Department of Nephrology, Hypertension and Clinical Pharmacology, University Hospital Berne, CH-3010 Berne, Switzerland Department of Neurology, University Hospital Zurich, Zurich, Switzerland Department of Medicine, University of California, San Francisco, California, USA Department of Internal Medicine, Emmental Hospital, Burgdorf, Switzerland Prince Henry's Institute, Clayton 3168, Victoria, Australia.
J Endocrinol. 2013 Oct 4;219(2):119-29. doi: 10.1530/JOE-13-0141. Print 2013 Nov.
The intracellular availability of glucocorticoids is regulated by the enzymes 11β-hydroxysteroid dehydrogenase 1 (HSD11B1) and 11β-hydroxysteroid dehydrogenase 2 (HSD11B2). The activity of HSD11B1 is measured in the urine based on the (tetrahydrocortisol+5α-tetrahydrocortisol)/tetrahydrocortisone ((THF+5α-THF)/THE) ratio in humans and the (tetrahydrocorticosterone+5α-tetrahydrocorticosterone)/tetrahydrodehydrocorticosterone ((THB+5α-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) down-regulates 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 (THF+5α-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 (THB+5α-THB)/THA was fourfold and that of B/A was twofold higher in KO mice than in their WT littermates. The (THB+5α-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.
糖皮质激素的细胞内可用性受 11β-羟甾脱氢酶 1（HSD11B1）和 11β-羟甾脱氢酶 2（HSD11B2）两种酶的调节。人类尿液中 HSD11B1 的活性是根据四氢皮质醇+5α-四氢皮质醇/四氢皮质酮（THF+5α-THF/THA）比值来衡量的，而小鼠尿液中则是根据四氢皮质醇酮+5α-四氢皮质醇酮/四氢去氢皮质酮（THB+5α-THB/THA）比值来衡量的。人类的皮质醇/皮质酮（F/E）比值和小鼠的皮质酮/11-去氢皮质酮（B/A）比值是 HSD11B2 活性的标志物。肝 X 受体（LXR）的体外激动剂治疗可下调 HSD11B1 的活性。固醇 27-羟化酶（CYP27A1）通过将胆固醇羟化为 27-羟胆固醇（27-OHC），催化胆汁酸合成的替代途径的第一步。由于 27-OHC 是 LXR 的天然配体，我们假设 CYP27A1 缺乏可能会上调 HSD11B1 的活性。在携带 CYP27A1 功能丧失突变的脑腱黄瘤病患者中，27-OHC 的血浆浓度显著降低（3.8 vs 健康对照组 90-140ng/ml），THF+5α-THF/THA 和 F/E 的尿比值升高，表明 HSD11B1 活性增强，HSD11B2 活性减弱。同样，在 Cyp27a1 敲除（KO）小鼠中，27-OHC 的血浆浓度检测不到（<1 vs Cyp27a1 WT 小鼠的 25-120ng/ml）。KO 小鼠的（THB+5α-THB）/THA 比值比其 WT 同窝仔鼠高 4 倍，B/A 比值高 2 倍。KO 小鼠的血浆、肝脏和肾脏中（THB+5α-THB）/THA 比值也显著升高。在这些小鼠的肝脏中，由于 Cyp27a1 缺乏导致肝重增加，活性糖皮质激素的浓度增加。体外，27-OHC 是 HSD11B1 活性的抑制剂。我们的研究表明，CYP27A1 的表达在人类和小鼠体内和体外均调节活性糖皮质激素的浓度。
