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

Fingerprint

Liver
Choline
Methionine
Nutrition
Diet
Oxidative stress
Oxidative Stress
Glutathione Disulfide
Nitric Oxide Synthase Type II
Cyclooxygenase 2
Malondialdehyde
Interleukin-1
Glutathione
Non-alcoholic Fatty Liver Disease
Polymorphism
Neutrophils
Transcription Factors
Tumor Necrosis Factor-alpha
Macros
Inflammation

Keywords

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

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)

Cite this

Chowdhry, S., Nazmy, M. H., Meakin, P. J., Dinkova-Kostova, A. T., Walsh, S. V., Tsujita, T., ... 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

Loss of Nrf2 markedly exacerbates nonalcoholic steatohepatitis. / Chowdhry, Sudhir; Nazmy, Maiiada H.; Meakin, Paul J.; Dinkova-Kostova, Albena T.; Walsh, Shaun V.; Tsujita, Tadayuki; Dillon, John F.; Ashford, Michael L J; Hayes, John D.

In: Free Radical Biology and Medicine, Vol. 48, No. 2, 15.01.2010, p. 357-371.

Research output: Contribution to journalArticle

Chowdhry, S, Nazmy, MH, Meakin, PJ, Dinkova-Kostova, AT, Walsh, SV, Tsujita, T, Dillon, JF, Ashford, MLJ & Hayes, JD 2010, 'Loss of Nrf2 markedly exacerbates nonalcoholic steatohepatitis', Free Radical Biology and Medicine, vol. 48, no. 2, pp. 357-371. https://doi.org/10.1016/j.freeradbiomed.2009.11.007
Chowdhry S, Nazmy MH, Meakin PJ, Dinkova-Kostova AT, Walsh SV, Tsujita T et al. Loss of Nrf2 markedly exacerbates nonalcoholic steatohepatitis. Free Radical Biology and Medicine. 2010 Jan 15;48(2):357-371. https://doi.org/10.1016/j.freeradbiomed.2009.11.007
Chowdhry, Sudhir ; Nazmy, Maiiada H. ; Meakin, Paul J. ; Dinkova-Kostova, Albena T. ; Walsh, Shaun V. ; Tsujita, Tadayuki ; Dillon, John F. ; Ashford, Michael L J ; Hayes, John D. / Loss of Nrf2 markedly exacerbates nonalcoholic steatohepatitis. In: Free Radical Biology and Medicine. 2010 ; Vol. 48, No. 2. pp. 357-371.
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