| First Author | Penno CA | Year | 2013 |
| Journal | J Lipid Res | Volume | 54 |
| Issue | 10 | Pages | 2874-83 |
| PubMed ID | 23933573 | Mgi Jnum | J:202616 |
| Mgi Id | MGI:5520120 | Doi | 10.1194/jlr.M042499 |
| Citation | Penno CA, et al. (2013) Impaired oxidoreduction by 11beta-hydroxysteroid dehydrogenase 1 results in the accumulation of 7-oxolithocholic acid. J Lipid Res 54(10):2874-83 |
| abstractText | 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) mediates glucocorticoid activation and is currently considered as therapeutic target to treat metabolic diseases; however, biomarkers to assess its activity in vivo are still lacking. Recent in vitro experiments suggested that human 11beta-HSD1 metabolizes the secondary bile acid 7-oxolithocholic acid (7-oxoLCA) to chenodeoxycholic acid (CDCA) and minor amounts of ursodeoxycholic acid (UDCA). Here, we provide evidence from in vitro and in vivo studies for a major role of 11beta-HSD1 in the oxidoreduction of 7-oxoLCA and compare its level and metabolism in several species. Hepatic microsomes from liver-specific 11beta-HSD1-deficient mice were devoid of 7-oxoLCA oxidoreductase activity. Importantly, circulating and intrahepatic levels of 7-oxoLCA and its taurine conjugate were significantly elevated in mouse models of 11beta-HSD1 deficiency. Moreover, comparative enzymology of 11beta-HSD1-dependent oxidoreduction of 7-oxoLCA revealed that the guinea-pig enzyme is devoid of 7-oxoLCA oxidoreductase activity. Unlike in other species, 7-oxoLCA and its glycine conjugate are major bile acids in guinea-pigs. In conclusion, the oxidoreduction of 7-oxoLCA and its conjugated metabolites are catalyzed by 11beta-HSD1, and the lack of this activity leads to the accumulation of these bile acids in guinea-pigs and 11beta-HSD1-deficient mice. Thus, 7-oxoLCA and its conjugates may serve as biomarkers of impaired 11beta-HSD1 activity. |
