Circulating intestinal fibroblast growth factor 19 has a pronounced diurnal variation and modulates hepatic bile acid synthesis in man

Lundåsen, Thomas; Gälman, Cecilia; Angelin, Bo; Rudling, Mats

doi:10.1111/j.1365-2796.2006.01731.x

Cited by 360 publications

(380 citation statements)

References 26 publications

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“…We also found that fasting and postprandial FGF-19 concentrations were negatively correlated with CDCA and CA synthesis in type 2 diabetes before treatment. Studies in healthy participants have suggested that BA synthesis is regulated in part by FGF-19 [12,48], but a similar relationship in type 2 diabetes was not seen in a previous study [12]. FGF-19 has been shown to inhibit fatty acid synthesis in cultured hepatocytes [49] and bile acid sequestration in diabetic db/db mice resulted in an increase in DNL [3].…”

Section: Discussionmentioning

confidence: 75%

Effect of bile acid sequestrants on glucose metabolism, hepatic de novo lipogenesis, and cholesterol and bile acid kinetics in type 2 diabetes: a randomised controlled study

et al. 2011

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Aims/hypothesis The primary aim of this completed multicentre randomised, parallel, double-blind placebo-controlled study was to elucidate the mechanisms of glucose-lowering with colesevelam and secondarily to investigate its effects on lipid metabolism (hepatic de novo lipogenesis, cholesterol and bile acid synthesis). Methods Participants with type 2 diabetes (HbA 1c 6.7-10.0% [50-86 mmol/mol], fasting glucose <16.7 mmol/l, fasting triacylglycerols <3.9 mmol/l and LDL-cholesterol >1.55 mmol/l) treated with diet and exercise, sulfonylurea, metformin or a combination thereof, were randomised by a central coordinator to either 3.75 g/day colesevelam (n=30) or placebo (n=30) for 12 weeks at three clinical sites in the USA. The primary measure was the change from baseline in glucose kinetics with colesevelam compared to placebo treatment. Fasting and postprandial glucose, lipid and bile acid pathways were measured at baseline and post-treatment using stable isotope techniques. Plasma glucose, insulin, total glucagon-like peptide-1 (GLP-1), total glucose-dependent insulinotropic polypeptide (GIP), glucagon and fibroblast growth factor-19 (FGF-19) concentrations were measured during the fasting state and following a meal tolerance test. Data was collected by people blinded to treatment. Colesevelam increased cholesterol and bile acid synthesis and decreased FGF-19 concentrations. However, no effect was seen on fractional hepatic de novo lipogenesis. Conclusions/interpretation Colesevelam, a non-absorbed bile acid sequestrant, increased circulating incretins and improved tissue glucose metabolism in both the fasting and postprandial states in a manner different from other approved oral agents.Trial registration: ClinicalTrials.gov NCT00596427 Funding: The study was funded by Daiichi Sankyo.

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Section: Discussionmentioning

confidence: 75%

Effect of bile acid sequestrants on glucose metabolism, hepatic de novo lipogenesis, and cholesterol and bile acid kinetics in type 2 diabetes: a randomised controlled study

et al. 2011

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“…4). Additionally, dietary manipulation of bile acids modulate the circulating levels of FGF19 in humans, indicating that the FGF signaling pathway plays a significant role in regulation of human bile acid metabolism (30). Thus, the mechanism described here is likely conserved in humans.…”

Section: Discussionmentioning

confidence: 75%

“…Another report demonstrated that serum levels of FGF19 in humans are increased by bile acid feeding and decreased by a bile acid sequestrant (30). Thus, it is likely that FGF-dependent bile acid regulation is conserved between rodents and humans.…”

mentioning

confidence: 99%

FGF15/FGFR4 Integrates Growth Factor Signaling with Hepatic Bile Acid Metabolism and Insulin Action

Shin

Osborne

2009

Journal of Biological Chemistry

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The current studies show FGF15 signaling decreases hepatic forkhead transcription factor 1 (FoxO1) activity through phosphatidylinositol (PI) 3-kinase-dependent phosphorylation. The bile acid receptor FXR (farnesoid X receptor) activates expression of fibroblast growth factor (FGF) 15 in the intestine, which acts through hepatic FGFR4 to suppress cholesterol-7␣ hydroxylase (CYP7A1) and limit bile acid production. Because FoxO1 activity and CYP7A1 gene expression are both increased by fasting, we hypothesized CYP7A1 might be a FoxO1 target gene. Consistent with recently reported results, we show CYP7A1 is a direct target of FoxO1. Additionally, we show that the PI 3-kinase pathway is key for both the induction of CYP7A1 by fasting and the suppression by FGF15. FGFR4 is the major hepatic FGF receptor isoform and is responsible for the hepatic effects of FGF15. We also show that expression of FGFR4 in liver was decreased by fasting, increased by insulin, and reduced by streptozotocin-induced diabetes, implicating FGFR4 as a primary target of insulin regulation. Because insulin and FGF both target the PI 3-kinase pathway, these observations suggest FoxO1 is a key node in the convergence of FGF and insulin signaling pathways and functions as a key integrator for the regulation of glucose and bile acid metabolism.Hepatic cholesterol is converted to bile acids, secreted into the gallbladder, and during a meal is released into the small intestine to enhance digestion and absorption of dietary lipids and fat-soluble vitamins. The majority of the bile acid pool (95%) is recycled back to the liver, whereas the remaining 5% is eliminated through fecal excretion (1, 2). This is an important route for the elimination of excess cholesterol and underscores the importance that bile acids play in regulating mammalian cholesterol metabolism. The initial and rate-controlling step in the classic pathway for cholesterol conversion into bile acids is catalyzed by cholesterol 7␣-hydroxylase (CYP7A1).2 CYP7A1 regulation is primarily transcriptional, and expression of its gene is dynamically regulated by hormones and metabolites (2-6). Importantly, bile acids themselves regulate CYP7A1 gene expression through a multicomponent negative feedback pathway. One of the molecular pathways for bile acid regulation is initiated by the activation of the farnesoid X receptor (FXR) responding directly to bile acid agonists (7). Ligand-activated FXR directly binds to a site in the promoter for the small heterodimer partner (SHP) gene and induces expression of SHP mRNA (8, 9). The translated SHP protein lacks the signature nuclear receptor zinc finger DNA binding domain but uses its conserved dimerization motif to form protein-protein contacts with DNA bound activators, usually other nuclear receptors, to inhibit or interfere with their activation potential (10, 11).The first identified target for SHP repression was the CYP7A1 promoter, and SHP was proposed to interfere with activation by the DNA-bound monomeric liver receptor homologue 1 (LRH-1) nucl...

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“…In addition, acidic glycosaminoglycans in the form of heparan sulfate proteoglycans function to retain these FGFs in the vicinity of FGF-producing sites, such that they primarily act in a paracrine manner. By contrast, the hFGFs have low-affinity heparin-binding sites and have been found to act in an endocrine manner (Tomlinson et al, 2002;Lundasen et al, 2006;Kharitonenkov et al, 2005Kharitonenkov et al, , 2007Fukumoto and Yamashita, 2007;Liu and Quarles, 2007).…”

Section: Identification Of the Mouse Fgf Gene Familymentioning

confidence: 99%

“…In addition, acidic glycosaminoglycans limit the diffusion of FGFs, localizing their activity to the vicinity of FGF-producing cells (Flaumenhaft et al, 1990). In contrast, hFGFs have poor heparin-binding affinity and act on target cells far from their site of production in an endocrine manner (Tomlinson et al, 2002;Lundasen et al, 2006;Kharitonenkov et al, 2005Kharitonenkov et al, , 2007Fukumoto et al, 2007;Liu et al, 2007). In addition, FGF15, FGF21, and FGF23 require co-receptors, Klotho or ␤Klotho, to activate FGFRs (Ogawa et al, 2007;Urakawa et al, 2006).…”

Section: Perspectivesmentioning

confidence: 99%

Functional evolutionary history of the mouse Fgf gene family

Itoh

Ornitz

2007

Developmental Dynamics

356

313

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Circulating intestinal fibroblast growth factor 19 has a pronounced diurnal variation and modulates hepatic bile acid synthesis in man

Cited by 360 publications

References 26 publications

Effect of bile acid sequestrants on glucose metabolism, hepatic de novo lipogenesis, and cholesterol and bile acid kinetics in type 2 diabetes: a randomised controlled study

Effect of bile acid sequestrants on glucose metabolism, hepatic de novo lipogenesis, and cholesterol and bile acid kinetics in type 2 diabetes: a randomised controlled study

FGF15/FGFR4 Integrates Growth Factor Signaling with Hepatic Bile Acid Metabolism and Insulin Action

Functional evolutionary history of the mouse Fgf gene family

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