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Free Radic Biol Med. 2010 Jan 15;48(2):357-71. doi: 10.1016/j.freeradbiomed.2009.11.007. Epub 2009 Nov 13.

Loss of Nrf2 markedly exacerbates nonalcoholic steatohepatitis.

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  • 1Biomedical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, UK.

Abstract

Nonalcoholic steatohepatitis (NASH) arises from nonalcoholic fatty liver disease (NAFLD) as a consequence of oxidative stress. Herein we report that the development of NASH is greatly accelerated in mice lacking transcription factor Nrf2 when they are challenged with a methionine- and choline-deficient (MCD) diet. After 14 days of feeding on an MCD diet, livers from Nrf2(-/-) mice showed a substantial increase in macro- and microvesicular steatosis and a massive increase in the number of neutrophil polymorphs, compared to livers from wild-type mice treated similarly. Livers of Nrf2(-/-) mice on the MCD diet suffered more oxidative stress than their wild-type counterparts as assessed by a significant depletion of reduced glutathione that was coupled with increases in oxidized glutathione and malondialdehyde. Furthermore, livers from Nrf2(-/-) mice on the MCD diet suffered heightened inflammation as judged by an approximately 10-fold increase in the amount of nuclear NF-kappaB p65 protein and approximately 5-fold increases in the levels of mRNA for interleukin-1beta, tumor necrosis factor alpha, cyclooxygenase 2, and inducible nitric oxide synthase compared with livers from similarly treated wild-type mice. Thus, impairment of Nrf2 activity may represent a major risk factor for the evolution of NAFLD to NASH.

Copyright 2009 Elsevier Inc. All rights reserved.

PMID:
19914374
[PubMed - indexed for MEDLINE]
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