Transcriptionfactorcarbohydrateresponsiveelementbindingprotein (ChREBP) is abundant in liver and adipose tissues. ChREBP promotes glycolysis and lipogenesis in metabolic tissues and cancer cells. ChREBP-a and ChREBP-b are two isoforms of ChREBP transcribed from different promoters. Both ChREBP-a and ChREBP-b are transcriptionally induced by glucose. However, the mechanism by which glucose promotes ChREBP transcription remains unclear. Here we report that hepatocyte nuclear factor 4 alpha (HNF-4a) mediates transcription of ChREBP-a and ChREBP-b induced by glucose. Ectopic HNF-4a expression promoted ChREBP transcription while knockdown of HNF-4a reduced ChREBP mRNA levels in liver cancer cells and mouse primary hepatocytes. We found that the expression of HNF-4a and ChREBP was positively correlated by analyzing levels of ChREBP and HNF-4a in the liver of mice under fasting and feeding conditions. HNF-4a directly bound to an E-box-containing region in intron 12 of the ChREBP gene, in addition to directly binding to DR1 sites of the ChREBP-b promoter. Moreover, HNF-4a interacted with ChREBP-a and synergistically promoted ChREBP-b transcription. Interestingly, HNF-4a knockdown decreased glucose-dependent ChREBP induction in liver cancer cells. Glucose increased expression and nuclear abundance of HNF-4a and its binding to cis-elements of ChREBP gene, which contributed to glucose-induced ChREBP transcription in liver cancer cells.

Taken together, our results revealed the novel mechanism by which HNF-4a increased ChREBP transcription in response to glucose in liver cancer cells.