Nrf2 inhibits hepatic iron accumulation and counteracts oxidative stress-induced liver injury in nutritional steatohepatitis

Kosuke Okada, Eiji Warabi, Hirokazu Sugimoto, Masaki Horie, Katsutoshi Tokushige, Tetsuya Ueda, Nobuhiko Harada, Keiko Taguchi, Etsuko Hashimoto, Ken Itoh, Tetsuro Ishii, Hirotoshi Utsunomiya, Masayuki Yamamoto, Junichi Shoda

Research output: Contribution to journalArticlepeer-review

46 Citations (Scopus)

Abstract

Background: The transcription factor nuclear factor-E2- related factor-2 (Nrf2) is a key regulator for induction of hepatic antioxidative stress systems.Weaimed to investigate whether activation of Nrf2 protects against steatohepatitis. Method Wild-type mice (WT), Nrf2 gene-null mice (Nrf2-null) and Keap1 gene-knockdown mice (Keap1-kd), which represent the sustained activation of Nrf2, were fed a methionine- and choline-deficient diet (MCDD) for 13 weeks and analyzed. Results: In Keap1-kd fed an MCDD, steatohepatitis did not develop over the observation periods; however, in Nrf2-null fed an MCDD, the pathological state of the steatohepatitis was aggravated in terms of fatty change, inflammation, fibrosis and iron accumulation. In WT mice fed an MCDD, Nrf2 and antioxidative stress genes regulated by Nrf2 were potently activated in the livers, and in Keap1-kd, their basal levels were potently activated. Oxidative stress was significantly increased in the livers of the Nrf2-null and suppressed in the livers of the Keap1-kd compared to that of WT, based on the levels of 4-hydroxy-2-nonenal and malondialdehyde. Iron accumulation was greater in the livers of the Nrf2-null mice compared to those of the WT mice, and it was not observed in Keap1-kd. Further, the iron release from the isolated hepatocyte of Nrf2-null mice was significantly decreased. Sulforaphane, an activator of Nrf2, suppressed the pathological states and oxidative stress in the livers. Conclusions: Nrf2 has protective roles against nutritional steatohepatitis through inhibition of hepatic iron accumulation and counteraction against oxidative stress-induced liver injury. Nrf2 activation by pharmaceutical intervention could be a new option for the prevention and treatment of steatohepatitis.

Original languageEnglish
Pages (from-to)924-935
Number of pages12
JournalJournal of gastroenterology
Volume47
Issue number8
DOIs
Publication statusPublished - 2012 Aug

Keywords

  • Iron metabolism
  • Keap1 gene-knockdown mouse
  • Methionine- and choline-deficient diet
  • Nrf2 gene-knockout mouse

ASJC Scopus subject areas

  • Gastroenterology

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