Emerging Role of Nrf2 in Protecting Against Hepatic and Gastrointestinal Disease

Abstract

Transcription factor NF-E2-related factor 2 (Nrf2) belongs to the basic region-leucine zipper family and is activated in response to electrophiles and reactive oxygen species. Nrf2 coordinately regulates the constitutive and inducible transcription of a wide array of genes involved in drug metabolism, detoxification, and antioxidant defenses. During periods of oxidative stress, Nrf2 is released from sequestration in the cytoplasm and translocates to the nucleus. Nrf2 binds antioxidant response elements (AREs) in the regulatory regions of target genes and activates transcription. Genetically modified mice lacking Nrf2 serve as a useful tool for identifying new ARE-regulated genes and assessing the ability of Nrf2 to confer protection against a variety of pathologies in numerous organs including the liver, intestine, lung, skin, and nervous system. With regards to the liver and gastrointestinal tract, Nrf2 knockout mice are more susceptible to acetaminophen-induced hepatocellular injury, benzo[a]pyrene-induced tumor formation and Fasand TNFα-mediated hepatocellular apoptosis. The higher sensitivity of Nrf2 knockout mice to chemical toxicity is due in part to reduced basal and inducible expression of detoxification enzymes. Nrf2 may also be important in protecting against liver fibrosis, gallstone development, and formation of aberrant crypt foci. Research of Nrf2 has opened up new opportunities in understanding how antioxidant defense pathways are regulated, how oxidative stress contributes to disease progression and may serve as a novel target for designing therapies to prevent and treat diseases in which oxidative stress is implicated.

Melatonin protects against burn-induced hepatic oxidative injury by inducing HO-1 via the Nrf2 pathway

“…We suggest that melatonin induces HO-1 via the Nrf2 pathway in liver in this model. Similar findings regarding upregulation of HO-1 and the Nrf2 system in other models of hepatic and oxidative stress have been reported (Osburn et al 2006;Aleksunes and Manautou 2007).…”

“…Melatonin induces the expression of antioxidant enzymes such as superoxide dismutase SOD, catalase and gluthatione peroxidase under conditions of elevated oxidative stress (Rodriguez et al 2004), through activation of Nrf2 (Jung et al 2009). Further, melatonin ameliorates oxidative stress through Nrf2 induction in experimental models of hepatic injury (Osburn et al 2006;Aleksunes and Manautou 2007;Crespo et al 2010;Yang et al 2011). Activation of Nrf2 by melatonin has been described to result in an increased expression of the antioxidant enzyme haem oxygenase-1 (HO-1) and a restriction of hepatic injury (Jung et al 2009;Crespo et al 2010).…”

Nrf2 target genes are induced under marginal selenium-deficiency

“…Nrf2 -/-mice are sensitive to chemical-induced toxicity and tumorigenesis [43]. Additionally, Nrf2 -/-mice are highly susceptible to oxidative stress [1] and have a lower basal glutathione (GSH) level [47]. Under unstimulated conditions, Nrf2 is kept in the cytosol bound to Keap1, which functions as a substrate adaptor for a Cul3-based E3 ubiquitin ligase and targets Nrf2 for degradation.…”

Hepatitis B Virus Induces Expression of Antioxidant Response Element-regulated Genes by Activation of Nrf2

“…The expression of these cytoprotective proteins is controlled by cis-acting elements in the promoters of these genes, the antioxidative response elements (AREs) (11). An important factor triggering the expression of ARE-regulated genes is the NF-E2-related factor 2 (Nrf2) (12). Nrf2 is a member of the cap "n" collar family of transcription factors.…”