Journal of Gastroenterology

, Volume 48, Issue 5, pp 620–632 | Cite as

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

  • Kosuke Okada
  • Eiji Warabi
  • Hirokazu Sugimoto
  • Masaki Horie
  • Naohiro Gotoh
  • Katsutoshi Tokushige
  • Etsuko Hashimoto
  • Hirotoshi Utsunomiya
  • Hiroshi Takahashi
  • Tetsuro Ishii
  • Masayuki Yamamoto
  • Junichi Shoda
Original Article—Liver, Pancreas, and Biliary Tract

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-), 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.

Keywords

Nrf2 gene-knockout mouse Transcription factor Atherogenic plus high-fat diet Fatty acid Oxidative stress 

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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Copyright information

© Springer 2012

Authors and Affiliations

  • Kosuke Okada
    • 1
    • 2
  • Eiji Warabi
    • 3
  • Hirokazu Sugimoto
    • 2
  • Masaki Horie
    • 1
  • Naohiro Gotoh
    • 4
  • Katsutoshi Tokushige
    • 5
  • Etsuko Hashimoto
    • 5
  • Hirotoshi Utsunomiya
    • 6
  • Hiroshi Takahashi
    • 7
  • Tetsuro Ishii
    • 3
  • Masayuki Yamamoto
    • 8
  • Junichi Shoda
    • 1
  1. 1.Division of Medical Science, Faculty of MedicineUniversity of TsukubaTsukubaJapan
  2. 2.Department of Gastroenterology, Faculty of MedicineThe University of TsukubaTsukubaJapan
  3. 3.Division of Biomedical Sciences, Faculty of MedicineUniversity of TsukubaTsukubaJapan
  4. 4.Department of Food Science and TechnologyTokyo University of Marine Science and TechnologyTokyoJapan
  5. 5.Department of Internal Medicine and GastroenterologyTokyo Women’s Medical UniversityTokyoJapan
  6. 6.Department of Strategic Surveillance for Functional Food and Comprehensive Traditional MedicineWakayama Medical UniversityWakayamaJapan
  7. 7.Department of Anesthesiology, Faculty of MedicineUniversity of TsukubaTsukubaJapan
  8. 8.Department of Medical BiochemistryTohoku University Graduate School of MedicineSendaiJapan

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