Ursodeoxycholate modulates bile flow and bile salt pool independently from the cystic fibrosis transmembrane regulator (Cftr) in mice.
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% wt/wt) 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 ∼250% and dietary UDCA by ∼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 μmol·h(-1)·100 g body wt (BW)(-1); P < 0.05] and CA pool size (28 ± 3 vs. 19 ± 1 μmol/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 μmol·day(-1)·100 g BW(-1); nonsignificant) and CA pool size (3.6 ± 0.6 vs. 1.5 ± 0.3 μmol/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.
Department of Pediatrics, University of Groningen, Beatrix Children's Hospital, University Medical Center, Groningen, The Netherlands. f.a.j.a.bodewes@umcg.nl
Frank A J A
FA
Bodewes
Marjan
M
Wouthuyzen-Bakker
Marcel J
MJ
Bijvelds
Rick
R
Havinga
Hugo R
HR
de Jonge
Henkjan J
HJ
Verkade
D000818:Animals; D001646:Bile / Q000378:metabolism*; D001647:Bile Acids and Salts / Q000378:metabolism*; D002756:Cholagogues and Choleretics; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016896:Treatment Outcome; D014580:Ursodeoxycholic Acid / Q000008:administration & dosage* / Q000378:metabolism
D001647:Bile Acids and Salts; D002756:Cholagogues and Choleretics; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D014580:Ursodeoxycholic Acid