Deletion of Nrf2 leads to rapid progression of steatohepatitis in mice fed atherogenic plus high-fat diet
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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.
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.
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.
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.
KeywordsNrf2 gene-knockout mouse Transcription factor Atherogenic plus high-fat diet Fatty acid Oxidative stress
Alpha-smooth muscle actin
- Ath + HF diet
Atherogenic plus high-fat diet
Elongation of long-chain fatty acids family member 6
Fatty acid synthase
Fatty acid transport protein
γ-Glutamyl cystein synthetase
Kelch-like Ech-associated protein 1
Liver fatty acid binding protein
Liver X receptor
Nuclear factor-E2-related factor-2
NAD(P)H: quinone oxidoreductase 1
Peroxisome proliferators activated receptor
Reactive oxygen species
Sterol regulatory element-binding protein
Transforming growth factor
Conflict of interest
The authors declare that they have no conflicts of interest.
- 8.Fromenty B, Robin MA, Igoudili A, Mansouri A, Pessayre D. The ins and outs of mitochondrial dysfunction in NASH. Diabetes Metab 2004;30:121–38.Google Scholar
- 35.Miquilena-Colina ME, Lima-Cabello E, Sanchez-Campos S, Garcia-Mediavilla MV, Fernandez-Beremejo M, Lazano-Rodriguez T, et al. Hepatic fatty acid translocase CD36 upregulation is associated with insulin resistance, hyperinsulinaemia and increased steatosis in non-alcoholic steatohepatitis and chronic hepatitis C. Gut. 2011;60:1394–402.PubMedCrossRefGoogle Scholar