HNF4α is required for Tkfcpromoter activation by ChREBP

Triokinase/FMN cyclase (Tkfc) is involved in fructose metabolism and is responsible for the phosphorylation of glyceraldehyde to glyceraldehyde-3-phosphate. In this study, we showed that refeeding induced hepatic expression of Tkfcin mice. Luciferase reporter gene assays using the Tkfcpromoter revealed the existence of 2 hepatocyte nuclear factor 4α (HNF4α)-responsive elements (HNF4RE1 and HNF4RE2) and 1 carbohydrate-responsive element-binding protein (ChREBP)-responsive element (ChoRE1). Deletion and mutation of HNF4RE1 and HNF4RE2 or ChoRE1 abolished HNF4α and ChREBP responsiveness, respectively. HNF4α and ChREBP synergistically stimulated Tkfcpromoter activity. ChoRE1 mutation attenuated but maintained HNF4α responsiveness, whereas HNF4RE1 and HNF4RE2 mutations abolished ChREBP responsiveness. Moreover, Tkfcpromoter activity stimulation by ChREBP was attenuated upon HNF4α knockdown. Furthermore, Tkfcexpression was decreased in the livers of ChREBP−/−and liver-specific HNF4−/−(Hnf4αΔHep) mice. Altogether, our data indicate that Tkfcis a target gene of ChREBP and HNF4α, and Tkfcpromoter activity stimulation by ChREBP requires HNF4α.Graphical AbstractTkfcpromoter activity stimulation by ChREBP and HNF4α during feeding.