Liver-selective transgene rescue of hypothalamic-pituitary-adrenal axis dysfunction in 11beta-hydroxysteroid dehydrogenase type 1-deficient mice.
Liver-selective transgene rescue of hypothalamic-pituitary-adrenal axis dysfunction in 11beta-hydroxysteroid dehydrogenase type 1-deficient mice.
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DOI：
10.1210/en.2006-0603
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发表时间：
2007-03
期刊：
影响因子：
4.8
通讯作者：
Seckl JR
中科院分区：
文献类型：
--
作者：
Paterson JM;Holmes MC;Kenyon CJ;Carter R;Mullins JJ;Seckl JR
11β-羟基类固醇脱氢酶1型（11β-HSD 1）在体内作为还原酶，从循环的惰性11-酮形式再生细胞内的活性糖皮质激素，从而放大局部糖皮质激素作用。11β-HSD 1主要在肝脏以及脂肪组织和脑中表达。缺乏11β-HSD 1（11β-HSD 1-/-）的小鼠表现出肾上腺增生、基础皮质酮水平升高和下丘脑-垂体-肾上腺（HPA）轴对应激的反应增加。外周糖皮质激素再生减少可以解释肾上腺肥大和过度的应激反应，而基础糖皮质激素水平升高支持脑内11β-HSD 1在放大糖皮质激素反馈中的作用。为了验证这一假设，将肝脏中过表达11β-HSD 1的载脂蛋白E-HSD 1小鼠与11β-HSD 1-/-小鼠杂交，以确定肝脏11β-HSD 1的互补是否可以恢复肾上腺和HPA缺陷。在11 β-HSD 1-/-小鼠中，转基因介导的11β-HSD 1活性向肝脏的传递挽救了肾上腺增生并逆转了过度的HPA应激反应。出乎意料的是，升高的最低血浆皮质酮水平也恢复到对照水平。与此一致，11β-HSD 1-/-小鼠肾上腺皮质中的CYP 11B 1 mRNA表达增加50%，但在携带载脂蛋白E-HSD 1转基因的11β HSD 1-/-小鼠中恢复至对照水平。11β-HSD 1-/-小鼠的血糖水平较低，但补充蔗糖后血浆皮质酮的下降在11β-HSD 1-/-和对照小鼠中相似，表明葡萄糖缺乏不是无效小鼠基础皮质酮水平升高的主要机制。因此，在肝脏中通过11β-HSD 1再生糖皮质激素使11β-HSD 1-/-小鼠中HPA轴失调的所有方面正常化，而没有恢复前脑关键反馈区域中的酶活性。因此，肝脏糖皮质激素代谢影响HPA轴的基础以及应激相关功能。
11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) acts as a reductase in vivo, regenerating active glucocorticoids within cells from circulating inert 11-keto forms, thus amplifying local glucocorticoid action. 11β-HSD1 is predominantly expressed in liver and also adipose tissue and brain. Mice deficient in 11β-HSD1 (11β-HSD1-/-) exhibit adrenal hyperplasia, raised basal corticosterone levels, and increased hypothalamic-pituitary-adrenal (HPA) axis responses to stress. Whereas reduced peripheral glucocorticoid regeneration may explain adrenal hypertrophy and exaggerated stress responses, elevated basal glucocorticoid levels support a role for 11β-HSD1 within the brain in amplifying glucocorticoid feedback. To test this hypothesis, apolipoprotein E-HSD1 mice overexpressing 11β-HSD1 in liver were intercrossed with 11βHSD1-/- mice to determine whether complementation of hepatic 11β-HSD1 can restore adrenal and HPA defects. Transgene-mediated delivery of 11β-HSD1 activity to the liver rescued adrenal hyperplasia and reversed exaggerated HPA stress responses in 11β-HSD1-/- mice. Unexpectedly, elevated nadir plasma corticosterone levels were also restored to control levels. Consistent with this, CYP11B1 mRNA expression in the adrenal cortex of 11β-HSD1-/- mice was increased by 50% but returned to control levels in 11βHSD1-/- mice bearing the apolipoprotein E-HSD1 trans-gene. 11β-HSD1-/- mice have lower plasma glucose levels, but the fall in plasma corticosterone with sucrose supplementation was similar in 11β-HSD1-/- and control mice, suggesting glucose deficiency is not the main mechanism whereby basal corticosterone levels are elevated in the null mice. Thus, regeneration of glucocorticoids by 11β-HSD1 in the liver normalizes all aspects of HPA axis dysregulation in 11β-HSD1-/- mice, without restoration of enzyme activity in key feedback areas of the forebrain. Therefore, hepatic glucocorticoid metabolism influences basal as well as stress-associated functions of the HPA axis.
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影响因子：
4.8
作者：
LAKSHMI, V;SAKAI, RR;MONDER, C
通讯作者：
MONDER, C
影响因子：
4.8
作者：
MOISAN, MP;SECKL, JR;EDWARDS, CRW
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EDWARDS, CRW
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2.9
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15.9
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2.9
作者：
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