Format

Send to

Choose Destination
Toxicol Sci. 2012 Sep;129(1):74-85. doi: 10.1093/toxsci/kfs193. Epub 2012 May 30.

Elevated hepatic iron activates NF-E2-related factor 2-regulated pathway in a dietary iron overload mouse model.

Author information

1
Department of Microbiology and Immunology, Milton S Hershey Medical Center, The Penn State College of Medicine, Hershey, Pennsylvania 17033, USA.

Abstract

Hepatic iron overload has been associated classically with the genetic disorder hereditary hemochromatosis. More recently, it has become apparent that mild-to-moderate degrees of elevated hepatic iron stores observed in other liver diseases also have clinical relevance. The goal was to use a mouse model of dietary hepatic iron overload and isobaric tag for relative and absolute quantitation proteomics to identify, at a global level, differentially expressed proteins in livers from mice fed a control or 3,5,5-trimethyl-hexanoyl-ferrocene (TMHF) supplemented diet for 4 weeks. The expression of 74 proteins was altered by ≥ ±1.5-fold, showing that the effects of iron on the liver proteome were extensive. The top canonical pathway altered by TMHF treatment was the NF-E2-related factor 2 (NRF2-)-mediated oxidative stress response. Because of the long-standing association of elevated hepatic iron with oxidative stress, the remainder of the study was focused on NRF2. TMHF treatment upregulated 25 phase I/II and antioxidant proteins previously categorized as NRF2 target gene products. Immunoblot analyses showed that TMHF treatment increased the levels of glutathione S-transferase (GST) M1, GSTM4, glutamate-cysteine ligase (GCL) catalytic subunit, GCL modifier subunit, glutathione synthetase, glutathione reductase, heme oxygenase 1, epoxide hydrolase 1, and NAD(P)H dehydrogenase quinone 1. Immunofluorescence, carried out to determine the cellular localization of NRF2, showed that NRF2 was detected in the nucleus of hepatocytes from TMHF-treated mice and not from control mice. We conclude that elevated hepatic iron in a mouse model activates NRF2, a key regulator of the cellular response to oxidative stress.

PMID:
22649188
PMCID:
PMC3499080
DOI:
10.1093/toxsci/kfs193
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Silverchair Information Systems Icon for PubMed Central
Loading ...
Support Center