Deletion of Nrf2 leads to hepatic insulin resistance via the activation of NF-κB in mice fed a high-fat diet.
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.
Department of Gastroenterology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China.
Zhenxiong
Z
Liu
Department of Gastroenterology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China.
Weijia
W
Dou
Department of Digestion, General Hospital of Chengdu Military Command, Chengdu, Sichuan 610000, P.R. China.
Zhen
Z
Ni
Department of Gastroenterology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China.
Qinsheng
Q
Wen
Department of Gastroenterology, Xianyang Hospital of Yan'an University, Xianyang, Shaanxi 712000, P.R. China.
Rong
R
Zhang
Department of Gastroenterology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China.
Ming
M
Qin
Department of Gastroenterology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China.
Xuxia
X
Wang
Department of Gastroenterology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China.
Hua
H
Tang
Department of Gastroenterology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China.
Ying
Y
Cao
Department of Gastroenterology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China.
Jingjie
J
Wang
Department of Gastroenterology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi 710038, P.R. China.
Shuguang
S
Zhao
D000818:Animals; D001786:Blood Glucose; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D017353:Gene Deletion; D005978:Glutathione / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D015227:Lipid Peroxidation; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D015398:Signal Transduction
D001786:Blood Glucose; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; D008315:Malondialdehyde; D005978:Glutathione