Impaired oxidoreduction by 11?-hydroxysteroid dehydrogenase 1 results in the accumulation of 7-oxolithocholic acid.

ABSTRACT: 11?-hydroxysteroid dehydrogenase type 1 (11?-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 11?-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 11?-HSD1 in the oxidoreduction of 7-oxoLCA and compare its level and metabolism in several species. Hepatic microsomes from liver-specific 11?-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 11?-HSD1 deficiency. Moreover, comparative enzymology of 11?-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 11?-HSD1, and the lack of this activity leads to the accumulation of these bile acids in guinea-pigs and 11?-HSD1-deficient mice. Thus, 7-oxoLCA and its conjugates may serve as biomarkers of impaired 11?-HSD1 activity.

SUBMITTER: Penno CA 

PROVIDER: S-EPMC3770100 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature