Activation of nuclear factor E2-related factor 2 in hereditary tyrosinemia type 1 and its role in survival and tumor development

Silke Marhenke, Jutta Lamlé, Laura Elisa Buitrago-Molina, José Manuel Fernández Cañón, Robert Geffers, Milton Finegold, Michael Sporn, Masayuki Yamamoto, Michael P. Manns, Markus Grompe, Arndt Vogel

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23 Citations (Scopus)

Abstract

In tyrosinemia type 1 (HT1), accumulation of toxic metabolites results in oxidative stress and DNA damage, leading to a high incidence of hepatocellular carcinomas. Nuclear factor erythroid-2 related factor 2 (Nrf2) is a key transcription factor important for cellular protection against oxidative stress and chemical induced liver damage. To specifically address the role of Nrf2 in HT1, fumarylacetoacetate hydrolase (Fah)/NrJ2-/- mice were generated. In acute HT1, loss of Nrf2 elicited a strong inflammatory response and dramatically increased the mortality of mice. Following low grade injury, Fah/Nrf2-/- mice develop a more severe hepatitis and liver fibrosis. The glutathione and cellular detoxification system was significantly impaired in Fah/Nrf2-/ - mice, resulting in increased oxidative stress and DNA damage. Consequently, tumor development was significantly accelerated by loss of Nrf2. Potent pharmacological inducers of Nrf2 such as the triterpenoid analogs 1[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl] imidazole have been developed as cancer chemoprevention agents. Pretreatment with 1[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole dramatically protected Fah-1- mice against fumarylacetoacetate (Faa)-induced toxicity. Our data establish a central role for Nrf2 in the protection against Faa-induced liver injury; the Nrf2 regulated cellular defense not only prevents acute Faa-induced liver failure but also delays hepatocarcinogenesis in HT1.

Original languageEnglish
Pages (from-to)487-496
Number of pages10
JournalHepatology
Volume48
Issue number2
DOIs
Publication statusPublished - 2008 Aug

ASJC Scopus subject areas

  • Hepatology

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    Marhenke, S., Lamlé, J., Buitrago-Molina, L. E., Cañón, J. M. F., Geffers, R., Finegold, M., Sporn, M., Yamamoto, M., Manns, M. P., Grompe, M., & Vogel, A. (2008). Activation of nuclear factor E2-related factor 2 in hereditary tyrosinemia type 1 and its role in survival and tumor development. Hepatology, 48(2), 487-496. https://doi.org/10.1002/hep.22391