Nrf2-Mediated heme oxygenase-1 upregulation as adaptive survival response to glucose deprivation-induced apoptosis in HepG2 cells.
Induction of heme oxygenase-1 (HO-1) represents an important cellular adaptive survival response to oxidative stress and other toxic insults. In the present study, HepG2 cells grown in glucose-free media underwent apoptotic cell death, but they exhibited elevated expression of HO-1 before apoptosis manifested. Treatment of HepG2 cells with SnCl₂, a HO-1 inducer, rescued these cells from glucose deprivation-induced apoptosis, while inhibition of the HO activity with zinc protoporphyrin IX exacerbated apoptosis under the same condition. HepG2 cells transfected with a dominant negative Nrf2 were more vulnerable to glucose deprivation-induced apoptosis compared to cells transfected with empty vector alone. To confirm the involvement of Nrf2 in the induction of HO-1 caused by glucose deprivation, we used embryonic fibroblasts prepared from nrf2⁻(/)⁻, nrf2(+/)⁻, and nrf2(+/+) embryos. Compared to the wild-type and the nrf2(+/)⁻ embryonic fibroblasts, nrf2⁻(/)⁻ cells were less prone to induce HO-1 expression upon glucose deprivation. Exposure of HepG2 cells to glucose-deprived media resulted in an elevated accumulation of reactive oxygen species (ROS). Pretreatment with N-acetylcysteine prevented the glucose deprivation-induced ROS accumulation and also the HO-1 expression. In conclusion, the Nrf2-mediated HO-1 upregulation upon glucose deprivation is mediated by ROS in HepG2 cells, and responsible for the adaptive survival response.
Lee
Hee Geum
HG
Seoul National University, South Korea.
Li
Mei-Hua
MH
Joung
Eun-Joo
EJ
Na
Hye-Kyung
HK
Cha
Young-Nam
YN
Surh
Young-Joon
YJ
D000111:Acetylcysteine / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D005260:Female; D005947:Glucose / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D008297:Male; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D011524:Protoporphyrins / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015854:Up-Regulation; D033921:Vesicular Transport Proteins / Q000378:metabolism
D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C495636:Nfe2l2 protein, mouse; D011524:Protoporphyrins; D017382:Reactive Oxygen Species; C115740:VPS52 protein, human; D033921:Vesicular Transport Proteins; C017803:zinc protoporphyrin; D051547:Heme Oxygenase-1; D005947:Glucose; D000111:Acetylcysteine