Developmental roles of the steroidogenic acute regulatory protein (StAR) as revealed by StAR knockout mice.
Developmental roles of the steroidogenic acute regulatory protein (StAR) as revealed by StAR knockout mice.
复制标题
DOI：
10.1210/mend.14.9.0515
复制
发表时间：
2000-09
影响因子：
--
通讯作者：
Tomonobu Hasegawa;Liping Zhao;K. Caron;Gregor Majdic;Takashi Suzuki;S. Shizawa;Hironobu Sasano;Keith L. Parker
中科院分区：
文献类型：
--
作者：
Tomonobu Hasegawa;Liping Zhao;K. Caron;Gregor Majdic;Takashi Suzuki;S. Shizawa;Hironobu Sasano;Keith L. Parker
类固醇生成急性调节蛋白（星星）是肾上腺和性腺类固醇生成所必需的，刺激胆固醇转运到线粒体内膜，类固醇生成开始。人类星星突变导致先天性类脂质肾上腺增生（类脂质CAH），这是一种常染色体隐性疾病，严重缺乏所有类别的类固醇激素。我们先前描述了星星敲除小鼠，其模仿脂质CAH患者的许多特征。通过用皮质类固醇替代保持星星敲除小鼠存活，我们现在研究星星缺乏对类固醇生成组织的结构和功能的时间影响。肾上腺在出生时受影响最严重，随着年龄的增长，脂质沉积逐渐增加。新生星星基因敲除小鼠的睾丸在间质区含有分散的脂质沉积物，可能是胎儿Leydig细胞的残余物。到8周龄时，间质脂质沉积显著恶化，并与Leydig细胞增生相关。尽管有这些变化，曲细精管中的生殖细胞在组织学上看起来是完整的，这表明星星敲除小鼠保留了一些雄激素生物合成的能力。精子成熟延迟，生殖细胞表现出凋亡的组织学特征，与次优雄激素产生一致。出生后，星星基因敲除小鼠的卵巢立即显示正常。然而，在正常青春期后，显著的脂质沉积在间质区，伴随着显著的基质细胞黄素化和卵泡不完全成熟，最终导致卵巢早衰。这些研究首次系统评价了星星缺乏对各种类固醇生成器官的发育影响。
Steroidogenic acute regulatory protein (StAR) is essential for adrenal and gonadal steroidogenesis, stimulating the translocation of cholesterol to the inner mitochondrial membrane where steroidogenesis commences. StAR mutations in humans cause congenital lipoid adrenal hyperplasia (lipoid CAH), an autosomal recessive condition with severe deficiencies of all classes of steroid hormones. We previously described StAR knockout mice that mimic many features of lipoid CAH patients. By keeping StAR knockout mice alive with corticosteroid replacement, we now examine the temporal effects of StAR deficiency on the structure and function of steroidogenic tissues. The adrenal glands, affected most severely at birth, exhibited progressive increases in lipid deposits with aging. The testes of newborn StAR knockout mice contained scattered lipid deposits in the interstitial region, presumably in remnants of fetal Leydig cells. By 8 weeks of age, the interstitial lipid deposits worsened considerably and were associated with Leydig cell hyperplasia. Despite these changes, germ cells in the seminiferous tubules appeared intact histologically, suggesting that the StAR knockout mice retained some capacity for androgen biosynthesis. Sperm maturation was delayed, and the germ cells exhibited histological features of apoptosis, consistent with suboptimal androgen production. Immediately after birth, the ovaries of StAR knockout mice appeared normal. After the time of normal puberty, however, prominent lipid deposits accumulated in the interstitial region, accompanied by marked luteinization of stromal cells and incomplete follicular maturation that ultimately culminated in premature ovarian failure. These studies provide the first systematic evaluation of the developmental consequences of StAR deficiency in the various steroidogenic organs.