How sweet it is to activate FXR

T he farnesoid X receptor (FXR) has emerged as a bile acid sensor and master regulator of diverse metabolic processes. FXR is a ligandactivated transcription factor, and is highly expressed in tissues with a high bile salt flux, i.e., the small intestine and liver. Both conjugated and unconjugated bile acids bind to FXR. Since FXR is an intracellular receptor, membrane-impermeable conjugated bile acids have to be taken up by way of an appropriate carrier protein. A main function of hepatic FXR is to prevent the harmful consequences of pathological bile acid overload in the hepatocyte. This is achieved through repression of bile acid uptake and synthesis, and stimulation of bile acid detoxification and secretion at the canalicular and basolateral poles. An important function of intestinal FXR is the suppression of bile acid synthesis in the postprandial phase. The FXR-inducible enterokine Fgf15/FGF19 plays a key role in this negative feedback loop by activating signaling pathways in the liver that target CYP7A1 expression, the main determinant of bile acid synthesis. Apart from their effects on bile acid homeostasis, intestinal (by way of Fgf15/FGF19) and hepatic FXR control the expression of numerous metabolic genes in the liver, thus affecting postprandial metabolism. Affected pathways include gluconeogenesis and lipogenesis, which are both repressed by activated FXR. Bile acids are the major endogenous ligands of FXR and determine its activation. During the day, portal and systemic bile acid levels are subject to major diurnal and meal-induced fluctuations. Since the influence of FXR extends far beyond control of bile acid homeostasis, crosstalk with other metabolic pathways that modulate its activity can be expected. A number of recent studies have shed light on this issue. FXR controls target gene expression in conjunction with a number of transcriptional cofactors (e.g., PGC1a, SIRT1) that affect interaction with the basal transcriptional machinery and modulate accessibility of the chromatin. FXR and its interacting cofactors are subject to (reversible) posttranslational modifications including methylation, acetylation and phosphorylation (Fig. 1). This couples the cellular metabolic state (i.e., availability of donor substrates and enzyme cofactors) to regulation of (metabolic) gene expression. The activity of FXR is greatly affected by these modifications either through effects on protein stability, interaction with cofactors, binding to genomic FXR-response elements, or transactivation potential. Berrabah et al. now report on the posttranslational modification of FXR by O-GlcNAcylation at presumably multiple residues including a highly conserved serine residue located in its N-terminal activating function domain (AF1, Fig. 1). O-GlcNAcylation of specific serine/threonine residues is a common and dynamic modification that serves to modulate signaling and transcriptional networks in response to nutrients and cellular stress. The synthesis of the donor substrate for O-GlcNAcylation, i.e., UDP-GlcNAc, is increased at high glucose levels when more glucose is shunted into the hexosamine biosynthetic pathway. Moreover, the enzyme responsible for O-GlcNAcylation (i.e., OGT) is activated by insulin signaling. Targeting proteins that direct OGT to its protein substrates include the transcriptional cofactor PGC1a, a common component of nuclear receptor transcriptional complexes. Berrabah et al. show that the degree of O-GlcNAcylation of FXR is increased by high glucose levels in vitro or by a fasting-refeeding regimen in vivo. O-GlcNAcylated FXR is more responsive to FXR agonists such as the synthetic compound GW4064. Thus, high glucose conditions confer increased sensitivity of FXR-regulated genes to agonist challenge. Transcript profiling indicated that augmented agonist-response under these conditions affects the vast majority of FXR-driven genes in HepG2 cells and immortalized human hepatocytes. The findings of Berrabah et al. interconnect glucose metabolism and FXR-regulated processes like bile acid homeostasis, and call for studies addressing how FXR activity is affected by chronic elevation of glucose levels and insulin resistance. It has already been Abbreviations: CES1, carboxylesterase-1; FXR, farnesoid X receptor; NAFLD, nonalcoholic fatty liver disease. Address reprint requests to: Peter L.M. Jansen, M.D., Ph.D., Division of Gastroenterology and Hepatology, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. E-mail: p.l. jansen@amc.uva. nl; fax: 131 20 5668278. Received September 20, 2013; accepted September 26, 2013. Copyright VC 2014 by the American Association for the Study of Liver Diseases. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.26778 Potential conflict of interest: Nothing to report.