Glucose sensing O-GlcNAcylation pathway regulates the nuclear bile acid receptor farnesoid X receptor (FXR)

Abstract

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 OGlcNAcylated by O-GlcNAc transferase in its N-terminal AF1 domain. Increased FXR OGlcNAcylation 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. (HEPATOLOGY 2014;59:2023-2034 See Editorial on Page 1665 T he liver plays an important role in energy homeostasis by constantly tuning metabolic networks in response to varying nutrient fluxes. Marked variations in blood glucose concentrations occur daily, which are rapidly compensated by an integrated response of several tissues, such as the liver, which reacts by adjusting the relative activity of gluconeogenic, glycogenogenic and glycolytic pathways, hence contributing to the maintenance of glucose homeostasis. Hepatocytes also direct glucose into the pentose phosphate shunt and the hexosamine biosynthetic pathways (HBP), the latter consuming up to 5% of the cellular glucose. HBP generates uridine diphosphate N-acetyl-glucosamine (UDP-GlcNAc) from glucose, glutamine, acetyl-coenzyme A, uridine, and adenosine triphosphate (ATP). UDP-GlcNAc synthesis is catalyzed by Abbreviations: BA, bile acid; DON,6

Bile Acid Signaling in Metabolic Disease and Drug Therapy

“…Bile acid synthesis was markedly increased during the postprandial period likely due to increased glucose influx and activation of insulin signaling . A more recent study showed that FXR was Bile Acid in Metabolic Diseases O-Glc-N-acylated under high glucose concentration to stimulate ligand-dependent FXR transactivating activity and increase cellular glucose flux and hexoseamine biosynthetic pathway (Berrabah et al, 2014). These studies indicate that FXR may be activated during the postprandial period to play a role in the regulation of glucose homeostasis (Kir et al, 2011;Potthoff et al, 2011;Li et al, 2012).…”

Pharmacology of bile acid receptors: Evolution of bile acids from simple detergents to complex signaling molecules

“…In addition, a recent study showed that FGF15 can act as a postprandial hormone and regulate glucose homeostasis in the liver [78,79]. Interesting, high glucose causes FXR O -Glc- N -acylation, and this posttranslational modification potentiates the ligand-dependent trans-activating activity of FXR, therefore linking hepatic glucose influx to FXR regulation of hepatic glucose metabolism [80]. The major functions of FXR are illustrated in Figure 1.…”

Hexosamine pathway and (ER) protein quality control

“…Thus it is possible that high energy sensing via the HP and subsequent O-GlcNAcylation might induce lifespan extension. Other prominent signaling proteins that are O-GlcNAcylated include, among others, beta catenin [23], FXR [24], NF-kB subunits [25,26], carbohydrate-responsive elementbinding protein (ChREBP) [27], as well as components of the circadian clock [28,29]. Elevation of mucin type O-glycosylation: Given the role of mucin type O-glycosylation in the secretory apparatus, it is possible that elevation of its precursor UDP-GalNAc/UDP-GlcNAc might lead to changes in the degree of glycosylation or in the abundance of substrate proteins.…”