Genetic Nrf2 Overactivation Inhibits the Deleterious Effects Induced by Hepatocyte-Specific c-met Deletion during the Progression of NASH

Pierluigi Ramadori, Hannah Drescher, Stephanie Erschfeld, Athanassios Fragoulis, Thomas W. Kensler, Christoph Jan Wruck, Francisco Javier Cubero, Christian Trautwein, Konrad L. Streetz, Daniela C. Kroy

Research output: Contribution to journalArticle

Abstract

We have recently shown that hepatocyte-specific c-met deficiency accelerates the progression of nonalcoholic steatohepatitis in experimental murine models resulting in augmented production of reactive oxygen species and accelerated development of fibrosis. The aim of this study focuses on the elucidation of the underlying cellular mechanisms driven by Nrf2 overactivation in hepatocytes lacking c-met receptor characterized by a severe unbalance between pro-oxidant and antioxidant functions. Control mice (c-metfx/fx), single c-met knockouts (c-metΔhepa), and double c-met/Keap1 knockouts (met/Keap1Δhepa) were then fed a chow or a methionine-choline-deficient (MCD) diet, respectively, for 4 weeks to reproduce the features of nonalcoholic steatohepatitis. Upon MCD feeding, met/Keap1Δhepa mice displayed increased liver mass albeit decreased triglyceride accumulation. The marked increase of oxidative stress observed in c-metΔhepa was restored in the double mutants as assessed by 4-HNE immunostaining and by the expression of genes responsible for the generation of free radicals. Moreover, double knockout mice presented a reduced amount of liver-infiltrating cells and the exacerbation of fibrosis progression observed in c-metΔhepa livers was significantly inhibited in met/Keap1Δhepa. Therefore, genetic activation of the antioxidant transcription factor Nrf2 improves liver damage and repair in hepatocyte-specific c-met-deficient mice mainly through restoring a balance in the cellular redox homeostasis.

Original languageEnglish (US)
Article number3420286
JournalOxidative medicine and cellular longevity
Volume2017
DOIs
StatePublished - Jan 1 2017
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Aging
  • Cell Biology

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    Ramadori, P., Drescher, H., Erschfeld, S., Fragoulis, A., Kensler, T. W., Wruck, C. J., Cubero, F. J., Trautwein, C., Streetz, K. L., & Kroy, D. C. (2017). Genetic Nrf2 Overactivation Inhibits the Deleterious Effects Induced by Hepatocyte-Specific c-met Deletion during the Progression of NASH. Oxidative medicine and cellular longevity, 2017, [3420286]. https://doi.org/10.1155/2017/3420286