Bile acid metabolism is intimately linked to the control of energy homeostasis 
and glucose and lipid metabolism. The nuclear receptor farnesoid X receptor 
(FXR) plays a major role in the enterohepatic cycling of bile acids, but the 
impact of nutrients on bile acid homeostasis is poorly characterized. 
Metabolically active hepatocytes cope with increases in intracellular glucose 
concentrations by directing glucose into storage (glycogen) or oxidation 
(glycolysis) pathways, as well as to the pentose phosphate shunt and the 
hexosamine biosynthetic pathway. Here we studied whether the glucose 
nonoxidative hexosamine biosynthetic pathway modulates FXR activity. Our results 
show that FXR interacts with and is O-GlcNAcylated by O-GlcNAc transferase in 
its N-terminal AF1 domain. Increased FXR O-GlcNAcylation enhances FXR gene 
expression and protein stability in a cell type-specific manner. High glucose 
concentrations increased FXR O-GlcNAcylation, hence its protein stability and 
transcriptional activity by inactivating corepressor complexes, which associate 
in a ligand-dependent manner with FXR, and increased FXR binding to chromatin. 
Finally, in vivo fasting-refeeding experiments show that FXR undergoes 
O-GlcNAcylation in fed conditions associated with increased direct FXR target 
gene expression and decreased liver bile acid content.
CONCLUSION: FXR activity is regulated by glucose fluxes in hepatocytes through a 
direct posttranslational modification catalyzed by the glucose-sensing 
hexosamine biosynthetic pathway.