Identification of a regulatory loop for the synthesis of neurosteroids: a steroidogenic acute regulatory protein-dependent mechanism involving hypothalamic-pituitary-gonadal axis receptors.
Identification of a regulatory loop for the synthesis of neurosteroids: a steroidogenic acute regulatory protein-dependent mechanism involving hypothalamic-pituitary-gonadal axis receptors.
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DOI：
10.1111/j.1471-4159.2009.06192.x
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发表时间：
2009-08
影响因子：
4.7
通讯作者：
Atwood CS
中科院分区：
文献类型：
--
作者：
Meethal SV;Liu T;Chan HW;Ginsburg E;Wilson AC;Gray DN;Bowen RL;Vonderhaar BK;Atwood CS
脑性类固醇来源于外周（主要是性腺）和局部（神经类固醇）来源，对神经发生、神经分化和神经功能至关重要。调节神经类固醇产生的机制尚不清楚。为了确定之前在下丘脑外脑中检测到的下丘脑-垂体-性腺轴成分是否包含一个调节神经性类固醇（NSS）产生的反馈回路，我们通过调节雌性小鼠的外周性激素水平，评估了类固醇生成的关键调节因子（StAR）蛋白和下丘脑-垂体-性腺内分泌的关键受体表达模式的动态变化。卵巢切除术（OVX；高血清促性腺激素，低血清性类固醇）对下丘脑外脑StAR蛋白水平有不同的影响；增加了30kda和32kda变体，但减少了37kda变体，这表明胆固醇转运到线粒体中进行类固醇生成。用E2、P4或E2 + P4治疗OVX动物3天，可以降低OVX诱导的GnRH/促性腺激素产生的增加，逆转了这种模式。使用GnRH激动剂醋酸leuprolide抑制OVX小鼠的促性腺激素水平，抑制了37-kDa StAR蛋白向30-kDa StAR蛋白的加工，证实了促性腺激素调节脑StAR蛋白的差异加工。OVX显著抑制下丘脑外脑促性腺激素释放激素1受体的表达，并在E2-或p4处理的OVX小鼠中进一步抑制。总之，这些数据表明存在调节NSS合成的内分泌和自分泌/旁分泌反馈回路。进一步描述这些调节NSS产生的反馈回路将有助于开发维持大脑性类固醇水平和认知的治疗方法。
Brain sex steroids are derived from both peripheral (primarily gonadal) and local (neurosteroids) sources and are crucial for neurogenesis, neural differentiation and neural function. The mechanism(s) regulating the production of neurosteroids is not understood. To determine whether hypothalamic-pituitary-gonadal axis components previously detected in the extra-hypothalamic brain comprise a feedback loop to regulate neuro-sex steroid (NSS) production, we assessed dynamic changes in expression patterns of steroidogenic acute regulatory (StAR) protein, a key regulator of steroidogenesis, and key hypothalamic-pituitary-gonadal endocrine receptors, by modulating peripheral sex hormone levels in female mice. Ovariectomy (OVX; high serum gonadotropins, low serum sex steroids) had a differential effect on StAR protein levels in the extrahypothalamic brain; increasing the 30- and 32-kDa variants but decreasing the 37-kDa variant and is indicative of cholesterol transport into mitochondria for steroidogenesis. Treatment of OVX animals with E2,P4,or E2 + P4 for 3 days, which decreases OVX-induced increases in GnRH/gonadotropin production, reversed this pattern. Suppression of gonadotropin levels in OVX mice using the GnRH agonist leuprolide acetate inhibited the processing of the 37-kDa StAR protein into the 30-kDa StAR protein, confirming that the differential processing of brain StAR protein is regulated by gonadotropins. OVX dramatically suppressed extra-hypothalamic brain gonadotropin-releasing hormone 1 receptor expression, and was further suppressed in E2- or P4-treated OVX mice. Together, these data indicate the existence of endocrine and autocrine/paracrine feedback loops that regulate NSS synthesis. Further delineation of these feedback loops that regulate NSS production will aid in developing therapies to maintain brain sex steroid levels and cognition.
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影响因子：
--
作者：
Couse, JF;Yates, MM;Korach, KS
通讯作者：
Korach, KS
DOI：
10.1074/jbc.m709221200
发表时间：
2008-04-04
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Bose M;Whittal RM;Miller WL;Bose HS
通讯作者：
Bose HS
影响因子：
5.8
作者：
Baracat, E;Haidar, R;Negro-Vilar, A
通讯作者：
Negro-Vilar, A
影响因子：
3.7
作者：
Chung, PH;Sandhoff, TW;McLean, MP
通讯作者：
McLean, MP
影响因子：
6.1
作者：
Eldar-Geva, T;Spitz, IM;Homburg, R
通讯作者：
Homburg, R