, it takes place a modiication in the oxidation status of particular cysteine residues in the Keap1 molecule leading to Nrf2 dissociation and migration to the nucleus where it binds to antioxidant response elements ARE within the promoters and activates the transcription of target genes [53] including antioxidant and GSH synthesis enzymes and also drug transporters like MRP2 [5 ]. Management of Nrf2 activation could be applied to other cases of oxidative stress-associated hepatic injury.…”