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.
Highlights
BILE ACIDS (BA) undergo an enterohepatic circulation
FXR activation was only observed with taurine- and glycine-conjugated BA when the cell lines were transfected with the apical membrane sodium bile acid transporter (ASBT), which would allow uptake of these more polar conjugated BA
Enterocytes in the terminal ileum are specialized to take up conjugated BA such as glyco-chenodeoxycholic acid (GCDCA) and tauro-chenodeoxycholic acid from the intestinal lumen
Summary
BILE ACIDS (BA) undergo an enterohepatic circulation. They are synthesized in the liver, secreted into the duodenum, reabsorbed in the terminal ileum, and recirculated back to the liver via the portal vein. Concentrations of the major physiological primary BA, unconjugated chenodeoxycholic acid (CDCA), ranging from 3–100 mol/l, have been demonstrated to be effective in activating FXR-mediated BA-response elements in reporter genes in human CV-1 cell lines [25, 31, 40]. FXR activation was only observed with taurine- and glycine-conjugated BA when the cell lines were transfected with the apical membrane sodium bile acid transporter (ASBT), which would allow uptake of these more polar conjugated BA. Enterocytes in the terminal ileum are specialized to take up conjugated BA such as glyco-chenodeoxycholic acid (GCDCA) and tauro-chenodeoxycholic acid from the intestinal lumen This function is mediated by the expression of the ileal ASBT. BA bind to the ileal bile acid-binding protein (IBABP) and are extruded at the basolateral membrane by the organic solute transporter (OST)-␣/ heterodimer [8]
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