Journal of Gastroenterology

, Volume 47, Issue 8, pp 924–935 | Cite as

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
Original Article—Liver, Pancreas, and Biliary Tract

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.

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.

Keywords

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

Abbreviations

α-Sma

Alpha-smooth muscle actin

ALP

Alkaline phosphatase

ALT

Alanine aminotransferase

AST

Aspartate aminotransferase

Fpn1

Ferroportin-1

γ-Gcs

γ-Glutamylcysteine synthetase

GSH

Glutathione

Gst

Glutathione S-transferase

Hamp

Hepcidin gene

4-HNE

4-Hydroxy-2-nonenal

Keap1

Kelch-like Ech-associated protein 1

MCDD

Methionine- and choline-deficient diet

MDA

Malondialdehyde

NASH

Non-alcoholic steatohepatitis

Nrf2

Nuclear factor-E2-related factor-2

Nqo1

NAD(P)H: quinone oxidoreductase 1

ROS

Reactive oxygen species

SFN

Sulforaphane

TfR

Transferrin receptor

Tgf

Transforming growth factor

WT

Wild type

Notes

Acknowledgments

This work was supported in part by a Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan (19791054) and Grants-in-Aid from Nakayama Cancer Research Institute (Tokyo, Japan).

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer 2012

Authors and Affiliations

  • Kosuke Okada
    • 1
  • Eiji Warabi
    • 2
  • Hirokazu Sugimoto
    • 3
  • Masaki Horie
    • 1
  • Katsutoshi Tokushige
    • 4
  • Tetsuya Ueda
    • 5
  • Nobuhiko Harada
    • 6
  • Keiko Taguchi
    • 7
  • Etsuko Hashimoto
    • 4
  • Ken Itoh
    • 6
  • Tetsuro Ishii
    • 2
  • Hirotoshi Utsunomiya
    • 8
  • Masayuki Yamamoto
    • 7
  • Junichi Shoda
    • 1
  1. 1.Field of Basic Sports Medicine, Sports Medicine, Faculty of Medicine, Graduate School of Comprehensive Human SciencesThe University of TsukubaTsukubaJapan
  2. 2.Biomedical Sciences, Faculty of Medicine, The University of TsukubaTsukubaJapan
  3. 3.Department of Gastroenterology, Faculty of MedicineThe University of TsukubaTsukubaJapan
  4. 4.Department of Internal Medicine and GastroenterologyTokyo Women’s Medical UniversityTokyoJapan
  5. 5.Drug Development Service Division, Pharmacodynamics Group, Medi-Chem Business SegmentMitsubishi Chemical Medience CorporationTokyoJapan
  6. 6.Department of Stress Response ScienceHirosaki University Graduate School of MedicineHiroksakiJapan
  7. 7.Department of Medical BiochemistryTohoku University Graduate School of MedicineSendaiJapan
  8. 8.Department of Strategic Surveillance for Functional Food and Comprehensive Traditional MedicineWakayama Medical UniversityWakayamaJapan

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