| Bile acids (BAs) possess a number of effects on hepatic lipid and carbohydrate metabolism, inflammation, fibrosis, and carcinogenesis through nuclear and transmembrane receptors. A mouse is the most commonly used laboratory animal to extrapolate the roles of BAs in human hepatobiliary diseases, but the composition of BAs is very different between these species. Chenodeoxycholic acid (CDCA) is one of the end products of BA biosynthetic pathways in human liver, but mouse liver further metabolizes to muricholic acids due to the expression of hepatic CDCA 6β-hydroxylase. CDCA is cytotoxic and the most potent physiological agonist of farnesoid X receptor (FXR). In addition, primary BAs, cholic acid and CDCA, are 7α-dehydroxylated by intestinal bacteria and transformed into deoxycholic acid (DCA) and lithocholic acid (LCA), respectively. In mice but not in humans, these secondary BAs revert to primary BAs due to the expression of hepatic BA 7α-hydroxylase. DCA and LCA are potent physiological agonists of Takeda G-protein receptor 5 (TGR5) and are believed to be cytotoxic and carcinogenic. Therefore, BA composition is a crucial factor to create relevant mouse models of human diseases. Here we report, for the first time, the phenotypes of 3 mice models disrupted CDCA 6β-hydroxylase alone, BA 7α-hydroxylase alone, and both enzymes. These mice appear to be more useful models for investigating human hepatobiliary diseases compared with conventional mice. |
