O-GIcNAcylation links ChREBP and FXR to glucose-sensing

Accumulating evidence suggests that O-GIcNAc transferase, an enzyme responsible for O-GIcNAc post-translational modification acts as a nutrient sensor that links glucose and the hexosamine biosynthetic pathway to the regulation of transcriptional factors involved in energy homeostasis. In liver, glucose signaling is mediated by carbohydrate response element-binding protein (ChREBP), which stimulates glycolytic and lipogenic gene expression through its binding on a specific ChoRE DNA sequence. Modulation of ChREBP by O-GIcNAcylation increases its DNA binding affinity and its activity. ChREBP transcriptional activity also depends on the presence of several other co-factors and transcriptional factors. Among them, the nuclear Farnesoid X Receptor (FXR), a key transcription factor of bile acid metabolism involved in the gut liver axis homeostasis was recently shown to directly interact with ChREBP acting as a repressor on the ChoRE of glycolytic genes. Interestingly, similarly to ChREBP FXR is O-GIcNAcylated in response to glucose. This review discusses the importance of ChREBP and FXR modifications through O-GIcNAcylation in liver and how glucose can modify their mutual affinity and transcriptional activity.