| First Author | Takahashi S | Year | 2016 |
| Journal | J Lipid Res | Volume | 57 |
| Issue | 12 | Pages | 2130-2137 |
| PubMed ID | 27638959 | Mgi Jnum | J:237369 |
| Mgi Id | MGI:5812623 | Doi | 10.1194/jlr.M071183 |
| Citation | Takahashi S, et al. (2016) Cyp2c70 is responsible for the species difference in bile acid metabolism between mice and humans. J Lipid Res 57(12):2130-2137 |
| abstractText | Bile acids are synthesized from cholesterol in the liver and subjected to multiple metabolic biotransformations in hepatocytes, including oxidation by cytochromes P450 (CYPs) and conjugation with taurine, glycine, glucuronic acid, and sulfate. Mice and rats can hydroxylate chenodeoxycholic acid (CDCA) at the 6beta-position to form alpha-muricholic acid (MCA) and ursodeoxycholic acid (UDCA) to form beta-MCA. However, MCA is not formed in humans to any appreciable degree and the mechanism for this species difference is not known. Comparison of several Cyp-null mouse lines revealed that alpha-MCA and beta-MCA were not detected in the liver samples from Cyp2c-cluster null (Cyp2c-null) mice. Global bile acid analysis further revealed the absence of MCAs and their conjugated derivatives, and high concentrations of CDCA and UDCA in Cyp2c-null mouse cecum and feces. Analysis of recombinant CYPs revealed that alpha-MCA and beta-MCA were produced by oxidation of CDCA and UDCA by Cyp2c70, respectively. CYP2C9-humanized mice have similar bile acid metabolites as the Cyp2c-null mice, indicating that human CYP2C9 does not oxidize CDCA and UDCA, thus explaining the species differences in production of MCA. Because humans do not produce MCA, they lack tauro-beta-MCA, a farnesoid X receptor antagonist in mouse that modulates obesity, insulin resistance, and hepatosteatosis. |
