Activation of the mitogen‐activated protein kinase ERK1/2 signaling pathway suppresses the expression of ChREBPα and β in HepG2 cells

Abstract

The carbohydrate response element binding protein (ChREBP), a glucose-responsive transcription factor that plays a critical role in the glucose mediated induction of genes involved in hepatic glycolysis and lipogenesis, exists as two isoforms: ChREBP and ChREBP. However, the mechanism responsible for regulating the expression of both ChREBP and  as well as the mechanism that determines which specific isoform is more responsive to different stimuli, remain unclear. To address this issue, we compared the effects of several stimuli, including oxidative stress, on the mRNA and protein expression levels of ChREBP and  in the hepatocyte cell line, HepG2 We found that H2O2 stimulation suppressed the expression of both mRNA and protein in HepG2 cells, but the mRNA expression level of ChREBP was less than 1% of that for ChREBP levels In addition, the reduction in both ChREBP and  mRNA levels was reversed by PD98059, a selective and cell permeable inhibitor of the MEK/ERK pathway. Additionally, the administration of 12-O-tetradecanoylphorbol 13-acetate (TPA) and staurosporine (STS), activators of ERK signaling, also resulted in a decrease in the levels of both ChREBP and  mRNA in HepG2 cells through ERK signaling. These collective data suggest that oxidative stress, including STS treatment, suppresses the expression of ChREBP and  via the activation of ERK signaling in HepG2 cells. Such a decrease in the levels of expression of ChREBP and  could result in the suppression of hepatic glycolysis and lipogenesis, and this would be expected to prevent further oxidative stress.