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Review
. 2019 Jan 8:9:1428.
doi: 10.3389/fphar.2018.01428. eCollection 2018.

The Role of Nrf2 in Liver Disease: Novel Molecular Mechanisms and Therapeutic Approaches

Dongwei Xu  1 , Min Xu  1 , Seogsong Jeong  1 , Yihan Qian  2 , Hailong Wu  3 , Qiang Xia  1 , Xiaoni Kong  1
Affiliations
Review

The Role of Nrf2 in Liver Disease: Novel Molecular Mechanisms and Therapeutic Approaches

Dongwei Xu et al. Front Pharmacol. .

Abstract

Oxidative stress and inflammation are the most important pathogenic events in the development and progression of liver diseases. Nuclear erythroid 2-related factor 2 (Nrf2) is the master regulator of the cellular protection via induction of anti-inflammatory, antioxidant, and cyto-protective genes expression. Multiple studies have shown that activation or suppression of this transcriptional factor significantly affect progression of liver diseases. Comprehensive understanding the roles of Nrf2 activation/expression and the outcomes of its activators/inhibitors are indispensable for defining the mechanisms and therapeutic strategies against liver diseases. In this current review, we discussed recent advances in the function and principal mechanisms by regulating Nrf2 in liver diseases, including acute liver failure, hepatic ischemia-reperfusion injury (IRI), alcoholic liver disease (ALD), viral hepatitis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and hepatocellular carcinoma (HCC).

Keywords: Nrf2; acute liver injury; cytoprotective genes; hepatocellular carcinoma; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis; oxidative stress; viral hepatitis.

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Figures

FIGURE 1
FIGURE 1
Role of Nrf2 in acute liver injury. The protective effects of Nrf2 in acute liver injury, one is through regulating antioxidant defense-related genes, including sulfiredoxin-1, glutamate-cysteine ligase, and glutathione peroxidase-2, and the other pathway is by promoting its target gene HO-1 and then enhanced autophagy. While its negative regulator-keap1, which by binding to it inhibits Nrf2 activation and Trx1-PI3K/AKT-HIF1-HO-1/CyclinD1 signal pathway and promotes liver injury.
FIGURE 2
FIGURE 2
Role of Nrf2 in alcoholic liver disease. Studies shown that oxidative stress promotes Nrf2 activation-induced hepatic VLDLR overexpression and ameliorates ALD. Nrf2 activator-Sulforaphane protects alcoholic fatty liver disease by activating Nrf2 signaling pathway and GSH levels. D3T through upregulate Nrf2 protein levels and decreased ROS levels and liver injuries.
FIGURE 3
FIGURE 3
Role of Nrf2 in viral hepatitis-associated liver diseases. Hepatitis C virus was reported that impaired the protection of Nrf2 by promoting sMaf bound to NS3 and brusatol suppressed HCV infection by promoting Nrf2 pathway. HBV-regulatory proteins, including its X protein (HBx) and large surface proteins were reported to activate Nrf2 and antioxidative responses via c-Raf and mitogen-activated protein kinase.
FIGURE 4
FIGURE 4
Role of Nrf2 in NAFLD. Multiple studies have shown that several pathways could activate Nrf2 and inhibit NAFLD and NASH including scutellarin-PPARγ/PGC1α-Nrf2-HO-1/NQO1/GST pathway; green tea extract and ezetimibe activated Nrf2 pathway; osteocalcin activated Nrf2 and subsequently inhibited JNK pathway.
FIGURE 5
FIGURE 5
Role of Nrf2 in HCC. P62 and FGF19 were reported to activate Nrf2 and promote HCC by competing with Keap1 or through FGFR4–GSK3β signal pathway. MiR-340, miR-144, camptothecin, valproic acid, and indazolo[3,2-b]quinazolinones, which were revealed in suppressing Nrf2-dependent pathway and sensitizing HCC cells to anticancer treatments.
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