Deletion of Nrf2 leads to hepatic insulin resistance via the activation of NF-κB in mice fed a high-fat diet

Abstract

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-κB (NF-κB) signaling pathway, as detected by an increase in the expression levels of nuclear NF-κB, and its downstream effectors interleukin-6 and tumor necrosis factor-α. 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-κB, 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.