Regulation of 11β-HSD1 by GH/IGF-1 in key metabolic tissues may contribute to metabolic disease in GH deficient patients

IF 1.6 4区 医学 Q4 CELL BIOLOGY
Stuart A. Morgan , Darlene E. Berryman , Edward O. List , Gareth G. Lavery , Paul M. Stewart , John J. Kopchick
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引用次数: 2

Abstract

Patients with growth hormone deficiency (GHD) have many clinical features in common with Cushing's syndrome (glucocorticoid excess) – notably visceral obesity, insulin resistance, muscle myopathy and increased vascular mortality. Within key metabolic tissues, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts cortisone to the active glucocorticoid, cortisol (11-dehydrocorticosterone and corticosterone in rodents respectively), and thus amplifies local glucocorticoid action.

We hypothesize that 11β-HSD1 expression is negatively regulated by growth hormone (GH), and that GHD patients have elevated 11β-HSD1 within key metabolic tissues (leading to increased intracellular cortisol generation) which contributes to the clinical features of this disease.

To identify the impact of GH excess/resistance on 11β-HSD1 in vivo, we measured mRNA expression in key metabolic tissues of giant mice expressing the bovine GH (bGH) gene, dwarf mice with a disrupted GH receptor (GHRKO) gene and mice expressing a gene encoding a GH receptor antagonist (GHA). Additionally, we assessed urine steroid markers of 11β-HSD1 activity in both GHRKO and bGH animals.

11β-HSD1 expression was decreased in gastrocnemius muscle (0.43-fold, p < 0.05), subcutaneous adipose (0.53-fold, p < 0.05) and epididymal adipose tissue (0.40-fold, p < 0.05), but not liver, in bGH mice compared to WT controls. This was paralleled by an increased percentage of 11-DHC (inactive glucocorticoid) present in the urine of bGH mice compared to WT controls (2.5-fold, p < 0.01) - consistent with decreased systemic 11β-HSD1 activity. By contrast, expression of 11β-HSD1 was increased in the liver of GHRKO (2.7-fold, p < 0.05) and GHA mice (2.0-fold, p < 0.05) compared to WT controls, but not gastrocnemius muscle, subcutaneous adipose tissue or epididymal adipose tissue.

In summary, we have demonstrated a negative relationship between GH action and 11β-HSD1 expression which appears to be tissue specific. These data provide evidence that increased intracellular cortisol production within key tissues may contribute to metabolic disease in GHD patients.

GH/IGF-1在关键代谢组织中调控11β-HSD1可能有助于GH缺乏患者的代谢性疾病
生长激素缺乏症(GHD)患者与库欣综合征(糖皮质激素过量)有许多共同的临床特征——尤其是内脏肥胖、胰岛素抵抗、肌肉肌病和血管死亡率增加。在关键代谢组织中,11β-羟基类固醇脱氢酶1型(11β-HSD1)将可的松转化为活性糖皮质激素皮质醇(啮齿动物分别为11-脱氢皮质酮和皮质酮),从而增强局部糖皮质激素的作用。我们假设11β-HSD1的表达受到生长激素(GH)的负调控,GHD患者在关键代谢组织中11β-HSD1升高(导致细胞内皮质醇生成增加),这有助于该疾病的临床特征。为了确定生长激素过量/抵抗对体内11β-HSD1的影响,我们测量了表达牛生长激素(bGH)基因的巨型小鼠、生长激素受体(GHRKO)基因中断的侏儒小鼠和表达编码生长激素受体拮抗剂(GHA)基因的小鼠关键代谢组织中的mRNA表达。此外,我们评估了GHRKO和bGH动物尿液中11β-HSD1活性的类固醇标志物。11β-HSD1在腓肠肌中的表达降低(0.43倍,p <0.05),皮下脂肪(0.53倍,p <0.05)和附睾脂肪组织(0.40倍,p <0.05),但与WT对照组相比,bGH小鼠的肝脏没有。与WT对照组相比,bGH小鼠尿液中11-DHC(无活性糖皮质激素)的百分比增加(2.5倍,p <0.01) -与系统11β-HSD1活性降低一致。相比之下,11β-HSD1在GHRKO的肝脏中表达增加(2.7倍,p <0.05)和GHA小鼠(2.0倍,p <0.05),但腓肠肌、皮下脂肪组织或附睾脂肪组织与WT对照组相比无显著差异。总之,我们已经证明了生长激素作用与11β-HSD1表达之间的负相关关系,这似乎是组织特异性的。这些数据提供了关键组织内细胞内皮质醇生成增加可能导致GHD患者代谢性疾病的证据。
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来源期刊
Growth Hormone & Igf Research
Growth Hormone & Igf Research 医学-内分泌学与代谢
CiteScore
3.30
自引率
0.00%
发文量
38
审稿时长
57 days
期刊介绍: Growth Hormone & IGF Research is a forum for research on the regulation of growth and metabolism in humans, animals, tissues and cells. It publishes articles on all aspects of growth-promoting and growth-inhibiting hormones and factors, with particular emphasis on insulin-like growth factors (IGFs) and growth hormone. This reflects the increasing importance of growth hormone and IGFs in clinical medicine and in the treatment of diseases.
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