Bile acid (BA) metabolism is impaired in mice with defective peroxisomal BA synthesis

Abstract

Impairment of peroxisomal BA synthesis is a characteristic feature of Scp2 (-/-) mice. This study investigated how this may impact BA metabolism. In separate groups of male mice (n=6–9) lipid analysis of hepatic and gallbladder bile was performed. Livers and sequential intestinal fractions were harvested to isolate total RNA, homogenate and plasma membranes. Steady-state gene expression of basolateral (Slc10a1, Slc21a1) and canalicular (Abcb4, Abcb11, Abcc2) transporters was studied and correlated with serum and biliary lipids. Size and composition of the BA pool was measured by GCMS and complemented with measurement of fecal BAs. Finally, gene expression of intestinal BA transporters (Fabp6, Slc10a2) were measured. Serum BAs were higher in -/- mice and composed of nor-BAs and bile alcohols which were absent in controls. Compared with controls, the BA pool of -/- mice was reduced 3-fold and enriched more than 30-fold (p<0.01) with nor-cholate whereas chenodeoxycholic acid was reduced 7-fold (p<0.01). Despite unchanged Abcc2 gene expression, bile flow was 1.5-fold higher (p<0.05) in -/- mice. BA output was reduced 68% (p<0.01) which correlated with a significant suppression of Abcb11 gene expression. Biliary excretion of cholesterol and phospholipids were unchanged in -/- mice and no significant change of Abcb4 gene expression could be detected. In contrast to controls, Slc10a1 gene expression was induced by 40% (p<0.05) whereas no significant changed was observed for Slc21a1. Fecal BA excretion was reduced to 50% (p<0.001) in -/- mice and bile alcohols were present -/- mice but not in controls. In all mice intestinal Slc10a2 and Fabp6 expression increased from proximal to distal. However, Slc10a2 and Fabp6 expression was significantly (p<0.01) lower in -/-mice. Our findings suggest that impaired peroxisomal BA synthesis is associated with adaptive changes of BA metabolism. More hydrophilic BAs of a smaller BA pool size are poor substrates for the BA export pump and explain the lower Abcb11 expression with a reduced BA output. This may further result in increased serum BA concentrations although we were unable to document inhibition of Slc10a1 or Slc21a1 expression. Decreased Slc10a2 and Fabp6 expression implies that conservation of the more hydrophilic BA pool was achieved by inducing BA absorption in more proximal parts of the intestine.