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

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    150 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)357-371
    Number of pages15
    JournalFree Radical Biology and Medicine
    Volume48
    Issue number2
    DOIs
    Publication statusPublished - 2010

    Keywords

    • Nonalcoholic steatohepatitis
    • Methionine- and choline-deficient diet
    • Nrf2
    • NF-kappa B
    • Glutathione
    • Free radicals
    • CHOLINE-DEFICIENT DIET
    • TRANSCRIPTION FACTOR NRF2
    • FATTY LIVER-DISEASE
    • GLUTAMATE-CYSTEINE LIGASE
    • OXIDATIVE STRESS
    • HEPATIC STEATOSIS
    • QUANTITATIVE-DETERMINATION
    • INDUCIBLE EXPRESSION
    • LIPID-PEROXIDATION
    • INSULIN-RESISTANCE

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