Chemistry and Physics of Lipids 164 (2011) 525–529 Contents lists available at ScienceDirect Chemistry and Physics of Lipids journal homepage: www.elsevier.com/locate/chemphyslip Bile acid signaling after an oral glucose tolerance test Silke Matysik a,∗ , Josefine Martin b , Margarita Bala b , Max Scherer a , Andreas Schäffler b , Gerd Schmitz a,∗ a Institute for Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Regensburg, Germany b Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany article info Article history: Available online 6 June 2011 Keywords: Postprandial response Oral glucose tolerance test Bile acids FGF19 7-Hydroxy-4-cholesten-3-one abstract Monitoring bile acids as signal molecules in combination with a bile acid synthesis marker and the FXR regulator fibroblast growth factor 19 (FGF19), this study addresses significant postprandial changes. The efficacy of the different pathways to regulate bile acid synthesis through short heterodimer partner (SHP) dependent FXR modulation in liver, and SHP independent activation via FGF19 is demonstrated. Char- acteristic changes of the bile acid profile during an oral glucose tolerance test (oGTT) were investigated in 73 individuals. 15 bile acid species including conjugated and unconjugated forms were quantitatively determined with LC–MS/MS in serum samples collected at three time points during the oGTT. All con- jugated bile acid species showed the same time course, a significant increase at 60 min after the glucose intake and an incline at 120 min. In contrast, a consistent decline of all unconjugated bile acids was mon- itored. 7-Hydroxy-4-cholesten-3-one, an early bile acid synthesis marker, showed an inverse response with a significant decrease at 60 min which proves the efficient and rapid downregulation of CYP7A1 via FXR activation through bile acid signaling. Significantly higher levels of FGF19 were observed 120 min after glucose intake and 60 min after bile acid excursion. © 2011 Elsevier Ireland Ltd. All rights reserved. 1. Introduction Bile acid biosynthesis from cholesterol is regulated by a feed- back inhibitory circuit that involves both the liver and the intestine. One target of this feedback circuit involves bile-acid mediated acti- vation of farnesoid X receptor FXR in the liver, which induces hepatic expression of short heterodimer partner (SHP). SHP binds to several nuclear receptors (such as LRH1) and interferes with their activity to repress the transcriptional expression of CYP7A1, the rate-limiting enzyme in bile-acid synthesis (Goodwin et al., 2000; Lu et al., 2000; Thomas et al., 2008). Furthermore, bile acid synthe- sis is regulated involving FXR-mediated induction of FGF19 in the intestine (Holt et al., 2003; Inagaki et al., 2005). Like FGF21 (PPAR/PPAR regulated) and FGF23 (Vit D regu- lated), FGF19 (FXR regulated) belongs to a subfamily of FGFs that have an endocrine function. FGF19 has emerged as a novel regula- tor of hepatic lipid homeostasis (Beenken and Mohammadi, 2009; Jones, 2008). FGF transcripts are found in the brain, cartilage, skin, retina, kidneys, gall bladder, and small intestine. FGF19 expression occurs primarily in the ileum from which the ligand circulates to the liver to exert its main functions through regulation of tran- ∗ Corresponding authors. Tel.: +49 941 9446281; fax: +49 941 9446202. E-mail addresses: silke.matysik@klinik.uni-regensburg.de (S. Matysik), gerd.schmitz@klinik.uni-regensburg.de (G. Schmitz). scription. FGF19 gene expression is directly induced through FXR activation with bile acids as potent ligands. In the liver, the recep- tor tyrosine kinase FGFR4 is the predominant receptor that binds FGF19 to inhibit CYP7A1, independent of SHP-gene induction. Diurnally varied serum FGF19 levels rise 1–2 h after a postpran- dial increase in bile acids (Lundasen et al., 2006). Reduced plasma levels of FGF19 have been reported in patients with type-2-diabetes (Stejskal et al., 2008). Furthermore, patients with non-alcoholic fatty liver disease (NAFLD) and insulin resistance show impaired hepatic response to FGF19 after an oral fat challenge (Schreuder et al., 2010). Bile acids are supposed to regulate not only their own synthesis, but also triglyceride, cholesterol, energy, and glucose homeosta- sis via activation of FXR/LXR and G-protein-coupled receptors such as TGR5 (Sinal et al., 2000; Watanabe et al., 2006). Through different steps, including activation of adenylate cyclase and cAMP-response-element-binding-protein (CREB), the TGR5 signal- ing pathway targets the endothelial nitric oxide synthase (eNOS) in the liver, the thyroid hormone production, and activation of thyroid receptors resulting in an enhanced energy expenditure in muscle cells (Thomas et al., 2008). Furthermore, FXR activation is supposed to induce the transcription of multiple genes involved in intesti- nal mucosa defense, such as inducible-nitric-oxide synthase and interleukin-18 (Fiorucci et al., 2007). To investigate time-dependent variations in bile acid signal- ing in the context of metabolic effects, standardized meals can 0009-3084/$ – see front matter © 2011 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.chemphyslip.2011.05.003