Journal
MOLECULAR MEDICINE REPORTS
Volume 14, Issue 2, Pages 1323-1331Publisher
SPANDIDOS PUBL LTD
DOI: 10.3892/mmr.2016.5393
Keywords
non-alcoholic fatty liver disease; insulin resistance; oxidative stress; nuclear erythroid 2-related factor 2; nuclear factor-kappa B
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Funding
- National Natural Science Foundation of China [30800515, 81270485, 81170376]
- Natural Science Foundation of Shaanxi Province [2013JM4021]
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Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. Insulin resistance (IR) is important in the development and progression of NAFLD. Nuclear erythroid 2-related factor 2 (Nrf2) has previously been reported to be a novel regulator in NAFLD. The present study determined that Nrf2 knockdown accelerated the onset of obesity and non-alcoholic steatohepatitis (NASH), via the induction of hepatic IR in mice fed a high-fat diet (HFD), which was confirmed by an increase in total and hepatic weight in Nrf2-null-HFD mice, in addition to marked structural disorder in liver tissues from the Nrf2-null-HFD group analyzed by histopathological examination. Subsequently, it was demonstrated that hepatic IR in Nrf2-null-HFD mice was influenced by oxidative stress; this was confirmed by an increase in malondialdehyde levels and a decrease in glutathione levels. In addition, it was determined that the induction of hepatic IR by Nrf2 knockdown in HFD-treated mice was regulated by activation of the nuclear factor-kappa B (NF-kappa B) signaling pathway, as detected by an increase in the expression levels of nuclear NF-kappa B, and its downstream effectors interleukin-6 and tumor necrosis factor-alpha. The present study provides insight into the function of Nrf2 in NAFLD, indicating that Nrf2 deletion may lead to hepatic IR by activation of NF-kappa B, which is often associated with oxidative stress. Therefore, activation of Nrf2 may limit disease progression and act as a therapeutic approach for the treatment of NASH.
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