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

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 alpha and ChREBP beta. However, the mechanism responsible for regulating the expression of both ChREBP alpha and beta, as well as the mechanism that determines which specific isoform is more responsive to different stimuli, remains unclear. To address this issue, we compared the effects of several stimuli, including oxidative stress, on the mRNA and protein expression levels of ChREBP alpha and beta 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 beta was < 1% of that for ChREBP alpha levels. In addition, the reduction in both ChREBP alpha and beta 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 extracellular-signal-regulated kinase (ERK) signaling, also resulted in a decrease in the levels of both ChREBP alpha and beta mRNA in HepG2 cells through ERK signaling. These collective data suggest that oxidative stress, including STS treatment, suppresses the expression of ChREBP alpha and beta via the activation of ERK signaling in HepG2 cells. Such a decrease in the levels of expression of ChREBP alpha and beta could result in the suppression of hepatic glycolysis and lipogenesis, and this would be expected to prevent further oxidative stress.