Bile acid signaling after an oral glucose tolerance test (original) (raw)
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The Journal of clinical endocrinology and metabolism, 2016
Bile acids regulate lipid and carbohydrate metabolism by interaction with membrane or intracellular proteins including the nuclear farnesoid X receptor (FXR). Postprandial activation of ileal FXR leads to secretion of fibroblast growth factor 19 (FGF-19), a gut hormone that may be implicated in postprandial glucose metabolism. To describe postprandial plasma concentrations of 12 individual bile acids and FGF-19 in patients with type 2 diabetes (T2D) and healthy controls. Descriptive study, performed at the Center for Diabetes Research, Gentofte Hospital, Hellerup, Denmark. Fifteen patients with T2D and 15 healthy matched controls with normal glucose tolerance. A 75-g oral glucose tolerance test and three isocaloric and isovolemic liquid meals with low, medium, and high fat content, respectively. Bile acid and FGF-19 concentrations. Postprandial total bile acid concentrations increased with increasing meal fat content (P < .05), peaked after 1-2 hours, and were higher in T2D patie...
An FXR Agonist Reduces Bile Acid Synthesis Independently of Increases in FGF19 in Healthy Volunteers
Gastroenterology, 2018
Interfering with bile acids (BAs) signaling within the enterohepatic circulation (EHC) has recently emerged as an important way of controlling human metabolic homeostasis. This is highly relevant to a number of frequent disease entities such as dyslipidemia, fatty liver disease, insulin resistance, obesity, type 2 diabetes, gallstone disease and BA-induced diarrhea. The studies presented in this thesis focus on exploring how changes in the fluxes of BAs in the EHC may influence the synthesis and turnover of BAs and cholesterol, the metabolic signaling by endocrine fibroblast growth factors (FGFs) 19 and 21, and the modulation of lipid and carbohydrate metabolism. LIST OF SCIENTIFIC PAPERS I. Asynchronous rhythms of circulating conjugated and unconjugated bile acids in the modulation of human metabolism.
Hepatology, 2009
Mouse fibroblast growth factor 15 (FGF15) and human ortholog FGF19 have been identified as the bile acid-induced intestinal factors that mediate bile acid feedback inhibition of cholesterol 7␣-hydroxylase gene (C YP7A1) transcription in mouse liver. The mechanism underlying FGF15/FGF19 inhibition of bile acid synthesis in hepatocytes remains unclear. Chenodeoxycholic acid (CDCA) and the farnesoid X receptor (FXR)-specific agonist GW4064 strongly induced FGF19 but inhibited CYP7A1 messenger RNA (mRNA) levels in primary human hepatocytes. FGF19 strongly and rapidly repressed CYP7A1 but not small heterodimer partner (SHP) mRNA levels. Kinase inhibition and phosphorylation assays revealed that the mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 (MAPK/Erk1/2) pathway played a major role in mediating FGF19 inhibition of CYP7A1. However, small interfering RNA (siRNA) knockdown of SHP did not affect FGF19 inhibition of CYP7A1. Interestingly, CDCA stimulated tyrosine phosphorylation of the FGF receptor 4 (FGFR4) in hepatocytes. FGF19 antibody and siRNA specific to FGFR4 abrogated GW4064 inhibition of CYP7A1. These results suggest that bile acid-activated FXR is able to induce FGF19 in hepatocytes to inhibit CYP7A1 by an autocrine/paracrine mechanism. Conclusion: The hepatic FGF19/FGFR4/Erk1/2 pathway may inhibit CYP7A1 independent of SHP. In addition to inducing FGF19 in the intestine, bile acids in hepatocytes may activate the liver FGF19/FGFR4 signaling pathway to inhibit bile acid synthesis and prevent accumulation of toxic bile acid in human livers. (HEPATOLOGY 2008;48:000-000.)
FGF21 acts as a negative regulator of bile acid synthesis
The Journal of endocrinology, 2018
Fibroblast growth factor 21 (FGF21) is a potent regulator of glucose and lipid homeostasis ; its most closely related subfamily member, FGF19, is known to be a critical negative regulator of bile acid synthesis. To delineate whether FGF21 also plays a functional role in bile acid metabolism, we evaluated the effects of short- and long-term exposure to native FGF21 and long-acting FGF21 analogs on hepatic signal transduction, gene expression and enterohepatic bile acid levels in primary hepatocytes and in rodent and monkey models. FGF21 acutely induced ERK phosphorylation and inhibited mRNA expression in primary hepatocytes and in different rodent models, although less potently than recombinant human FGF19. Long-term administration of FGF21 in mice fed a standard chow diet resulted in a 50-60% decrease in bile acid levels in the liver and small intestines and consequently a 60% reduction of bile acid pool size. In parallel, colonic and fecal bile acid was decreased, whereas fecal cho...
American Journal of Physiology-Endocrinology and Metabolism
Context: Bile acids, glucagon-like peptide-1 (GLP-1) and fibroblast growth factor 19 (FGF19) play an important role in postprandial metabolism. In this study, we investigated the postprandial bile acid response in plasma and its relation to insulin, GLP-1 and FGF19. Objective: First, we investigated the postprandial response to 40-hour fasting. Then we administered glycine-conjugated deoxycholic acid (gDCA) with the meal. Design: Two separate observational randomized crossover studies Subjects: Healthy lean male subjects Intervention: Study 1: a 4-hour mixed meal test after an overnight fast and a 40 hour fast. Study 2: a 4-hour mixed meal test with and without gDCA supplementation. Main outcome measures: postprandial glucose, insulin, bile acids, GLP-1, FGF19. Results: In study 1, 40 hours of fasting induced insulin resistance and increased postprandial GLP-1 and FGF19 concentrations. After an overnight fast, we observed strong correlations between postprandial insulin and gDCA lev...
Laboratory Investigation, 2010
Hepatic bile acid synthesis is subject to complex modes of transcriptional control, in which the bile acid-activated nuclear receptor farnesoid X receptor (FXR) in liver and intestine-derived, FXR-controlled fibroblast growth factor 15 (Fgf15) are involved. The Fgf15 pathway is assumed to contribute significantly to control of hepatic bile acid synthesis. However, scientific evidence supporting this assumption is primarily based on gene expression data. Using intestine-selective FXR knockout mice (iFXR-KO), we show that contribution of intestinal FXR-Fgf15 signalling in regulation of hepatic cholesterol 7a-hydroxylase (Cyp7A1) expression depends on time of the day with increased hepatic Cyp7A1 expression in iFXR-KO mice compared with controls exclusively during the dark phase. To assess the physiological relevance hereof, we determined effects of intestine-selective deletion of FXR on physiological parameters such as bile formation and kinetics of the enterohepatic circulation of bile acids. It appeared that intestinal FXR deficiency leads to a modest but significant increase in cholic acid pool size, without changes in fractional turnover rate. As a consequence, bile flow and biliary bile acid secretion rates were increased in iFXR-KO mice compared with controls. Feeding a bile acid-containing diet or treatment with a bile acid sequestrant similarly affected bile formation in iFXR-KO and control mice and induced similar changes in Cyp7A1 and Cyp8B1 expression patterns. In conclusion, this study is the first to demonstrate the physiological relevance of the contribution of the intestinal FXR-Fgf15 signalling pathway in control of hepatic bile acid synthesis. Fgf15 contributes to the regulation of hepatic bile acid synthesis in mice mainly during the dark phase. Expansion of the circulating bile acid pool as well as bile acid sequestration diminishes the contribution of intestinal FXR-Fgf15 signalling in control of hepatic bile acid synthesis and bile formation.
Bile acids and signal transduction: Role in glucose homeostasis
Cellular Signalling, 2008
Bile acids are mainly recognized for their role in dietary lipid absorption and cholesterol homeostasis. However, recent progress in bile acid research suggests that bile acids are important signaling molecules that play a role in glucose homeostasis. Among the various supporting evidence, several reports have demonstrated an improvement of the glycemic index of type 2 diabetic patients treated with diverse bile acid binding resins. Herein, we review the diverse interactions of bile acids with various signaling/response pathways, including calcium mobilization and protein kinase activation, membrane receptor-mediated responses, and nuclear receptor responses. Some of the effects of the bile acids are direct through the activation of specific receptors, i.e., TGR5, CAR, VDR, and FXR, while others imply modulation of the hormonal, growth factor and/or neuromediator responses, i.e., glucagon, EGF, and acetylcholine. We also discuss recent evidence implicating the interaction of bile acids with glucose homeostasis mechanisms, with the integration of our understanding of how the signaling mechanisms modulated by bile acid could regulate glucose metabolism.
Regulation of bile acid synthesis
Hepatology, 1991
Bile salts play crucial roles in allowing the gastrointestinal system to digest, transport and metabolize nutrients. They function as nutrient signaling hormones by activating specific nuclear receptors (FXR, PXR, Vitamin D) and G-protein coupled receptors [TGR5, sphingosine-1 phosphate receptor 2 (S1PR2), muscarinic receptors]. Bile acids and insulin appear to collaborate in regulating the metabolism of nutrients in the liver. They both activate the AKT and ERK1/2 signaling pathways. Bile acid induction of the FXR-α target gene, small heterodimer partner (SHP), is highly dependent on the activation PKCζ, a branch of the insulin signaling pathway. SHP is an important regulator of glucose and lipid metabolism in the liver. One might hypothesize that chronic low grade inflammation which is associated with insulin resistance, may inhibit bile acid signaling and disrupt lipid metabolism. The disruption of these signaling pathways may increase the risk of fatty liver and non-alcoholic fatty liver disease (NAFLD). Finally, conjugated bile acids appear to promote cholangiocarcinoma growth via the activation of S1PR2.