The ratio of ursodeoxycholyltaurine to 7-oxolithocholyltaurine serves as a biomarker of decreased 11β-hydroxysteroid dehydrogenase 1 activity in mouse
© 2021 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society..
BACKGROUND AND PURPOSE: 11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) regulates tissue-specific glucocorticoid metabolism and its impaired expression and activity are associated with major diseases. Pharmacological inhibition of 11β-HSD1 is considered a promising therapeutic strategy. This study investigated whether alternative 7-oxo bile acid substrates of 11β-HSD1 or the ratios to their 7-hydroxy products can serve as biomarkers for decreased enzymatic activity.
EXPERIMENTAL APPROACH: Bile acid profiles were measured by ultra-HPLC tandem-MS in plasma and liver tissue samples of four different mouse models with decreased 11β-HSD1 activity: global (11KO) and liver-specific 11β-HSD1 knockout mice (11LKO), mice lacking hexose-6-phosphate dehydrogenase (H6pdKO) that provides cofactor NADPH for 11β-HSD1 and mice treated with the pharmacological inhibitor carbenoxolone. Additionally, 11β-HSD1 expression and activity were assessed in H6pdKO- and carbenoxolone-treated mice.
KEY RESULTS: The enzyme product to substrate ratios were more reliable markers of 11β-HSD1 activity than absolute levels due to large inter-individual variations in bile acid concentrations. The ratio of the 7β-hydroxylated ursodeoxycholyltaurine (UDC-Tau) to 7-oxolithocholyltaurine (7oxoLC-Tau) was diminished in plasma and liver tissue of all four mouse models and decreased in H6pdKO- and carbenoxolone-treated mice with moderately reduced 11β-HSD1 activity. The persistence of 11β-HSD1 oxoreduction activity in the face of H6PD loss indicates the existence of an alternative NADPH source in the endoplasmic reticulum.
CONCLUSIONS AND IMPLICATIONS: The plasma UDC-Tau/7oxo-LC-Tau ratio detects decreased 11β-HSD1 oxoreduction activity in different mouse models. This ratio may be a useful biomarker of decreased 11β-HSD1 activity in pathophysiological situations or upon pharmacological inhibition.
LINKED ARTICLES: This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:178 |
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| Enthalten in: |
British journal of pharmacology - 178(2021), 16 vom: 01. Aug., Seite 3309-3326 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Weingartner, Michael [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 21.09.2021 Date Revised 21.09.2021 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1111/bph.15367 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM32013234X |
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| 100 | 1 | |a Weingartner, Michael |e verfasserin |4 aut | |
| 245 | 1 | 4 | |a The ratio of ursodeoxycholyltaurine to 7-oxolithocholyltaurine serves as a biomarker of decreased 11β-hydroxysteroid dehydrogenase 1 activity in mouse |
| 264 | 1 | |c 2021 | |
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| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 21.09.2021 | ||
| 500 | |a Date Revised 21.09.2021 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2021 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. | ||
| 520 | |a BACKGROUND AND PURPOSE: 11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) regulates tissue-specific glucocorticoid metabolism and its impaired expression and activity are associated with major diseases. Pharmacological inhibition of 11β-HSD1 is considered a promising therapeutic strategy. This study investigated whether alternative 7-oxo bile acid substrates of 11β-HSD1 or the ratios to their 7-hydroxy products can serve as biomarkers for decreased enzymatic activity | ||
| 520 | |a EXPERIMENTAL APPROACH: Bile acid profiles were measured by ultra-HPLC tandem-MS in plasma and liver tissue samples of four different mouse models with decreased 11β-HSD1 activity: global (11KO) and liver-specific 11β-HSD1 knockout mice (11LKO), mice lacking hexose-6-phosphate dehydrogenase (H6pdKO) that provides cofactor NADPH for 11β-HSD1 and mice treated with the pharmacological inhibitor carbenoxolone. Additionally, 11β-HSD1 expression and activity were assessed in H6pdKO- and carbenoxolone-treated mice | ||
| 520 | |a KEY RESULTS: The enzyme product to substrate ratios were more reliable markers of 11β-HSD1 activity than absolute levels due to large inter-individual variations in bile acid concentrations. The ratio of the 7β-hydroxylated ursodeoxycholyltaurine (UDC-Tau) to 7-oxolithocholyltaurine (7oxoLC-Tau) was diminished in plasma and liver tissue of all four mouse models and decreased in H6pdKO- and carbenoxolone-treated mice with moderately reduced 11β-HSD1 activity. The persistence of 11β-HSD1 oxoreduction activity in the face of H6PD loss indicates the existence of an alternative NADPH source in the endoplasmic reticulum | ||
| 520 | |a CONCLUSIONS AND IMPLICATIONS: The plasma UDC-Tau/7oxo-LC-Tau ratio detects decreased 11β-HSD1 oxoreduction activity in different mouse models. This ratio may be a useful biomarker of decreased 11β-HSD1 activity in pathophysiological situations or upon pharmacological inhibition | ||
| 520 | |a LINKED ARTICLES: This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a 11β-hydroxysteroid dehydrogenase | |
| 650 | 4 | |a bile acid | |
| 650 | 4 | |a biomarker | |
| 650 | 4 | |a disease | |
| 650 | 4 | |a glucocorticoid | |
| 650 | 4 | |a inhibitor | |
| 650 | 7 | |a Bile Acids and Salts |2 NLM | |
| 650 | 7 | |a Biomarkers |2 NLM | |
| 650 | 7 | |a Glucocorticoids |2 NLM | |
| 650 | 7 | |a 11-beta-Hydroxysteroid Dehydrogenase Type 1 |2 NLM | |
| 650 | 7 | |a EC 1.1.1.146 |2 NLM | |
| 700 | 1 | |a Stücheli, Simon |e verfasserin |4 aut | |
| 700 | 1 | |a Kratschmar, Denise V |e verfasserin |4 aut | |
| 700 | 1 | |a Birk, Julia |e verfasserin |4 aut | |
| 700 | 1 | |a Klusonova, Petra |e verfasserin |4 aut | |
| 700 | 1 | |a Chapman, Karen E |e verfasserin |4 aut | |
| 700 | 1 | |a Lavery, Gareth G |e verfasserin |4 aut | |
| 700 | 1 | |a Odermatt, Alex |e verfasserin |4 aut | |
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