Carbohydrate response element
binding protein (ChREBP) regulates
insulin-independent de novo lipogenesis. Recently, a novel ChREBPβ
isoform was identified. The purpose of the current study was to define the effect of
dietary carbohydrates (CHO) and
obesity on the transcriptional activity of ChREBP
isoforms and their respective target genes. Mice were subjected to fasting-refeeding of high-CHO diets. In all three CHO-refeeding groups, mice failed to induce ChREBPα, yet ChREBPβ increased 10- to 20-fold. High-fat fed mice increased hepatic ChREBPβ
mRNA expression compared to chow-fed along with increased
protein expression. To better assess the independent effect of
fructose on ChREBPα/β activity, HepG2 cells were treated with
fructose ± a
fructose-1,6-bisphosphatase inhibitor to suppress gluconeogenesis.
Fructose treatment in the absence of gluconeogenesis resulted in increased ChREBP activity. To confirm the existence of ChREBPβ in human tissue, primary hepatocytes were incubated with high-
glucose and the expression of ChREBPα and -β was determined. As with the animal models,
glucose induced ChREBPβ expression while ChREBPα was decreased. Taken together, ChREBPβ is more responsive to changes in dietary CHO availability than the -α
isoform. Diet-induced
obesity increases basal expression of ChREBPβ, which may increase the risk of developing hepatic steatosis, and
fructose-induced activation is independent of gluconeogenesis.