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11β-Hydroxysteroid dehydrogenase type 1 contributes to the balance between 7-keto- and 7-hydroxy-oxysterols in vivo
11β-Hydroxysteroid dehydrogenase 1 (11βHSD1; EC 1.1.1.146) generates active glucocorticoids from inert 11-keto metabolites. However, it can also metabolize alternative substrates, including 7β-hydroxy- and 7-keto-cholesterol (7βOHC, 7KC). This has been demonstrated in vitro but its consequences in v...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier Science
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3694296/ https://www.ncbi.nlm.nih.gov/pubmed/23415904 http://dx.doi.org/10.1016/j.bcp.2013.02.002 |
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author | Mitić, Tijana Shave, Steven Semjonous, Nina McNae, Iain Cobice, Diego F. Lavery, Gareth G. Webster, Scott P. Hadoke, Patrick W.F. Walker, Brian R. Andrew, Ruth |
author_facet | Mitić, Tijana Shave, Steven Semjonous, Nina McNae, Iain Cobice, Diego F. Lavery, Gareth G. Webster, Scott P. Hadoke, Patrick W.F. Walker, Brian R. Andrew, Ruth |
author_sort | Mitić, Tijana |
collection | PubMed |
description | 11β-Hydroxysteroid dehydrogenase 1 (11βHSD1; EC 1.1.1.146) generates active glucocorticoids from inert 11-keto metabolites. However, it can also metabolize alternative substrates, including 7β-hydroxy- and 7-keto-cholesterol (7βOHC, 7KC). This has been demonstrated in vitro but its consequences in vivo are uncertain. We used genetically modified mice to investigate the contribution of 11βHSD1 to the balance of circulating levels of 7KC and 7βOHC in vivo, and dissected in vitro the kinetics of the interactions between oxysterols and glucocorticoids for metabolism by the mouse enzyme. Circulating levels of 7KC and 7βOHC in mice were 91.3 ± 22.3 and 22.6 ± 5.7 nM respectively, increasing to 1240 ± 220 and 406 ± 39 nM in ApoE(−/−) mice receiving atherogenic western diet. Disruption of 11βHSD1 in mice increased (p < 0.05) the 7KC/7βOHC ratio in plasma (by 20%) and also in isolated microsomes (2 fold). The 7KC/7βOHC ratio was similarly increased when NADPH generation was restricted by disruption of hexose-6-phosphate dehydrogenase. Reduction and oxidation of 7-oxysterols by murine 11βHSD1 proceeded more slowly and substrate affinity was lower than for glucocorticoids. in vitro 7βOHC was a competitive inhibitor of oxidation of corticosterone (K(i) = 0.9 μM), whereas 7KC only weakly inhibited reduction of 11-dehydrocorticosterone. However, supplementation of 7-oxysterols in cultured cells, secondary to cholesterol loading, preferentially slowed reduction of glucocorticoids, rather than oxidation. Thus, in mouse, 11βHSD1 influenced the abundance and balance of circulating and tissue levels of 7βOHC and 7KC, promoting reduction of 7KC. In health, 7-oxysterols are unlikely to regulate glucocorticoid metabolism. However, in hyperlipidaemia, 7-oxysterols may inhibit glucocorticoid metabolism and modulate signaling through corticosteroid receptors. |
format | Online Article Text |
id | pubmed-3694296 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Elsevier Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-36942962013-07-01 11β-Hydroxysteroid dehydrogenase type 1 contributes to the balance between 7-keto- and 7-hydroxy-oxysterols in vivo Mitić, Tijana Shave, Steven Semjonous, Nina McNae, Iain Cobice, Diego F. Lavery, Gareth G. Webster, Scott P. Hadoke, Patrick W.F. Walker, Brian R. Andrew, Ruth Biochem Pharmacol Article 11β-Hydroxysteroid dehydrogenase 1 (11βHSD1; EC 1.1.1.146) generates active glucocorticoids from inert 11-keto metabolites. However, it can also metabolize alternative substrates, including 7β-hydroxy- and 7-keto-cholesterol (7βOHC, 7KC). This has been demonstrated in vitro but its consequences in vivo are uncertain. We used genetically modified mice to investigate the contribution of 11βHSD1 to the balance of circulating levels of 7KC and 7βOHC in vivo, and dissected in vitro the kinetics of the interactions between oxysterols and glucocorticoids for metabolism by the mouse enzyme. Circulating levels of 7KC and 7βOHC in mice were 91.3 ± 22.3 and 22.6 ± 5.7 nM respectively, increasing to 1240 ± 220 and 406 ± 39 nM in ApoE(−/−) mice receiving atherogenic western diet. Disruption of 11βHSD1 in mice increased (p < 0.05) the 7KC/7βOHC ratio in plasma (by 20%) and also in isolated microsomes (2 fold). The 7KC/7βOHC ratio was similarly increased when NADPH generation was restricted by disruption of hexose-6-phosphate dehydrogenase. Reduction and oxidation of 7-oxysterols by murine 11βHSD1 proceeded more slowly and substrate affinity was lower than for glucocorticoids. in vitro 7βOHC was a competitive inhibitor of oxidation of corticosterone (K(i) = 0.9 μM), whereas 7KC only weakly inhibited reduction of 11-dehydrocorticosterone. However, supplementation of 7-oxysterols in cultured cells, secondary to cholesterol loading, preferentially slowed reduction of glucocorticoids, rather than oxidation. Thus, in mouse, 11βHSD1 influenced the abundance and balance of circulating and tissue levels of 7βOHC and 7KC, promoting reduction of 7KC. In health, 7-oxysterols are unlikely to regulate glucocorticoid metabolism. However, in hyperlipidaemia, 7-oxysterols may inhibit glucocorticoid metabolism and modulate signaling through corticosteroid receptors. Elsevier Science 2013-07-01 /pmc/articles/PMC3694296/ /pubmed/23415904 http://dx.doi.org/10.1016/j.bcp.2013.02.002 Text en © 2013 Elsevier Inc. https://creativecommons.org/licenses/by/3.0/ Open Access under CC BY 3.0 (https://creativecommons.org/licenses/by/3.0/) license |
spellingShingle | Article Mitić, Tijana Shave, Steven Semjonous, Nina McNae, Iain Cobice, Diego F. Lavery, Gareth G. Webster, Scott P. Hadoke, Patrick W.F. Walker, Brian R. Andrew, Ruth 11β-Hydroxysteroid dehydrogenase type 1 contributes to the balance between 7-keto- and 7-hydroxy-oxysterols in vivo |
title | 11β-Hydroxysteroid dehydrogenase type 1 contributes to the balance between 7-keto- and 7-hydroxy-oxysterols in vivo |
title_full | 11β-Hydroxysteroid dehydrogenase type 1 contributes to the balance between 7-keto- and 7-hydroxy-oxysterols in vivo |
title_fullStr | 11β-Hydroxysteroid dehydrogenase type 1 contributes to the balance between 7-keto- and 7-hydroxy-oxysterols in vivo |
title_full_unstemmed | 11β-Hydroxysteroid dehydrogenase type 1 contributes to the balance between 7-keto- and 7-hydroxy-oxysterols in vivo |
title_short | 11β-Hydroxysteroid dehydrogenase type 1 contributes to the balance between 7-keto- and 7-hydroxy-oxysterols in vivo |
title_sort | 11β-hydroxysteroid dehydrogenase type 1 contributes to the balance between 7-keto- and 7-hydroxy-oxysterols in vivo |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3694296/ https://www.ncbi.nlm.nih.gov/pubmed/23415904 http://dx.doi.org/10.1016/j.bcp.2013.02.002 |
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