272* Ursodeoxycholate reduces cholate biosynthesis rate and pool size in Cftr−/− mice

Abstract

Objectives: Ursodeoxycholate (UDCA) is used as treatment for cystic fibrosis liver disease (CFLD). It is hypothesized that the therapeutic action of UDCA is either mediated via choleretic activity or via effects on bile salt (BS) metabolism. However, the effects of UDCA on biliary BS composition and the enterohepatic circulation of bile salts in CF conditions are unclear. Methods: Cfr-/- and control mice were either fed UDCA enriched chow (0.5% wt/wt) for 3 weeks. We evaluated the effects on the biliary BS composition and on the biosynthesis rate (SR) and pool size (PS) of cholate (CA), the mayor hydrophobic BS. Results: In non UDCA treated Cftr- mice the fractional biliary CA content was significantly higher compared to controls (61% vs. 46%, resp.; p <0.01). However, the biliary UDCA enrichment was ∼50% lower in Cftr- mice compared to controls (3% vs. 6%, resp.; p <0.01). Both the SR (16±1 vs.10±2 μmol-100g-1 BW-1-day, resp.; p <0.01) and PS (28±3 vs. 18±1 μmol-100g-1-BW-1, resp.; p <0.01) were significantly higher in Cfr-/- mice compared to controls. After UDCA the biliary BS composition consisted for more than ∼80% of UDCA in both Cftr-mice and controls. Both in Cftr- mice and controls UDCA treatment drastically diminished the SR (-85% and -81%, resp. each p <0.01) and PS (-87% and -92%, resp. each p <0.01). Conclusion: Cftr- - mice have a more hydrophobic biliary BS composition compared to controls. In Cftr- - mice the SR and the PS of CA are increased compared to controls, leading to a more cytotoxic BS profile. UDCA reduces the hydrophobic BS profile of Cftr-∼ mice. This favorable effect of UDCA on bile salt metabolism could contribute to the assumed beneficial effects of UDCA in CFLD.