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Impaired oxidoreduction by 11β-hydroxysteroid dehydrogenase 1 results in the accumulation of 7-oxolithocholic acid.
- Source :
-
Journal of lipid research [J Lipid Res] 2013 Oct; Vol. 54 (10), pp. 2874-83. Date of Electronic Publication: 2013 Aug 09. - Publication Year :
- 2013
-
Abstract
- 11β-hydroxysteroid dehydrogenase type 1 (11β-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 11β-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 11β-HSD1 in the oxidoreduction of 7-oxoLCA and compare its level and metabolism in several species. Hepatic microsomes from liver-specific 11β-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 11β-HSD1 deficiency. Moreover, comparative enzymology of 11β-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 11β-HSD1, and the lack of this activity leads to the accumulation of these bile acids in guinea-pigs and 11β-HSD1-deficient mice. Thus, 7-oxoLCA and its conjugates may serve as biomarkers of impaired 11β-HSD1 activity.
- Subjects :
- 11-beta-Hydroxysteroid Dehydrogenase Type 1 chemistry
11-beta-Hydroxysteroid Dehydrogenase Type 1 deficiency
Animals
Cricetinae
Dogs
Guinea Pigs
Humans
Lithocholic Acid blood
Lithocholic Acid metabolism
Male
Mesocricetus
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Microsomes, Liver enzymology
Molecular Docking Simulation
Oxidation-Reduction
Rats
Rats, Sprague-Dawley
Rats, Wistar
Species Specificity
11-beta-Hydroxysteroid Dehydrogenase Type 1 genetics
Lithocholic Acid analogs & derivatives
Subjects
Details
- Language :
- English
- ISSN :
- 1539-7262
- Volume :
- 54
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Journal of lipid research
- Publication Type :
- Academic Journal
- Accession number :
- 23933573
- Full Text :
- https://doi.org/10.1194/jlr.M042499