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 7oxolithocholyltaurine (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.

Targeted bile acid profiles reveal the liver injury amelioration of Da-Chai-Hu decoction against ANIT- and BDL-induced cholestasis

“…If the BAs synthesized by the alternative pathway are inhibited, the proportion of 12-OH-BAs synthesized by the classical pathway will increase, which will further lead to a decrease in the liver's ability to respond to hepatic lipid homeostasis and the inflammatory state, and the degree of liver fibrosis was significantly associated with 12-OH-BAs (Jia et al, 2018;Jia et al, 2021;Xie et al, 2021). Along this line, we calculated the ratio of CA to CDCA because the ratio of CA to CDCA was selected to test if a possible shift in BA synthesis from the classical to the alternative BA pathway occurs in the liver (Chen et al, 2019;MahmoudianDehkordi et al, 2019;Weingartner et al, 2021). In the present investigation, we found that the BA synthesis in the ANIT-induced intrahepatic cholestatic model was still dominated by the classical pathway; however, the BA synthesis pathway in the BDL-induced extrahepatic cholestatic model shifted to the alternative pathway, and the proportion of TCA and TMCA in the two types of model mouse's liver supported this conclusion.…”

Albendazole reduces hepatic inflammation and endoplasmic reticulum-stress in a mouse model of chronic Echinococcus multilocularis infection

“…The procedures for liver sample preparation and Western blotting have been previously described [66]. Briefly, liver samples (approximately 7 mg) were homogenized (30s, 6500 rpm, at 4˚C, using a Precellys-24 tissue homogenizer) in 450 μL RIPA buffer (50 mM Tris-HCl, pH 8.0, with 150 mM NaCl, 1.0% NP-40, 0.5% sodium deoxycholate and 0.1% sodium dodecyl sulfate) containing protease inhibitor cocktail and centrifuged (4 min, 16,000 × g, 4˚C).…”

Identification of a human blood biomarker of pharmacological 11β-hydroxysteroid dehydrogenase 1 inhibition

“…Earlier studies showed that human 11β-HSD1 is capable of metabolizing 7-oxo-cholesterol metabolites (Beck, Inderbinen, et al, 2019;Hult et al, 2004;Mitić et al, 2013;Schweizer et al, 2004) but also the secondary bile acid 7oxolithocholic acid (7oxoLCA) to ursodeoxycholic acid (UDCA) and to a lesser extent to chenodeoxycholic acid (CDCA) (Figure 1) (Mitić et al, 2013;Odermatt et al, 2011;Penno et al, 2013). A lack of this activity in guinea-pigs and in 11β-HSD1-deficient mice results in an accumulation of 7oxoLCA and its taurine conjugated form (Penno et al, 2013(Penno et al, , 2014Weingartner et al, 2021). A recent preclinical study employing three different transgenic mouse models of 11β-HSD1 deficiency and a model of pharmacological inhibition proposed the ratio of taurine conjugated UDCA (TUDCA) to 7oxoLCA (T7oxoLCA) in plasma samples as a biomarker to detect decreased 11β-HSD1 oxoreductase activity (Weingartner et al, 2021).…”