Loss of Nrf2 markedly exacerbates nonalcoholic steatohepatitis

Sudhir Chowdhry, Maiiada H. Nazmy, Paul J. Meakin, Albena T. Dinkova-Kostova, Shaun V. Walsh, Tadayuki Tsujita, John F. Dillon, Michael L J Ashford, John D. Hayes

Research output: Contribution to journalArticle

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 ∼10-fold increase in the amount of nuclear NF-κB p65 protein and ∼5-fold increases in the levels of mRNA for interleukin-1β, tumor necrosis factor α, 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.

Original languageEnglish (US)
Pages (from-to)357-371
Number of pages15
JournalFree Radical Biology and Medicine
Volume48
Issue number2
DOIs
StatePublished - Jan 15 2010

Keywords

  • Free radicals
  • Glutathione
  • Methionine- and choline-deficient diet
  • NF-κB
  • Nonalcoholic steatohepatitis
  • Nrf2

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

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    Chowdhry, S., Nazmy, M. H., Meakin, P. J., Dinkova-Kostova, A. T., Walsh, S. V., Tsujita, T., Dillon, J. F., Ashford, M. L. J., & Hayes, J. D. (2010). Loss of Nrf2 markedly exacerbates nonalcoholic steatohepatitis. Free Radical Biology and Medicine, 48(2), 357-371. https://doi.org/10.1016/j.freeradbiomed.2009.11.007