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Loss of Nrf2 markedly exacerbates nonalcoholic steatohepatitis

Loss of Nrf2 markedly exacerbates nonalcoholic steatohepatitis

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Original languageEnglish
Pages357-371
Number of pages15
JournalFree Radical Biology and Medicine
Journal publication date2010
Journal number2
Volume48
DOIs
StatePublished

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 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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