Biomarkers of hypothalamic-pituitary-adrenal axis activity in mice lacking 11β-HSD1 and H6PDH.
Biomarkers of hypothalamic-pituitary-adrenal axis activity in mice lacking 11β-HSD1 and H6PDH.
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DOI：
10.1530/joe-12-0178
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发表时间：
2012-09
期刊：
影响因子：
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通讯作者：
Stewart PM
中科院分区：
文献类型：
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作者：
Abrahams L;Semjonous NM;Guest P;Zielinska A;Hughes B;Lavery GG;Stewart PM
糖皮质激素浓度是在负反馈控制下的产生和下丘脑-垂体-肾上腺（HPA）轴的昼夜节律与外周代谢之间的平衡，例如通过酶1型11β-羟基类固醇脱氢酶（11β-HSD 1），其催化无活性可的松（小鼠中的11-脱氢皮质酮（11-DHC））还原为皮质醇（小鼠中的皮质酮）。还原酶活性由己糖-6-磷酸脱氢酶（H6 PDH）赋予11β-HSD 1。11β-HSD 1与肥胖的发生有关，目前正在开发选择性11β-HSD 1抑制剂。我们试图解决与11β-HSD 1抑制相关的HPA轴潜在上调的问题。我们评估了来自双杂合小鼠杂交的11β-HSD 1和H6 PDH的等位基因组合的生物标志物。H6 PDH敲除（KO）肾上腺比WT大69%，而11β-HSD 1 KO和双KO（DKO）肾上腺比WT大约30%-表明KO动物中HPA轴驱动增加。与WT相比，ACTH刺激的循环皮质酮浓度在H6 PDH KO动物中高2.2倍，在11β-HSD 1 KO和DKO动物中高1.5倍，与观察到的肾上腺肥大成比例。KO H6 PDH导致雄性（65%）和雌性（61%）的尿DHC代谢物大幅增加。仅在雌性动物中，11β-HSD 1单独KO或与H6 PDH联合KO导致尿DHC代谢物显著增加（分别为36%和42%）。中间型11β-HSD 1/H6 PDH杂合子HPA轴保持正常。尿甾体代谢物的气相色谱/质谱分析作为一种生物标志物检测可能有助于临床上检测先天性和获得性11β-HSD 1/H6 PDH缺乏症患者的HPA轴状态。
Glucocorticoid concentrations are a balance between production under the negative feedback control and diurnal rhythm of the hypothalamic–pituitary–adrenal (HPA) axis and peripheral metabolism, for example by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which catalyses the reduction of inactive cortisone (11-dehydrocorticosterone (11-DHC) in mice) to cortisol (corticosterone in mice). Reductase activity is conferred upon 11β-HSD1 by hexose-6-phosphate dehydrogenase (H6PDH). 11β-HSD1 is implicated in the development of obesity, and selective 11β-HSD1 inhibitors are currently under development. We sought to address the concern regarding potential up-regulation of the HPA axis associated with inhibition of 11β-HSD1. We assessed biomarkers for allele combinations of 11β-HSD1 and H6PDH derived from double heterozygous mouse crosses. H6PDH knock out (KO) adrenals were 69% larger than WT while 11β-HSD1 KO and double KO (DKO) adrenals were ∼30% larger than WT – indicative of increased HPA axis drive in KO animals. ACTH-stimulated circulating corticosterone concentrations were 2·2-fold higher in H6PDH KO animals and ∼1·5-fold higher in 11β-HSD1 KO and DKO animals compared with WT, proportional to the observed adrenal hypertrophy. KO of H6PDH resulted in a substantial increase in urinary DHC metabolites in males (65%) and females (61%). KO of 11β-HSD1 alone or in combination with H6PDH led to significant increases (36 and 42% respectively) in urinary DHC metabolites in females only. Intermediate 11β-HSD1/H6PDH heterozygotes maintained a normal HPA axis. Urinary steroid metabolite profile by gas chromatography/mass spectrometry as a biomarker assay may be beneficial in assaying HPA axis status clinically in cases of congenital and acquired 11β-HSD1/H6PDH deficiency.