Journal
JOURNAL OF LIPID RESEARCH
Volume 54, Issue 10, Pages 2874-2883Publisher
ELSEVIER
DOI: 10.1194/jlr.M042499
Keywords
bile acid; metabolism; species; biomarker; glucocorticoid; metabolic disease
Categories
Funding
- Swiss National Science Foundation [31003A_140961]
- David Philips Fellowship, Biotechnology and Biological Sciences Research Council (BBSRC) [BB/G023468/1]
- Novartis Research Foundation
- Austrian Academy of Sciences (OAW) Grant
- Young Talents Grants (Nachwuchsforderung), University of Innsbruck
- Erika Cremer Habilitation Program, University of Innsbruck
- Biotechnology and Biological Sciences Research Council [BB/G023468/1] Funding Source: researchfish
- BBSRC [BB/G023468/1] Funding Source: UKRI
- Swiss National Science Foundation (SNF) [31003A_140961] Funding Source: Swiss National Science Foundation (SNF)
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11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-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 beta-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 beta-HSD1 in the oxidoreduction of 7-oxoLCA and compare its level and metabolism in several species. Hepatic microsomes from liver-specific 11 beta-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 beta-HSD1 deficiency. Moreover, comparative enzymology of 11 beta-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.(jlr) In conclusion, the oxidoreduction of 7-oxoLCA and its conjugated metabolites are catalyzed by 11 beta-HSD1, and the lack of this activity leads to the accumulation of these bile acids in guinea-pigs and 11 beta-HSD1-deficient mice. Thus, 7-oxoLCA and its conjugates may serve as biomarkers of impaired 11 beta-HSD1 activity.
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