title: Effect of cholecystectomy on bile acid synthesis and circulating levels of fibroblast growth factor 19.
abstract: Background and rationale for the study. FGF19/15 is a gut-derived hormone presumably governing bile acid (BA) synthesis and gallbladder (GB) refilling. FGF19 mRNA is present in human GB cholangiocytes (hGBECs); however, the physiological significance of GB-derived FGF19 remains unknown. We investigated whether hGBECs secrete FGF19 and the effects of cholecystectomy on serum FGF19 ([FGF19]s) and BA synthesis.
  
  
  METHODS
  FGF19 expression was assessed by qRT-PCRs and immunostaining in hGBECs and terminal ileum, and quantified in bile and serum by ELISA. Basal and BA (chenodexycholic acid, CDCA) induced FGF19 expression and secretion was analyzed in primary cultured hGBECs and GB-d1 cell line. Pre and postprandial serum changes in [FGF19]s, 7α-hydroxy-4-cholestene-3-one (C4, a marker of BA synthesis) and BA were evaluated in plasma of gallstone disease patients at baseline and after cholecystectomy.
  
  
  RESULTS
  FGF19 mRNA levels were ~250-fold higher in hGBECs compared to distal ileum. GB bile contained ~23-fold higher FGF19 levels compared to serum (p < 0.0001). CDCA induced dose-dependent expression and secretion of FGF19 in hGBECs and GB-d1 cells. Cholecystectomy increased plasma BA synthesis ≥ 2-fold (p < 0.0001), and altered the diurnal rhythm and significantly reduced [FGF19]s noon peak. BA serum levels, serum cholesterol and triglyceride content remained unchanged.
  
  
  CONCLUSIONS
  In conclusion human GB cholangiocytes constitutively express and secrete high levels of FGF19 in a process regulated by BA. Resection of this organ doubles BA synthesis concomitantly with changes in [FGF19]s. These findings suggest a potential connection between GB cholangiocytes-derived FGF19 and BA metabolism that could lead to metabolic dysregulation following cholecystectomy.
authors.affiliation: Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile. Santiago, Chile.
authors.forename: Francisco
authors.initials: F
authors.lastname: Barrera
authors.affiliation: Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile. Santiago, Chile.
authors.forename: Lorena
authors.initials: L
authors.lastname: Azócar
authors.affiliation: Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile. Santiago, Chile.
authors.forename: Héctor
authors.initials: H
authors.lastname: Molina
authors.affiliation: Anatomía Patológica, Facultad de Medicina, Pontificia Universidad Católica de Chile. Santiago, Chile.
authors.forename: Kurt A
authors.initials: KA
authors.lastname: Schalper
authors.affiliation: Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile. Santiago, Chile.
authors.forename: Marcia
authors.initials: M
authors.lastname: Ocares
authors.affiliation: Nutrición y Diabetes, Facultad de Medicina, Pontificia Universidad Católica de Chile. Santiago, Chile.
authors.forename: Jessica
authors.initials: J
authors.lastname: Liberona
authors.affiliation: Salud Pública y Facultad de Medicina, Pontificia Universidad Católica de Chile. Santiago, Chile.
authors.forename: Luis
authors.initials: L
authors.lastname: Villarroel
authors.affiliation: Cirugía Digestiva, Facultad de Medicina, Pontificia Universidad Católica de Chile. Santiago, Chile.
authors.forename: Fernando
authors.initials: F
authors.lastname: Pimentel
authors.affiliation: Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile. Santiago, Chile.
authors.forename: Rosa M
authors.initials: RM
authors.lastname: Pérez-Ayuso
authors.affiliation: Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile. Santiago, Chile.
authors.forename: Flavio
authors.initials: F
authors.lastname: Nervi
authors.affiliation: Department of Pediatrics and Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Albert K
authors.initials: AK
authors.lastname: Groen
authors.affiliation: Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile. Santiago, Chile.
authors.forename: Juan F
authors.initials: JF
authors.lastname: Miquel
mesh_terms: D000328:Adult; D000368:Aged; D001647:Bile Acids and Salts / Q000096:biosynthesis*; D016022:Case-Control Studies; D002460:Cell Line; D002763:Cholecystectomy; D002940:Circadian Rhythm; D005260:Female; D005346:Fibroblast Growth Factors / Q000097:blood* / Q000235:genetics; D005704:Gallbladder / Q000378:metabolism* / Q000601:surgery*; D042882:Gallstones / Q000097:blood* / Q000235:genetics / Q000601:surgery*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D012333:RNA, Messenger / Q000097:blood; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D001647:Bile Acids and Salts; C117476:FGF19 protein, human; D012333:RNA, Messenger; D005346:Fibroblast Growth Factors