title: Defects in gallbladder emptying and bile Acid homeostasis in mice with cystic fibrosis transmembrane conductance regulator deficiencies.
abstract: OBJECTIVE
  Patients with cystic fibrosis (CF) have poorly defined defects in biliary function. We evaluated the effects of cystic fibrosis transmembrane conductance regulator (CFTR) deficiency on the enterohepatic disposition of bile acids (BAs).
  
  
  METHODS
  Bile secretion and BA homeostasis were investigated in Cftr(tm1Unc) (Cftr-/-) and CftrΔF508 (ΔF508) mice.
  
  
  RESULTS
  Cftr-/- and ΔF508 mice did not grow to normal size, but did not have liver abnormalities. The gallbladders of Cftr-/- mice were enlarged and had defects in emptying, based on (99m)technetium-mebrofenin scintigraphy or post-prandial variations in gallbladder volume; gallbladder contraction in response to cholecystokinin-8 was normal. Cftr-/- mice had abnormal gallbladder bile and duodenal acidity, and overexpressed the vasoactive intestinal peptide-a myorelaxant factor for the gallbladder. The BA pool was larger in Cftr-/- than wild-type mice, although there were no differences in fecal loss of BAs. Amounts of secondary BAs in portal blood, liver, and bile of Cftr-/- mice were much lower than normal. Expression of genes that are induced by BAs, including fibroblast growth factor-15 and BA transporters, was lower in the ileum but higher in the gallbladders of Cftr-/- mice, compared with wild-type mice, whereas enzymes that synthesize BA were down-regulated in livers of Cftr-/- mice. This indicates that BAs underwent a cholecystohepatic shunt, which was confirmed using cholyl-(Ne-NBD)-lysine as a tracer. In Cftr-/- mice, cholecystectomy reversed most changes in gene expression and partially restored circulating levels of secondary BAs. The ΔF508 mice overexpressed vasoactive intestinal peptide and had defects in gallbladder emptying and in levels of secondary BAs, but these features were less severe than in Cftr-/- mice.
  
  
  CONCLUSIONS
  Cftr-/- and CftrΔF508 mice have defects in gallbladder emptying that disrupt enterohepatic circulation of BAs. These defects create a shunt pathway that restricts the amount of toxic secondary BAs that enter the liver.
authors.affiliation: UPMC Univ Paris 06 and INSERM, UMR_S 938, CdR Saint-Antoine, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Debray
authors.forename: Dominique
authors.initials: D
authors.lastname: Rainteau
authors.forename: Véronique
authors.initials: V
authors.lastname: Barbu
authors.forename: Myriam
authors.initials: M
authors.lastname: Rouahi
authors.forename: Haquima
authors.initials: H
authors.lastname: El Mourabit
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Lerondel
authors.forename: Colette
authors.initials: C
authors.lastname: Rey
authors.forename: Lydie
authors.initials: L
authors.lastname: Humbert
authors.forename: Dominique
authors.initials: D
authors.lastname: Wendum
authors.forename: Charles-Henry
authors.initials: CH
authors.lastname: Cottart
authors.forename: Paul
authors.initials: P
authors.lastname: Dawson
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chignard
authors.forename: Chantal
authors.initials: C
authors.lastname: Housset
mesh_terms: D000818:Animals; D001646:Bile; D001647:Bile Acids and Salts / Q000378:metabolism*; D002763:Cholecystectomy; D003550:Cystic Fibrosis / Q000503:physiopathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000172:deficiency* / Q000502:physiology; D016473:Gallbladder Emptying / Q000502:physiology*; D006706:Homeostasis / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D001647:Bile Acids and Salts; D019005:Cystic Fibrosis Transmembrane Conductance Regulator