Abstract
11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) mediates glucocorticoid activation and is currently considered as therapeutic target to treat metabolic diseases; however, biomarkers to assess its activity in vivo are still lacking. Recent in vitro experiments suggested that human 11β-HSD1 metabolizes the secondary bile acid 7-oxolithocholic acid (7-oxoLCA) to chenodeoxycholic acid (CDCA) and minor amounts of ursodeoxycholic acid (UDCA). Here, we provide evidence from in vitro and in vivo studies for a major role of 11β-HSD1 in the oxidoreduction of 7-oxoLCA and compare its level and metabolism in several species. Hepatic microsomes from liver-specific 11β-HSD1-deficient mice were devoid of 7-oxoLCA oxidoreductase activity. Importantly, circulating and intrahepatic levels of 7-oxoLCA and its taurine conjugate were significantly elevated in mouse models of 11β-HSD1 deficiency. Moreover, comparative enzymology of 11β-HSD1-dependent oxidoreduction of 7-oxoLCA revealed that the guinea-pig enzyme is devoid of 7-oxoLCA oxidoreductase activity. Unlike in other species, 7-oxoLCA and its glycine conjugate are major bile acids in guinea-pigs. In conclusion, the oxidoreduction of 7-oxoLCA and its conjugated metabolites are catalyzed by 11β-HSD1, and the lack of this activity leads to the accumulation of these bile acids in guinea-pigs and 11β-HSD1-deficient mice. Thus, 7-oxoLCA and its conjugates may serve as biomarkers of impaired 11β-HSD1 activity.
Highlights
11-hydroxysteroid dehydrogenase type 1 (11HSD1) mediates glucocorticoid activation and is currently considered as therapeutic target to treat metabolic diseases; biomarkers to assess its activity in vivo are still lacking
We investigated whether these observations are due to species-specific differences in the stereoselective product formation by 11-HSD1 or whether additional enzymes might be involved in the carbonyl reduction of 7-oxoLCA in rats and mice
Due to the fact that, in humans, circulating glycine-conjugated bile acids are more abundant than taurine-conjugated metabolites [52], we propose that 7-oxoLCA, 7-oxoLC-Gly, and the sum of these two bile acids may be used as biomarkers for impaired 11-HSD1 function
Summary
11-hydroxysteroid dehydrogenase type 1 (11HSD1) mediates glucocorticoid activation and is currently considered as therapeutic target to treat metabolic diseases; biomarkers to assess its activity in vivo are still lacking. We provide evidence from in vitro and in vivo studies for a major role of 11-HSD1 in the oxidoreduction of 7-oxoLCA and compare its level and metabolism in several species. The oxidoreduction of 7-oxoLCA and its conjugated metabolites are catalyzed by 11-HSD1, and the lack of this activity leads to the accumulation of these bile acids in guinea-pigs and 11-HSD1-deficient mice. 11-Hydroxysteroid dehydrogenase type 1 (11-HSD1) is a NADPH-dependent enzyme catalyzing the regeneration of cortisol (in humans, higher mammals) and corticosterone (in rodents) from inactive cortisone and 11-dehydrocorticosterone, respectively, thereby controlling the tissue- and cell-specific exposure to active glucocorticoids [1]. Circulating concentrations of glucocorticoids and their metabolites are not suitable biomarkers because their levels in plasma and urine are a result of combined activities of 11-HSD1 and 11-HSD2. An ideal biomarker should be independent of mechanisms of negative feedback regulation, such as the control of circulating glucocorticoid levels by the hypothalamuspituitary-adrenal (HPA) axis and stress-induced fluctuations [18, 19]
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