Hepatic reduction of the secondary bile acid 7-oxolithocholic acid is mediated by 11β-hydroxysteroid dehydrogenase 1

Abstract

The oxidized bile acid 7-oxoLCA (7-oxolithocholic acid), formed primarily by gut micro-organisms, is reduced in human liver to CDCA (chenodeoxycholic acid) and, to a lesser extent, UDCA (ursodeoxycholic acid). The enzyme(s) responsible remained unknown. Using human liver microsomes, we observed enhanced 7-oxoLCA reduction in the presence of detergent. The reaction was dependent on NADPH and stimulated by glucose 6-phosphate, suggesting localization of the enzyme in the ER (endoplasmic reticulum) and dependence on NADPH-generating H6PDH (hexose-6-phosphate dehydrogenase). Using recombinant human 11β-HSD1 (11β-hydroxysteroid dehydrogenase 1), we demonstrate efficient conversion of 7-oxoLCA into CDCA and, to a lesser extent, UDCA. Unlike the reversible metabolism of glucocorticoids, 11β-HSD1 mediated solely 7-oxo reduction of 7-oxoLCA and its taurine and glycine conjugates. Furthermore, we investigated the interference of bile acids with 11β-HSD1-dependent interconversion of glucocorticoids. 7-OxoLCA and its conjugates preferentially inhibited cortisone reduction, and CDCA and its conjugates inhibited cortisol oxidation. Three-dimensional modelling provided an explanation for the binding mode and selectivity of the bile acids studied. The results reveal that 11β-HSD1 is responsible for 7-oxoLCA reduction in humans, providing a further link between hepatic glucocorticoid activation and bile acid metabolism. These findings also suggest the need for animal and clinical studies to explore whether inhibition of 11β-HSD1 to reduce cortisol levels would also lead to an accumulation of 7-oxoLCA, thereby potentially affecting bile acid-mediated functions.

Impaired oxidoreduction by 11β-hydroxysteroid dehydrogenase 1 results in the accumulation of 7-oxolithocholic acid

“…Human 11 ␤ -HSD1 preferentially formed CDCA with minor amounts of UDCA as reported earlier ( 26 ). Canine and hamster 11 ␤ -HSD1 almost completely converted the substrate and presented similar stereoselectivity to human 11 ␤ -HSD1, thus mainly producing the 7 ␣ -hydroxylated bile acid CDCA, with minor amounts of the 7 ␤ -hydroxylated UDCA.…”

“…Performing in vitro experiments, we recently identifi ed a novel role for human 11 ␤ -HSD1 in the metabolism of the secondary bile acid 7-oxoLCA ( 26 ). We observed that recombinant human 11 ␤ -HSD1 preferentially reduced 7-oxoLCA to the 7 ␣ -hydroxylated bile acid chenodeoxycholic acid (CDCA) and, to a lesser extent, to the 7 ␤ -hydroxylated ursodeoxycholic acid (UDCA) ( 26 ). We hypothesized that the metabolism by 11 ␤ -HSD1 might be responsible for the very low circulating levels of this secondary bile acid.…”

“…The inhibitory impact of bile acids on the interconversion of glucocorticoids by 11 ␤ -HSD1 of six species was performed as described previously ( 26 ). Briefl y, lysates were incubated for 10 min at 37°C in a total volume of 22 l containing 200 nM and 10 nCi of [1,2-3 H]cortisone or [1,2,6, H]cortisol and 500 M cofactor NADPH or NADP + , respectively, and vehicle or various concentrations of bile acids.…”

“…Concomitantly, lysates were used in parallel experiments to assess the conversion of cortisone to cortisol. Reaction products were directly measured by mass spectrometry as described previously ( 26,31 ). The rate of all reactions was kept below 25% of substrate conversion, with the exception of the comparison of product formation from 7-oxoLCA shown in Fig.…”

Consequences of bile salt biotransformations by intestinal bacteria

“…Recent studies reported that 7-oxo-lithocholic acid (7-oxo-LCA), a bacterial metabolite of CDCA, acts as a competitive inhibitor of human hepatic 11b-hydroxysteroid dehydrogenase-1 (11b-HSDH1). 93 Hepatic 11b-HSDH1 recognizes 7-oxo-LCA as a substrate and reduces this bacterial metabolite back to CDCA. 94 However, in the process, 7-oxo-LCA inhibits cortisone reduction back to active cortisol.…”