Modulation of 11beta-hydroxysteroid dehydrogenase isozymes by growth hormone and insulin-like growth factor: in vivo and in vitro studies.
Modulation of 11beta-hydroxysteroid dehydrogenase isozymes by growth hormone and insulin-like growth factor: in vivo and in vitro studies.
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DOI：
10.1210/jcem.84.11.6108
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发表时间：
1999-11
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影响因子：
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通讯作者：
Jasbir S. Moore;J. Monson;G. Kaltsas;P. Putignano;P. Wood;M. Sheppard;G. Besser;N. Taylor;P. Stewart
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文献类型：
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作者：
Jasbir S. Moore;J. Monson;G. Kaltsas;P. Putignano;P. Wood;M. Sheppard;G. Besser;N. Taylor;P. Stewart
具有生理活性的皮质醇（F）和无活性的可的松（E）的相互转化由11 β-羟基类固醇脱氢酶（11 β HSD）的两种同工酶催化，即将E转化为F的氧化还原酶（11 β HSD 1）和将F转化为E的脱氢酶（11 β HSD 2）。11 β HSD 1在调节糖皮质激素调节的葡萄糖稳态和局部脂肪细胞分化中是重要的。早期对GH缺乏受试者进行的替代GH研究表明，GH可能调节11 β HSD 1活性。在7例停止药物治疗的肢端肥大症受试者中（Sandostatin-LAR; 20-40 mg/月，至少12个月），GH从7.1 +/- 1.5升至17.5 +/- 4.3 mU/L胰岛素样生长因子I（IGF-I）在治疗后4个月从43.0 ± 8.8上升到82.1 ± 13.7 nmol/L（均P < 0.05）。F到E相互转化的正常设定点向E方向有显著改变。尿四氢皮质醇/四氢皮质醇比值下降（THF+allo-THF/THE; 0.82 +/- 0.06至0.60 +/- 0.06; P < 0.02），但尿游离F/尿游离E比值（11 β HSD 2活性的标志物）不变，表明这是由于11 β HSD 1活性受到抑制。GH与THF+allo-THF/THE比值呈负相关（r = -0.422; P < 0.05）。相反，在12例接受经蝶手术治疗的肢端肥大症患者中（GH从124 +/- 49.2下降到29.3 +/- 15.4 mU/L; P < 0.01），THF+allo-THF/THE比值从0.53 +/- 0.06上升到0.63 +/- 0.07（P < 0.05）。来自任一组的未能证明GH水平变化的患者显示THF+allo-THF/THE比率没有变化。对稳定转染人11 β HSD 1或11 β HSD 2互补DNA的细胞和仅表达11 β HSD 1同工酶的人网膜脂肪基质细胞的原代培养物进行的体外研究表明，IGF-I对11 β HSD 1氧化还原酶活性具有剂量依赖性抑制作用，但GH无此作用。IGF-I和GH对11 β HSD 2活性均无影响。GH通过IGF-I介导的作用抑制11 β HSD 1活性。这种E向F转化的减少将增加F的MCR，在肢端肥大症受试者和开始替代GH治疗的GH缺乏、低血糖患者中，应注意监测下丘脑-垂体-肾上腺轴功能的充分性。相反，增强E到F的转换发生在GH水平降低;在肝脏和脂肪组织中，这将导致肝葡萄糖输出增加和内脏肥胖，这表明目前可归因于成人GH缺乏症的表型的一部分可能是其通过11 β HSD 1表达对组织F代谢的影响的间接结果。
The interconversion of hormonally active cortisol (F) and inactive cortisone (E) is catalyzed by two isozymes of 11beta-hydroxysteroid dehydrogenase (11betaHSD), an oxo-reductase converting E to F (11betaHSD1) and a dehydrogenase (11betaHSD2) converting F to E. 11betaHSD1 is important in mediating glucocorticoid-regulated glucose homeostasis and regional adipocyte differentiation. Earlier studies conducted with GH-deficient subjects treated with replacement GH suggested that GH may modulate 11betaHSD1 activity. In 7 acromegalic subjects withdrawing from medical therapy (Sandostatin-LAR; 20-40 mg/month for at least 12 months), GH rose from 7.1 +/- 1.5 to 17.5 +/- 4.3 mU/L (mean +/- SE), and insulin-like growth factor I (IGF-I) rose from 43.0 +/- 8.8 to 82.1 +/- 13.7 nmol/L (both P < 0.05) 4 months after treatment. There was a significant alteration in the normal set-point of F to E interconversion toward E. The fall in the urinary tetrahydrocortisols/tetrahydocortisone ratio (THF+allo-THF/THE; 0.82 +/- 0.06 to 0.60 +/- 0.06; P < 0.02) but unaltered urinary free F/urinary free E ratio (a marker for 11betaHSD2 activity) suggested that this was due to inhibition of 11betaHSD1 activity. An inverse correlation between GH and the THF+allo-THF/THE ratio was observed (r = -0.422; P < 0.05). Conversely, in 12 acromegalic patients treated by transsphenoidal surgery (GH falling from 124 +/- 49.2 to 29.3 +/- 15.4 mU/L; P < 0.01), the THF+allo-THF/THE ratio rose from 0.53 +/- 0.06 to 0.63 +/- 0.07 (P < 0.05). Patients from either group who failed to demonstrate a change in GH levels showed no change in the THF+allo-THF/THE ratio. In vitro studies conducted on cells stably transfected with either the human 11betaHSD1 or 11betaHSD2 complementary DNA and primary cultures of human omental adipose stromal cells expressing only the 11betaHSD1 isozyme indicated a dose-dependent inhibition of 11betaHSD1 oxo-reductase activity with IGF-I, but not GH. Neither IGF-I nor GH had any effect on 11betaHSD2 activity. GH, through an IGF-I-mediated effect, inhibits 11betaHSD1 activity. This reduction in E to F conversion will increase the MCR of F, and care should be taken to monitor the adequacy of function of the hypothalamo-pituitary-adrenal axis in acromegalic subjects and in GH-deficient, hypopituitary patients commencing replacement GH therapy. Conversely, enhanced E to F conversion occurs with a reduction in GH levels; in liver and adipose tissue this would result in increased hepatic glucose output and visceral adiposity, suggesting that part of the phenotype currently attributable to adult GH deficiency may be an indirect consequence of its effect on tissue F metabolism via 11betaHSD1 expression.