Wang Minghan
Department of Metabolic Disorders, Amgen Inc., One Amgen Center Drive, Mail Stop 29-1-A, Thousand Oaks, CA 91320, USA.
Handb Exp Pharmacol. 2011(203):127-46. doi: 10.1007/978-3-642-17214-4_6.
Glucocorticoid action is mediated by glucocorticoid receptor (GR), which upon cortisol binding is activated and regulates the transcriptional expression of target genes and downstream physiological functions. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the conversion of inactive cortisone to active cortisol. Since cortisol is also produced through biosynthesis in the adrenal glands, the total cortisol level in a given tissue is determined by both the circulating cortisol concentration and the local 11β-HSD1 activity. 11β-HSD1 is expressed in liver, adipose, brain, and placenta. Since it contributes to the local cortisol levels in these tissues, 11β-HSD1 plays a critical role in glucocorticoid action. The metabolic symptoms caused by glucocorticoid excess in Cushing's syndrome overlap with the characteristics of the metabolic syndrome, suggesting that increased glucocorticoid activity may play a role in the etiology of the metabolic syndrome. Consistent with this notion, elevated adipose expression of 11β-HSD1 induced metabolic syndrome-like phenotypes in mice. Thus, 11β-HSD1 is a proposed therapeutic target to normalize glucocorticoid excess in a tissue-specific manner and mitigate obesity and insulin resistance. Selective inhibitors of 11β-HSD1 are under development for the treatment of type 2 diabetes and other components of the metabolic syndrome.
糖皮质激素的作用是由糖皮质激素受体（GR）介导的，皮质醇与之结合后，GR被激活，进而调节靶基因的转录表达及下游生理功能。11β-羟基类固醇脱氢酶1型（11β-HSD1）催化无活性的可的松转化为有活性的皮质醇。由于皮质醇也通过肾上腺的生物合成产生，所以特定组织中的总皮质醇水平由循环皮质醇浓度和局部11β-HSD1活性共同决定。11β-HSD1在肝脏、脂肪组织、脑和胎盘中表达。由于它影响这些组织中的局部皮质醇水平，11β-HSD1在糖皮质激素作用中起关键作用。库欣综合征中糖皮质激素过量引起的代谢症状与代谢综合征的特征重叠，这表明糖皮质激素活性增加可能在代谢综合征的病因中起作用。与这一观点一致的是，小鼠脂肪组织中11β-HSD1表达升高会诱发类似代谢综合征的表型。因此，11β-HSD1是一种有望以组织特异性方式使糖皮质激素过量正常化并减轻肥胖和胰岛素抵抗的治疗靶点。11β-HSD1的选择性抑制剂正在研发中，用于治疗2型糖尿病和代谢综合征的其他组分。
