1. Deletion of Nrf2 leads to hepatic insulin resistance via the activation of NF-κB in mice fed a high-fat diet
- Author
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Xuxia Wang, Dou Weijia, Liu Zhenxiong, Shuguang Zhao, Wang Jingjie, Ming Qin, Zhen Ni, Hua Tang, Rong Zhang, Cao Ying, and Qin-Sheng Wen
- Subjects
Blood Glucose ,Male ,0301 basic medicine ,Cancer Research ,medicine.disease_cause ,environment and public health ,Biochemistry ,Lipid peroxidation ,Mice ,chemistry.chemical_compound ,0302 clinical medicine ,Non-alcoholic Fatty Liver Disease ,Malondialdehyde ,Mice, Knockout ,Gene knockdown ,Fatty liver ,NF-kappa B ,respiratory system ,Glutathione ,Liver ,Oncology ,030220 oncology & carcinogenesis ,Molecular Medicine ,Signal Transduction ,medicine.medical_specialty ,NF-E2-Related Factor 2 ,Biology ,Diet, High-Fat ,digestive system ,03 medical and health sciences ,Insulin resistance ,Internal medicine ,Genetics ,medicine ,Animals ,Molecular Biology ,nutritional and metabolic diseases ,medicine.disease ,Disease Models, Animal ,Oxidative Stress ,030104 developmental biology ,Endocrinology ,chemistry ,Lipid Peroxidation ,Insulin Resistance ,Metabolic syndrome ,Steatohepatitis ,Gene Deletion ,Oxidative stress - 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.
- Published
- 2016