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Deletion of Nrf2 leads to rapid progression of steatohepatitis in mice fed atherogenic plus high-fat diet

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
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Abstract

Background

The transcription factor nuclear factor-E2-related factor-2 (Nrf2) inhibits lipid accumulation and oxidative stress in the liver by interfering with lipogenic pathways and inducing antioxidative stress genes.

Methods

The involvement of Nrf2 in defense against the development of steatohepatitis was studied in an experimental model induced by an atherogenic plus high-fat (Ath + HF) diet. Wild-type (WT) and Nrf2-null mice were fed the diet. Their specimens were analyzed for pathology as well as for the expression levels of genes involved in fatty acid metabolism and those involved via the Nrf2 transcriptional pathway.

Results

In Nrf2-null mice fed the diet, steatohepatitis developed rapidly, leading to precirrhosis. The Ath + HF diet increased hepatic triglyceride levels and changed fatty acid composition in both mouse groups. However, oleic acid (C18:1 n-9) predominated in the livers of Nrf2-null mice. Correlating well with the pathology, the mRNA levels of the factors involved in fatty acid metabolism (Lxr, Srebp-1a, 1c, Acc-1, Fas, Scd-1, and Fatty acid transporting peptides 1, 3, 4), the inflammatory cytokine genes (Tnf-α and IL-1β), and the fibrogenesis-related genes (Tgf-β1 and α-Sma) were significantly increased in the livers of Nrf2-null mice fed the diet, compared with the levels of these factors in matched WT mice. Oxidative stress was significantly increased in the livers of Nrf2-null mice fed the diet. This change was closely associated with the decreased levels of antioxidative stress genes.

Conclusions

Nrf2 deletion leads to the rapid onset and progression of steatohepatitis induced by an Ath + HF diet, through both up-regulation of co-regulators of fatty acid metabolism and down-regulation of oxidative metabolism regulators in the liver.

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Abbreviations

Acc-1:

Acetyl-CoA carboxylase

Aco:

Acyl-CoA oxidase

α-Sma:

Alpha-smooth muscle actin

Ath + HF diet:

Atherogenic plus high-fat diet

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

Cpt:

Carnitine palmitoyltransferase

Elovl6:

Elongation of long-chain fatty acids family member 6

Fas:

Fatty acid synthase

Fatp:

Fatty acid transport protein

γ-Gcs:

γ-Glutamyl cystein synthetase

GSH:

Glutathione

Gst:

Glutathione S-transferase

4-HNE:

4-Hydroxy-2-nonenal

Keap1:

Kelch-like Ech-associated protein 1

L-Fabp:

Liver fatty acid binding protein

Lxr:

Liver X receptor

NASH:

Non-alcoholic steatohepatitis

Nrf2:

Nuclear factor-E2-related factor-2

Nqo1:

NAD(P)H: quinone oxidoreductase 1

Ppar:

Peroxisome proliferators activated receptor

ROS:

Reactive oxygen species

Scd-1:

Stearoyl-CoA desaturase-1

Srebp:

Sterol regulatory element-binding protein

Tgf:

Transforming growth factor

WT:

Wild type

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Conflict of interest

The authors declare that they have no conflicts of interest.

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Authors and Affiliations

  1. Division of Medical Science, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8574, Japan

    Kosuke Okada, Masaki Horie & Junichi Shoda

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

    Kosuke Okada & Hirokazu Sugimoto

  3. Division of Biomedical Sciences, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, 305-8575, Japan

    Eiji Warabi & Tetsuro Ishii

  4. Department of Food Science and Technology, Tokyo University of Marine Science and Technology, Tokyo, 108-8477, Japan

    Naohiro Gotoh

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

    Katsutoshi Tokushige & Etsuko Hashimoto

  6. Department of Strategic Surveillance for Functional Food and Comprehensive Traditional Medicine, Wakayama Medical University, Wakayama, 641-8509, Japan

    Hirotoshi Utsunomiya

  7. Department of Anesthesiology, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, 305-8575, Japan

    Hiroshi Takahashi

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

    Masayuki Yamamoto

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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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  4. Masaki Horie
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  9. Hiroshi Takahashi
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  10. Tetsuro Ishii
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  11. Masayuki Yamamoto
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  12. Junichi Shoda
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Correspondence to Junichi Shoda.

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Okada, K., Warabi, E., Sugimoto, H. et al. Deletion of Nrf2 leads to rapid progression of steatohepatitis in mice fed atherogenic plus high-fat diet. J Gastroenterol 48, 620–632 (2013). https://doi.org/10.1007/s00535-012-0659-z

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  • DOI: https://doi.org/10.1007/s00535-012-0659-z

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