The ratio of ursodeoxycholyltaurine to 7-oxolithocholyltaurine serves as a biomarker of decreased 11β-hydroxysteroid dehydrogenase 1 activity in mouse

Background and Purpose 11 beta-Hydroxysteroid dehydrogenase 1 (11 beta-HSD1) regulates tissue-specific glucocorticoid metabolism and its impaired expression and activity are associated with major diseases. Pharmacological inhibition of 11 beta-HSD1 is considered a promising therapeutic strategy. This study investigated whether alternative 7-oxo bile acid substrates of 11 beta-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 11 beta-HSD1 activity: global (11KO) and liver-specific 11 beta-HSD1 knockout mice (11LKO), mice lacking hexose-6-phosphate dehydrogenase (H6pdKO) that provides cofactor NADPH for 11 beta-HSD1 and mice treated with the pharmacological inhibitor carbenoxolone. Additionally, 11 beta-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 11 beta-HSD1 activity than absolute levels due to large inter-individual variations in bile acid concentrations. The ratio of the 7 beta-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 11 beta-HSD1 activity. The persistence of 11 beta-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 11 beta-HSD1 oxoreduction activity in different mouse models. This ratio may be a useful biomarker of decreased 11 beta-HSD1 activity in pathophysiological situations or upon pharmacological inhibition.

Automated summary

The study found that the plasma ratio of UDC-Tau to 7oxoLC-Tau can serve as a biomarker for decreased 11 beta-HSD1 oxoreduction activity in different mouse models. Enzyme product to substrate ratios were more reliable markers of 11 beta-HSD1 activity than absolute levels due to large inter-individual variations in bile acid concentrations. The persistence of oxoreduction activity in the face of cofactor loss indicates the existence of an alternative NADPH source in the endoplasmic reticulum.