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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.
Original language | English |
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Pages (from-to) | 2874-83 |
Number of pages | 10 |
Journal | Journal of Lipid Research |
Volume | 54 |
Issue number | 10 |
DOIs | |
Publication status | Published - Oct 2013 |
Keywords
- 11-beta-Hydroxysteroid Dehydrogenase Type 1
- Animals
- Cricetinae
- Dogs
- Guinea Pigs
- Humans
- Lithocholic Acid
- Male
- Mesocricetus
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Mice, Knockout
- Microsomes, Liver
- Molecular Docking Simulation
- Oxidation-Reduction
- Rats
- Rats, Sprague-Dawley
- Rats, Wistar
- Species Specificity
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- 1 Finished
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Investigating Hexose-6-Phosphate Dehydrogenase in the Control of Skeletal Muscle Function and Carbohydrate Metabolism
Lavery, G.
Biotechnology & Biological Sciences Research Council
1/09/09 → 31/08/14
Project: Research Councils