Ursodeoxycholate modulates bile flow and bile salt pool independently from the cystic fibrosis transmembrane regulator (Cftr) in mice

Frank A. J. A. Bodewes*, Marjan Wouthuyzen-Bakker, Marcel J. Bijvelds, Rick Havinga, Hugo R. de Jonge, Henkjan J. Verkade

*Corresponding author for this work

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Abstract

Bodewes FAJA, Wouthuyzen-Bakker M, Bijvelds MJ, Havinga R, de Jonge HR, Verkade HJ. Ursodeoxycholate modulates bile flow and bile salt pool independently from the cystic fibrosis transmembrane regulator (Cftr) in mice. Am J Physiol Gastrointest Liver Physiol 302: G1035-G1042, 2012. First published February 2, 2012; doi:10.1152ajpgi.00258.2011.-Cystic fibrosis liver disease (CFLD) is treated with ursodeoxycholate (UDCA). Our aim was to evaluate, in cystic fibrosis transmembrane regulator knockout (Cftr(-/-)) mice and wild-type controls, whether the supposed therapeutic action of UDCA is mediated via choleretic activity or effects on bile salt metabolism. Cftr(-/-) mice and controls, under general anesthesia, were intravenously infused with tauroursodeoxycholate (TUDCA) in increasing dosage or were fed either standard or UDCA-enriched chow (0.5% wtwt) for 3 wk. Bile flow and bile composition were characterized. In chow-fed mice, we analyzed bile salt synthesis and pool size of cholate (CA). In both Cftr(-/-) and controls intravenous TUDCA stimulated bile flow by similar to 250% and dietary UDCA by similar to 500%, compared with untreated animals (P <0.05). In non-UDCA-treated Cftr(-/-) mice, the proportion of CA in bile was higher compared with that in controls (61 +/- 4 vs. 46 +/- 4%; P <0.05), accompanied by an increased CA synthesis [16 +/- 1 vs. 10 +/- 2 mu mol.h(-1).100 g body wt (BW)(-1); P <0.05] and CA pool size (28 +/- 3 vs. 19 +/- 1 mu mol/100 g BW; P <0.05). In both Cftr(-/-) and controls, UDCA treatment drastically reduced the proportion of CA in bile below 5% and diminished CA synthesis (2.3 +/- 0.3 vs. 2.2 +/- 0.4 mu mol.day(-1).100 g BW-1; nonsignificant) and CA pool size (3.6 +/- 0.6 vs. 1.5 +/- 0.3 mu mol/100 g BW; P <0.05). Acute TUDCA infusion and chronic UDCA treatment both stimulate bile flow in cystic fibrosis conditions independently from Cftr function. Chronic UDCA treatment reduces the hydrophobicity of the bile salt pool in Cftr(-/-) mice. These results support a potential beneficial effect of UDCA on bile flow and bile salt metabolism in cystic fibrosis conditions.

Original languageEnglish
Pages (from-to)G1035-G1042
Number of pages8
JournalAmerican Journal of Physiology-Gastrointestinal and Liver Physiology
Volume302
Issue number9
DOIs
Publication statusPublished - May-2012

Keywords

  • ursodeoxycholic acid
  • cystic fibrosis liver disease
  • mouse model
  • bile salt kinetics
  • PRIMARY SCLEROSING CHOLANGITIS
  • CHOLESTATIC LIVER-DISEASE
  • ACID KINETICS
  • ENTEROHEPATIC CIRCULATION
  • CONDUCTANCE REGULATOR
  • ISOTOPE-DILUTION
  • DEFICIENT MICE
  • CHOLIC-ACID
  • SECRETION
  • CHOLESTEROL

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