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

Abstract

Background and Purpose 11β‐hydroxysteroid dehydrogenase 1 (11β‐HSD1) regulates tissue‐specific glucocorticoid metabolism, and its impaired expression and activity is 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‐high performance liquid chromatography tandem‐mass spectrometry 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 (CBX). Additionally, 11β‐HSD1 expression and activity were assessed in H6pdKO and CBX 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 CBX 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 patho‐physiological situations or upon pharmacological inhibition.