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Review
. 2020 Oct 13;9(10):980.
doi: 10.3390/antiox9100980.

Roles of Nrf2 in Liver Diseases: Molecular, Pharmacological, and Epigenetic Aspects

Marina Galicia-Moreno  1 , Silvia Lucano-Landeros  1 , Hugo Christian Monroy-Ramirez  1 , Jorge Silva-Gomez  1 , Jorge Gutierrez-Cuevas  1 , Arturo Santos  2 , Juan Armendariz-Borunda  1   2
Affiliations
Review

Roles of Nrf2 in Liver Diseases: Molecular, Pharmacological, and Epigenetic Aspects

Marina Galicia-Moreno et al. Antioxidants (Basel). .

Abstract

Liver diseases represent a critical health problem with 2 million deaths worldwide per year, mainly due to cirrhosis and its complications. Oxidative stress plays an important role in the development of liver diseases. In order to maintain an adequate homeostasis, there must be a balance between free radicals and antioxidant mediators. Nuclear factor erythroid 2-related factor (Nrf2) and its negative regulator Kelch-like ECH-associated protein 1 (Keap1) comprise a defense mechanism against oxidative stress damage, and growing evidence considers this signaling pathway as a key pharmacological target for the treatment of liver diseases. In this review, we provide detailed and updated evidence regarding Nrf2 and its involvement in the development of the main liver diseases such as alcoholic liver damage, viral hepatitis, steatosis, steatohepatitis, cholestatic damage, and liver cancer. The molecular and cellular mechanisms of Nrf2 cellular signaling are elaborated, along with key and relevant antioxidant drugs, and mechanisms on how Keap1/Nrf2 modulation can positively affect the therapeutic response are described. Finally, exciting recent findings about epigenetic modifications and their link with regulation of Keap1/Nrf2 signaling are outlined.

Keywords: Nrf2; antioxidants; epigenetics; liver damage.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Schematic representation of the primary structure of Nrf2 (A) and Keap1 (B) domains and their respective functions. (C) Representation of regulatory mechanisms in Keap1/Nrf2 signaling. In normal conditions, Nrf2 remains inactive bound to its endogenous inhibitor Keap1; this heterodimer binds the Cul3-Rbx E3 ubiquitin ligase complex that triggers Nrf2 degradation by the proteasome. Under oxidative stress conditions, Nrf2 is released from Keap1 and translocates to the nucleus, forming a heterodimer with sMaf. Nrf2-sMaf heterodimers bind to ARE sequences promoting the expression of antioxidant genes. Alternatively, when Nrf2 is phosphorylated by GSK-3, β-TrCP mediates its interaction with a Cul1 ubiquitin ligase complex (Skp1-Cul1-Rbx1/Roc1) to promote the proteasomal degradation of Nrf2, thus inhibiting the expression of cytoprotective genes.
Figure 2
Figure 2
Epigenetic modifications of NFE2L2. The left panel shows epigenetic modifications that lead to downregulation of NFE2L2. Hypermethylation of both, DNA and histones, reduces the mRNA expression levels of Nrf2. The right panel shows that hypomethylation and acetylation of histones increase the mRNA expression levels of Nrf2 and consequently the activation of cytoprotective genes. Resveratrol and curcumin analog (FN1) reduce the activity of DNMT1 and increase the activity of HDACs, promoting the expression of Nrf2.
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