NRF2 Protection against Liver Injury Produced by Various Hepatotoxicants

Abstract

To investigate the role of Nrf2 as a master defense against the hepatotoxicity produced by various chemicals, Nrf2-null, wild-type, Keap1-knock down (Keap1-Kd) and Keap1-hepatocyte knockout (Keap1-HKO) mice were used as a “graded Nrf2 activation” model. Mice were treated with 14 hepatotoxicants at appropriate doses, and blood and liver samples were collected thereafter (6 h to 7 days depending on the hepatotoxicant). Graded activation of Nrf2 offered a Nrf2-dependent protection against the hepatotoxicity produced by carbon tetrachloride, acetaminophen, microcystin, phalloidin, furosemide, cadmium, and lithocholic acid, as evidenced by serum alanine aminotransferase (ALT) activities and by histopathology. Nrf2 activation also offered moderate protection against liver injury produced by ethanol, arsenic, bromobenzene, and allyl alcohol but had no effects on the hepatotoxicity produced by D-galactosamine/endotoxin and the Fas ligand antibody Jo-2. Graded Nrf2 activation reduced the expression of inflammatory genes (MIP-2, mKC, IL-1β, IL-6, and TNFα), oxidative stress genes (Ho-1, Egr1), ER stress genes (Gadd45 and Gadd153), and genes encoding cell death (Noxa, Bax, Bad, and caspase3). Thus, this study demonstrates that Nrf2 prevents the liver from many, but not all, hepatotoxicants. The Nrf2-mediated protection is accompanied by induction of antioxidant genes, suppression of inflammatory responses, and attenuation of oxidative stress.

Protective effects of luteolin against acetaminophen-induced acute liver failure in mouse

“…Perturbations of ER homeostasis affect protein folding and cause ER stress [30]. ER stress is implicated in chemical-induced hepatotoxicity [31]. The results of the present study show that APAP administration causes severe ER stress in mice, demonstrated by remarkable elevations of hepatic GRP78, ATF-4, XBP-1s, and CHOP protein levels.…”

Cytoprotection of Human Endothelial Cells from Oxidant Stress with CDDO Derivatives: Network Analysis of Genes Responsible for Cytoprotection

“…In the comparison between the different derivatives, it was determined that both are potent inducers of HMOX1, which was confirmed by RT-PCR and Western blot; nevertheless, the results showed that CDDO-Im was a better inducer of the cytoprotective gene than CDDO-Me. Under oxidative stress conditions, HMOX1 expression is rapidly induced in most cell types, including HUVEC [5,48,49,50,51]. HMOX1 becomes the rate-limiting enzyme responsible for the initial step in the oxidative degradation of heme into biliverdin, iron, and carbon monoxide (CO) [52].…”

Protective effects of ursolic acid in an experimental model of liver fibrosis through Nrf2/ARE pathway

“…Nuclear factor E2-related factor 2 (Nrf2) is referred to as the ''master regulator'' of the antioxidant response via the antioxidant response elements (ARE), modulating the expression of hundreds of genes, including not only the familiar antioxidant enzymes, but large numbers of genes that control seemingly disparate processes such as immune and inflammatory responses, tissue remodelling and fibrosis, carcinogenesis and metastasis, and even cognitive dysfunction and addictive behavior [7][8][9]. Many researches have demonstrated that Nrf2 prevents the liver from many hepatotoxicants.…”

“…Many researches have demonstrated that Nrf2 prevents the liver from many hepatotoxicants. The Nrf2-mediated protection is accompanied by induction of antioxidant genes, suppression of inflammatory responses, inhibition of apoptosis and attenuation of oxidative stress [7,8,10].…”