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

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

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.

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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

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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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Authors and Affiliations

  1. 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

    Kosuke Okada, Masaki Horie & Junichi Shoda

  2. Biomedical Sciences, Faculty of Medicine, The University of Tsukuba, Tsukuba, Ibaraki, 305-8575, Japan

    Eiji Warabi & Tetsuro Ishii

  3. Department of Gastroenterology, Faculty of Medicine, The University of Tsukuba, Tsukuba, Ibaraki, 305-8575, Japan

    Hirokazu Sugimoto

  4. Department of Internal Medicine and Gastroenterology, Tokyo Women’s Medical University, Shinjuku-ku, Tokyo, 162-8666, Japan

    Katsutoshi Tokushige & Etsuko Hashimoto

  5. Drug Development Service Division, Pharmacodynamics Group, Medi-Chem Business Segment, Mitsubishi Chemical Medience Corporation, Itabashi-ku, Tokyo, 174-8555, Japan

    Tetsuya Ueda

  6. Department of Stress Response Science, Hirosaki University Graduate School of Medicine, Zaifu-cho, Hiroksaki, Aomori, 036-8562, Japan

    Nobuhiko Harada & Ken Itoh

  7. Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, 980-8675, Japan

    Keiko Taguchi & Masayuki Yamamoto

  8. Department of Strategic Surveillance for Functional Food and Comprehensive Traditional Medicine, Wakayama Medical University, Wakayama, 641-0012, Japan

    Hirotoshi Utsunomiya

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  1. Kosuke Okada
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  2. Eiji Warabi
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  3. Hirokazu Sugimoto
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  7. Nobuhiko Harada
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  9. Etsuko Hashimoto
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  10. Ken Itoh
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  13. Masayuki Yamamoto
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  14. Junichi Shoda
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Corresponding author

Correspondence to Junichi Shoda.

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Okada, K., Warabi, E., Sugimoto, H. et al. Nrf2 inhibits hepatic iron accumulation and counteracts oxidative stress-induced liver injury in nutritional steatohepatitis. J Gastroenterol 47, 924–935 (2012). https://doi.org/10.1007/s00535-012-0552-9

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  • DOI: https://doi.org/10.1007/s00535-012-0552-9

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