Journal
FREE RADICAL BIOLOGY AND MEDICINE
Volume 48, Issue 2, Pages 357-371Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2009.11.007
Keywords
Nonalcoholic steatohepatitis; Methionine- and choline-deficient diet; Nrf2; NF-kappa B; Glutathione; Free radicals
Funding
- Cancer Research-UK [C4909/A7161]
- Association for International Cancer Research [07-0074]
- Tenovus Scotland [T07/39]
- Wellcome Trust [068692]
- Egyptian government
- Research Councils UK
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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 similar to 10-fold increase in the amount of nuclear NF-kappa B p65 protein and similar to 5-fold increases in the levels of mRNA for interleukin-1 beta, 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. (C) 2009 Elsevier Inc. All rights reserved.
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