title: Nrf2 inhibits hepatic iron accumulation and counteracts oxidative stress-induced liver injury in nutritional steatohepatitis.
abstract: BACKGROUND
  The transcription factor nuclear factor-E2-related factor-2 (Nrf2) is a key regulator for induction of hepatic antioxidative stress systems. We aimed to investigate whether activation of Nrf2 protects against steatohepatitis.
  
  
  METHODS
  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.
authors.affiliation: Field of Basic Sports Medicine, Sports Medicine, Faculty of Medicine, Graduate School of Comprehensive Human Sciences, The University of Tsukuba, Tsukuba, Ibaraki, 305-8574, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Okada
authors.forename: Eiji
authors.initials: E
authors.lastname: Warabi
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Sugimoto
authors.forename: Masaki
authors.initials: M
authors.lastname: Horie
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Tokushige
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Ueda
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Harada
authors.forename: Keiko
authors.initials: K
authors.lastname: Taguchi
authors.forename: Etsuko
authors.initials: E
authors.lastname: Hashimoto
authors.forename: Ken
authors.initials: K
authors.lastname: Itoh
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Ishii
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Utsunomiya
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Junichi
authors.initials: J
authors.lastname: Shoda
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use; D002796:Choline Deficiency; D003598:Cytoskeletal Proteins / Q000235:genetics; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000378:metabolism / Q000517:prevention & control*; D005786:Gene Expression Regulation; D007501:Iron / Q000378:metabolism*; D017879:Isothiocyanates; D000072019:Kelch-Like ECH-Associated Protein 1; D008099:Liver / Q000378:metabolism*; D008297:Male; D008715:Methionine / Q000172:deficiency; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D018384:Oxidative Stress / Q000187:drug effects*; D060888:Real-Time Polymerase Chain Reaction; D013454:Sulfoxides; D013861:Thiocyanates / Q000627:therapeutic use
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016588:Anticarcinogenic Agents; D003598:Cytoskeletal Proteins; D017879:Isothiocyanates; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D013454:Sulfoxides; D013861:Thiocyanates; D008715:Methionine; D007501:Iron; C016766:sulforaphane