| First Author | Weingartner M | Year | 2021 |
| Journal | Br J Pharmacol | Volume | 178 |
| Issue | 16 | Pages | 3309-3326 |
| PubMed ID | 33450045 | Mgi Jnum | J:360191 |
| Mgi Id | MGI:7660870 | Doi | 10.1111/bph.15367 |
| Citation | Weingartner M, et al. (2021) The ratio of ursodeoxycholyltaurine to 7-oxolithocholyltaurine serves as a biomarker of decreased 11beta-hydroxysteroid dehydrogenase 1 activity in mouse. Br J Pharmacol 178(16):3309-3326 |
| abstractText | BACKGROUND AND PURPOSE: 11beta-Hydroxysteroid dehydrogenase 1 (11beta-HSD1) regulates tissue-specific glucocorticoid metabolism and its impaired expression and activity are associated with major diseases. Pharmacological inhibition of 11beta-HSD1 is considered a promising therapeutic strategy. This study investigated whether alternative 7-oxo bile acid substrates of 11beta-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 11beta-HSD1 activity: global (11KO) and liver-specific 11beta-HSD1 knockout mice (11LKO), mice lacking hexose-6-phosphate dehydrogenase (H6pdKO) that provides cofactor NADPH for 11beta-HSD1 and mice treated with the pharmacological inhibitor carbenoxolone. Additionally, 11beta-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 11beta-HSD1 activity than absolute levels due to large inter-individual variations in bile acid concentrations. The ratio of the 7beta-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 11beta-HSD1 activity. The persistence of 11beta-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 11beta-HSD1 oxoreduction activity in different mouse models. This ratio may be a useful biomarker of decreased 11beta-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. |
