HNF4α is Required for Tkfc Promoter 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 Tkfc in mice. Luciferase reporter gene assays using the Tkfc promoter revealed the existence of 2 hepatocyte nuclear factor 4 alpha (HNF4 alpha)-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 HNF4 alpha and ChREBP responsiveness, respectively. HNF4 alpha and ChREBP synergistically stimulated Tkfc promoter activity. ChoRE1 mutation attenuated but maintained HNF4 alpha responsiveness, whereas HNF4RE1 and HNF4RE2 mutations abolished ChREBP responsiveness. Moreover, Tkfc promoter activity stimulation by ChREBP was attenuated upon HNF4 alpha knockdown. Furthermore, Tkfc expression was decreased in the livers of ChREBP-/- and liver-specific HNF4-/- (Hnf4 alpha Delta Hep) mice. Altogether, our data indicate that Tkfc is a target gene of ChREBP and HNF4 alpha, and Tkfc promoter activity stimulation by ChREBP requires HNF4 alpha. Graphical Abstract Tkfc promoter activity stimulation by ChREBP and HNF4 alpha during feeding.