Evidence for a role of sterol 27-hydroxylase in glucocorticoid metabolism in vivo

Abstract

The intracellular availability of glucocorticoids is regulated by the enzymes 11b-hydroxysteroid dehydrogenase 1 (HSD11B1) and 11b-hydroxysteroid dehydrogenase 2 (HSD11B2). The activity of HSD11B1 is measured in the urine based on the (tetrahydrocortisolC5a-tetrahydrocortisol)/tetrahydrocortisone ((THFC5a-THF)/THE) ratio in humans and the (tetrahydrocorticosteroneC5a-tetrahydrocorticosterone)/tetrahydrodehydrocorticosterone ((THBC5a-THB)/THA) ratio in mice. The cortisol/cortisone (F/E) ratio in humans and the corticosterone/11-dehydrocorticosterone (B/A) ratio in mice are markers of the activity of HSD11B2. In vitro agonist treatment of liver X receptor (LXR) downregulates the activity of HSD11B1. Sterol 27-hydroxylase (CYP27A1) catalyses the first step in the alternative pathway of bile acid synthesis by hydroxylating cholesterol to 27-hydroxycholesterol (27-OHC). Since 27-OHC is a natural ligand for LXR, we hypothesised that CYP27A1 deficiency may up-regulate the activity of HSD11B1. In a patient with cerebrotendinous xanthomatosis carrying a loss-of-function mutation in CYP27A1, the plasma concentrations of 27-OHC were dramatically reduced (3.8 vs 90-140 ng/ml in healthy controls) and the urinary ratios of (THFC5a-THF)/THE and F/E were increased, demonstrating enhanced HSD11B1 and diminished HSD11B2 activities. Similarly, in Cyp27a1 knockout (KO) mice, the plasma concentrations of 27-OHC were undetectable (!1 vs 25-120 ng/ml in Cyp27a1 WT mice). The urinary ratio of (THBC5a-THB)/THA was fourfold and that of B/A was twofold higher in KO mice than in their WT littermates. The (THBC5a-THB)/THA ratio was also significantly increased in the plasma, liver and kidney of KO mice. In the liver of these mice, the increase in the concentrations of active glucocorticoids was due to increased liver weight as a consequence of Cyp27a1 deficiency. In vitro, 27-OHC acts as an inhibitor of the activity of HSD11B1. Our studies suggest that the expression of CYP27A1 modulates the concentrations of active glucocorticoids in both humans and mice and in vitro. Journal of EndocrinologyResearch I VÖ GELI and others CYP27A1 and glucocorticoid metabolism in vivo

Maternal Serum Lipid, Estradiol, and Progesterone Levels in Pregnancy, and the Impact of Placental and Hepatic Pathologies

“…Steroid metabolites (DHEA, estradiol, and progesterone metabolites) were quantified by GC-MS in plasma (100-1000 µl) using the following procedure [21]. Following an extraction step with 10 vol dichloromethane, steroids were extracted in the organic phase containing unconjugated steroids and derivatized with 100 µl methoxyamine-HCl (Pierce Biotechnology, Rockford, IL, USA) in pyridine for 1 h at 60°C.…”

Single-cell metabolic profiling reveals subgroups of primary human hepatocytes showing heterogeneous responses to drug challenge

“…3D, left). For instance, CYP27A1 in subgroup I was pericentrally enriched [48, 69, 70]; while HS D11B1, involved in bile synthesis [71] was distributed periportally (Supp. Table 1; Supp.…”

Genetic obesity increases pancreatic expression of mitochondrial proteins which regulate cholesterol efflux in BRIN-BD11 insulinoma cells

“…It is possible that induction of Cyp27A1 may therefore be an autocrine or paracrine response to limit adipocyte hyperplasia during overfeeding, and could exert a similarly protective function in pancreatic tissue to prevent cholesterol accumulation in genetic obesity [52,53]. Loss of Cyp27A1 activity has also been linked to increased concentrations of active glucocorticoids [54], so one hypothesis could be that pancreatic induction of Cyp27A1 expression, possibly mediated by activation of glucocorticoid receptors [55,56], could help to reduce the impact of increased circulating concentrations of these stress hormones in obesity [57]. Alternatively, pancreatic induction of Cyp27A1 may contribute to the compensatory response leading to hyperinsulinaemia in fa/fa Zucker rats.…”