Chronic elevation of plasma fibroblast growth factor 19 in long‐term farnesoid X receptor agonist therapy, a happy marriage or cause for oncological concern?

Hepatology ◽  
2017 ◽  
Vol 67 (2) ◽  
pp. 782-784 ◽  
Author(s):  
Frank G. Schaap ◽  
Peter L.M. Jansen ◽  
Steven W.M. Olde Damink
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Receptor Agonist ◽  
Farnesoid X Receptor ◽  
Fibroblast Growth ◽  
Agonist Therapy ◽  
Happy Marriage ◽  
Fibroblast Growth Factor 19

scholarly journals Potent stimulation of fibroblast growth factor 19 expression in the human ileum by bile acids

2013 ◽  
Vol 304 (10) ◽  
pp. G940-G948 ◽  
Author(s):  
Justine H. Zhang ◽  
Jonathan D. Nolan ◽  
Sarah L. Kennie ◽  
Ian M. Johnston ◽  
Tracy Dew ◽  
...  
Keyword(s):  
Bile Acid ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Culture Fluid ◽  
Farnesoid X Receptor ◽  
Transcript Expression ◽  
Fibroblast Growth ◽  
Primary Explants ◽  
Fgf19 Expression ◽  
Fibroblast Growth Factor 19

Fibroblast growth factor 19 (FGF19) is proposed to be a negative feedback regulator of hepatic bile acid (BA) synthesis. We aimed to clarify the distribution of FGF19 expression in human intestine and to investigate induction in a novel explant system. Ileal and colonic mucosal biopsies were obtained at endoscopy and analyzed for FGF19 transcript expression. Primary explants were incubated with physiological concentrations of various BA for up to 6 h, and expression of FGF19 and other genes was determined. FGF19 transcripts were detected in ileum but were unquantifiable in colon. No loss of FGF19 mRNA occurred as a consequence of the explant system. Ileal FGF19 transcript expression was induced 350-fold by 50 μM chenodeoxycholate (CDCA, n = 24, P < 0.0001) and 161-fold by 50 μM glycochenodeoxycholate (GCDCA, n = 12, P = 0.0005). The responses of other genes to CDCA or GCDCA (50 μM) were smaller: median increases of ileal bile acid binding protein, organic solute transporter-α and -β, and short heterodimer partner were 2.4- to 4.0-fold; apical membrane sodium bile acid transporter and farnesoid X receptor (FXR) showed little change. The EC50 for FGF19 transcript induction by CDCA was 20 μM. FGF19 protein concentrations were significantly higher in the culture fluid from BA-stimulated explants. FGF19 induction with cholate was 81% of that found with CDCA, but deoxycholate (40%) and lithocholate (4%) were significantly less potent. The synthetic FXR agonist obeticholic acid was much more potent than CDCA with a 70-fold FGF19 stimulation at 1 μM. We concluded that FGF19 expression in human ileum is very highly responsive to BA. Changes in FGF19 induction are a potential mechanism involved in disorders of BA homeostasis.

scholarly journals Corrigendum to ‘Fibroblast growth factor 19 modulates intestinal microbiota and inflammation in presence of farnesoid x receptor’

EBioMedicine ◽  
2020 ◽  
Vol 57 ◽  
pp. 102873
Author(s):  
Raffaella Maria Gadaleta ◽  
Oihane Garcia-Irigoyen ◽  
Marica Cariello ◽  
Natasha Scialpi ◽  
Claudia Peres ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Intestinal Microbiota ◽  
Farnesoid X Receptor ◽  
Fibroblast Growth ◽  
Fibroblast Growth Factor 19

scholarly journals The hormone Fibroblast Growth Factor 19 stimulates water intake

2021 ◽  
Author(s):  
José Ursic-Bedoya ◽  
Carine Chavey ◽  
Lucy Meunier ◽  
Guillaume Desandré ◽  
Anne-Marie Dupuy ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Water Intake ◽  
Metabolic Disorders ◽  
Fibroblast Growth ◽  
Metabolic Functions ◽  
The Central Nervous System ◽  
Ongoing Development ◽  
Fibroblast Growth Factor 19

Fibroblast growth factor 19 (FGF19) is a hormone with pleiotropic metabolic functions, leading to ongoing development of analogues for the treatment of metabolic disorders. On the other hand, FGF19 is overexpressed in a sub-group of hepatocellular carcinoma (HCC) patients and has oncogenic properties. It is therefore crucial to precisely define FGF19 effects, notably chronic exposure to elevated concentrations of the hormone. We used hydrodynamic gene transfer approach to generate a transgenic mouse model with long-term FGF19 hepatic overexpression. Here we describe a novel effect of FGF19, namely stimulation of water intake. This phenotype, lasting at least over a 6-month period, depends on signaling in the central nervous system and is independent of FGF21, although it mimics some of its features. We further show that HCC patients with high levels of circulating FGF19 have a reduced natremia, indicating dispogenic features. The present study provides evidence of a new activity for FGF19, which could be clinically relevant in the context of FGF19 overexpressing cancers and treatment of metabolic disorders by FGF19 analogues.

scholarly journals Dysregulated FXR-FGF19 signaling and choline metabolism are associated with gut dysbiosis and hyperplasia in a novel pig model of pediatric NASH

2020 ◽  
Vol 318 (3) ◽  
pp. G582-G609 ◽  
Author(s):  
Gabriella V. Hernandez ◽  
Victoria A. Smith ◽  
Megan Melnyk ◽  
Matthew A. Burd ◽  
Kimberly A. Sprayberry ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Nonalcoholic Steatohepatitis ◽  
Liver Lipid ◽  
Farnesoid X Receptor ◽  
Swine Model ◽  
Fibroblast Growth ◽  
Gut Dysbiosis ◽  
Gene And Protein Expression ◽  
Fibroblast Growth Factor 19

To investigate the role of bile acids (BAs) in the pathogenesis of diet-induced nonalcoholic steatohepatitis (NASH), we fed a “Western-style diet” [high fructose, high fat (HFF)] enriched with fructose, cholesterol, and saturated fat for 10 wk to juvenile Iberian pigs. We also supplemented probiotics with in vitro BA deconjugating activity to evaluate their potential therapeutic effect in NASH. Liver lipid and function, cytokines, and hormones were analyzed using commercially available kits. Metabolites, BAs, and fatty acids were measured by liquid chromatography-mass spectrometry. Histology and gene and protein expression analyses were performed using standard protocols. HFF-fed pigs developed NASH, cholestasis, and impaired enterohepatic Farnesoid-X receptor (FXR)-fibroblast growth factor 19 (FGF19) signaling in the absence of obesity and insulin resistance. Choline depletion in HFF livers was associated with decreased lipoprotein and cholesterol in serum and an increase of choline-containing phospholipids in colon contents and trimethylamine- N-oxide in the liver. Additionally, gut dysbiosis and hyperplasia increased with the severity of NASH, and were correlated with increased colonic levels of choline metabolites and secondary BAs. Supplementation of probiotics in the HFF diet enhanced NASH, inhibited hepatic autophagy, increased excretion of taurine and choline, and decreased gut microbial diversity. In conclusion, dysregulation of BA homeostasis was associated with injury and choline depletion in the liver, as well as increased biliary secretion, gut metabolism and excretion of choline-based phospholipids. Choline depletion limited lipoprotein synthesis, resulting in hepatic steatosis, whereas secondary BAs and choline-containing phospholipids in colon may have promoted dysbiosis, hyperplasia, and trimethylamine synthesis, causing further damage to the liver. NEW & NOTEWORTHY Impaired Farnesoid-X receptor (FXR)-fibroblast growth factor 19 (FGF19) signaling and cholestasis has been described in nonalcoholic fatty liver disease (NAFLD) patients. However, therapeutic interventions with FXR agonists have produced contradictory results. In a swine model of pediatric nonalcoholic steatohepatitis (NASH), we show that the uncoupling of intestinal FXR-FGF19 signaling and a decrease in FGF19 levels are associated with a choline-deficient phenotype of NASH and increased choline excretion in the gut, with the subsequent dysbiosis, colonic hyperplasia, and accumulation of trimethylamine- N-oxide in the liver.

scholarly journals Fibroblast Growth Factor 19 modulates intestinal microbiota and inflammation in presence of Farnesoid X Receptor

EBioMedicine ◽  
2020 ◽  
Vol 54 ◽  
pp. 102719 ◽  
Author(s):  
Raffaella Maria Gadaleta ◽  
Oihane Garcia-Irigoyen ◽  
Marica Cariello ◽  
Natasha Scialpi ◽  
Claudia Peres ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Intestinal Microbiota ◽  
Farnesoid X Receptor ◽  
Fibroblast Growth ◽  
Fibroblast Growth Factor 19
Sign in / Sign up

Export Citation Format

Share Document