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

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Berrabah, Wahiba Aumercier, Pierrette Gheeraert, Céline Dehondt, Hélène Bouchaert, Emmanuel Alexandre, Jérémy Ploton, Maheul Mazuy, Claire Caron, Sandrine Tailleux, Anne Eeckhoute, Jérôme Lefebvre, Tony Staels, Bart Lefebvre, Philippe
Description	Country affiliation: France Author Affiliation: Berrabah W ( European Genomic Institute for Diabetes (EGID), Lille, France)
Abstract	UNLABELLED: 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.
File Format	HTM / HTML
ISSN	02709139
Issue Number	5
Volume Number	59
e-ISSN	15273350
Journal	Hepatology
Language	English
Publisher	Wiley
Publisher Date	2014-05-01
Publisher Place	United States
Access Restriction	Subscribed
Subject Keyword	Discipline Hepatology Bile Acids And Salts Metabolism Glucose N-acetylglucosaminyltransferases Physiology Receptors, Cytoplasmic And Nuclear Acylation Animals Gene Expression Regulation Hep G2 Cells Hepatocytes Hexosamines Biosynthesis Humans Male Mice Mice, Inbred C57bl Pentose Phosphate Pathway Genetics Signal Transduction Journal Article Research Support, Non-u.s. Gov't
Content Type	Text
Resource Type	Article
Subject	Hepatology

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