title: Potent stimulation of fibroblast growth factor 19 expression in the human ileum by bile acids.
abstract: 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.
authors.affiliation: Section of Hepatology and Gastroenterology, Department of Medicine, Imperial College Londonand Imperial College Healthcare, London, UK.
authors.forename: Justine H
authors.initials: JH
authors.lastname: Zhang
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Nolan
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Kennie
authors.forename: Ian M
authors.initials: IM
authors.lastname: Johnston
authors.forename: Tracy
authors.initials: T
authors.lastname: Dew
authors.forename: Peter H
authors.initials: PH
authors.lastname: Dixon
authors.forename: Catherine
authors.initials: C
authors.lastname: Williamson
authors.forename: Julian R F
authors.initials: JR
authors.lastname: Walters
mesh_terms: D000328:Adult; D001647:Bile Acids and Salts / Q000378:metabolism / Q000494:pharmacology*; D001706:Biopsy; D002635:Chenodeoxycholic Acid / Q000494:pharmacology; D003106:Colon / Q000378:metabolism; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D004764:Enterohepatic Circulation / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D005346:Fibroblast Growth Factors / Q000096:biosynthesis*; D015870:Gene Expression / Q000187:drug effects; D005999:Glycochenodeoxycholic Acid / Q000494:pharmacology; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000378:metabolism*; D009924:Organ Culture Techniques; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D060888:Real-Time Polymerase Chain Reaction; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects; D013268:Stimulation, Chemical; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D002635:Chenodeoxycholic Acid; D018076:DNA, Complementary; D005346:Fibroblast Growth Factors; D005999:Glycochenodeoxycholic Acid; D012313:RNA; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C117476:FGF19 protein, human
keywords: bile acid diarrhea; enterohepatic circulation; intestine; organ culture