Targeted disruption of the mouse gene encoding steroidogenic acute regulatory protein provides insights into congenital lipoid adrenal hyperplasia
Targeted disruption of the mouse gene encoding steroidogenic acute regulatory protein provides insights into congenital lipoid adrenal hyperplasia
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DOI：
10.1073/pnas.94.21.11540
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发表时间：
1997-10-14
影响因子：
11.1
通讯作者：
Parker, KL
中科院分区：
文献类型：
--
作者：
Caron, KM;Soo, SC;Parker, KL
调节类固醇生成的一个重要组成部分是胆固醇从细胞质转运到线粒体内膜，其中胆固醇侧链裂解酶进行类固醇生成的第一个关键步骤。最近的研究表明，30 kDa的线粒体磷蛋白，命名为类固醇生成急性调节蛋白（星星），是这种易位所必需的，使我们能够探索星星在一个易于实验操作的系统中的作用，并建立一个人类脂质先天性肾上腺皮质增生症的动物模型（类脂CAH），我们使用靶向基因破坏来产生星星敲除小鼠，这些星星敲除小鼠最初与野生型同窝出生的小鼠没有区别，除了雄性和雌性具有雌性外生殖器，出生后，他们不能正常生长，死于肾上腺皮质功能不全。激素测定证实肾上腺类固醇严重缺陷-下丘脑-垂体水平负反馈调节丧失-而构成性腺轴的激素与野生型同窝仔的水平没有显著差异。组织学上，星星基因敲除小鼠的肾上腺皮质含有丰富的脂质沉积，睾丸的类固醇生成室中的沉积较少，卵巢中没有沉积，性腺参与的性别特异性差异支持星星缺乏症发病机制的两阶段模型，其中营养激素刺激诱导类固醇生成细胞内脂质的进行性积累并最终导致其死亡，这些星星基因敲除小鼠提供了一个有用的模型系统，以确定星星在肾上腺皮质和性腺类固醇生成中的重要作用的机制。
An essential component of regulated steroidogenesis is the translocation of cholesterol from the cytoplasm to the inner mitochondrial membrane where the cholesterol side-chain cleavage enzyme carries out the first committed step in steroidogenesis. Recent studies shelved that a 30-kDa mitochondrial phosphoprotein, designated steroidogenic acute regulatory protein (StAR), is essential for this translocation, To allow us to explore the roles of StAR in a system amenable to experimental manipulation and to develop an animal model for the human disorder lipoid congenital adrenal hyperplasia (lipoid CAH), we used targeted gene disruption to produce StAR knockout mice, These StAR knockout mice were indistinguishable initially from wild-type littermates, except that males and females had female external genitalia, After birth, they failed to grow normally and died from adrenocortical insufficiency. Hormone assays confirmed severe defects in adrenal steroids-with loss of negative feedback regulation at hypothalamic-pituitary levels-whereas hormones constituting the gonadal axis did not differ significantly from levels in wild-type littermates, Histologically, the adrenal cortex of StAR knockout mice contained florid lipid deposits, with lesser deposits in the steroidogenic compartment of the testis and none in the ovary, The sex-specific differences in gonadal involvement support a two-stage model of the pathogenesis of StAR deficiency, with trophic hormone stimulation inducing progressive accumulation of lipids within the steroidogenic cells and ultimately causing their death, These StAR knockout mice provide a useful model system in which to determine the mechanisms of StAR's essential roles in adrenocortical and gonadal steroidogenesis.