Transcription factor NRF2 protects mice against dietary iron-induced liver injury by preventing hepatocytic cell death

Abstract

Background & Aims:The l i v e r , being the major site of i r o n storage, is particularly exposed to the toxic effects of iron. Tran-scription factor NRF2 is critical for protecting the l i v e r a g a i n s t disease by activating the transcription of genes encoding detoxification/antioxidant enzymes. We aimed to determine if the NRF2 pathway plays a significant role in the protection against hepatic iron overload. Methods: Wild type and Nrf2 _ /_ mouse primary hepatocytes Wereincubated with ferric ammonium citrate. Wild type and Nrf2 -/-mice w e r e fed s t anda rd rodent chow or iron-rich diet for 2 weeks, with or without daily i n j e c t i o n of the a n t i o x i d a n t mito-TEMPOL. Results: In mouse hepatocytes, iron induced the nuclear translo-cation of NRF2 and the expression of cytoprotective genes in an NRF2-dependent manner. Moreover, Nrf2 _ /_ hepatocytes were highly susceptible to i r o n -induced cell d e a t h . Wild-type and Nrf2 _ /_ mice fed iron-rich diet accumulated similar amounts of iron in the liver and were equally able to increase the expression of hepatic hepcidin and ferritin. Nevertheless, in Nrf2-null mice the iron loading resulted in progressive liver injury, ranging from mild confluent necrosis to s e v e r e necroinflammatory lesio ns. Hepatocytic cell death was associated with gross ul t r a s t r u c t u r a l damage to the mitochondria. Notably, liver injury was prevented in iron-fed animals that received mito-TEMPOL. Conclusions: NRF2 protects the m o u s e liver against the t o x i c i t y of dietary iron o v e r l o a d by p r e v e n t i n g hepatocytic cell d e a t h . We identify NRF2 as a potential modifier of liver disease in iron overload pathology and show the beneficial effect of the antiox-idant mito-TEMPOL in a mouse model of dietary iron-induced liver injury. ©2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.Version: Postprint (identical content as published paper) This is a self-archived document from i3S -Instituto de Investigação e Inovação em Saúde in the University of Porto Open Repository For Open Access to more of our publications, please visit http://repositorio-aberto.up.pt/ A01/00 INTRODUCTIONIron is a component of several metalloproteins involved in crucial metabolic processes such as oxygen sensing and transport, energy metabolism and DNA synthesis. However, iron in excess is detrimental, as it can catalyze the formation of damaging radical species via Fenton-type reactions [1]. In normal conditions, iron toxicity is prevented by the binding of extracellular iron in the plasma to transferrin and by storage of intracellular iron in a protein with high storage capacity, ferritin [2]. In addition, plasma iron levels are tightly regulated by the action of the peptide hormone hepcidin. Hepcidin, which is mostly secreted in the liver, promotes the degradation of the iron exporter ferroportin expressed on the surface of iron-releasing cells, thus reducing intestinal iron absorption and its mobilization fr...

Propofol alleviates liver oxidative stress via activating Nrf2 pathway

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Genetic disruption of NRF2 promotes the development of necroinflammation and liver fibrosis in a mouse model of HFE-hereditary hemochromatosis

“…Fragmented DNA was detected through TdT-mediated dUTP nick-end labeling (TUNEL) staining as described by Silva-Gomes et al [15]. For the detection of F4/80, samples were blocked with 5% bovine serum albumin and 0.05% Tween 20 in phosphate buffer and incubated with rat anti-F4/80 (Serotec, Oxford, UK), followed by goat anti-rat IgG AlexaFluor 647 (Life Technologies, Carlsblad, CA, USA).…”

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Physiology and pathophysiology of iron in hemoglobin-associated diseases

“…Mutations in iron regulatory genes modulate iron loading in humans with thalassemia syndromes [100, 163–168], while mutations in oxidant protective pathways modulate the clinical expression of hemoglobinopathies [169–173] and have been associated with other disorders, including propensity to malignancy [174–177]. The FOXO3 family of transcription factors plays a major role in the regulation of oxidative stress, is essential for red cell survival and its absence results in early red cell maturation arrest that can be partly rescued by antioxidant treatment [95, 178, 179].…”