Molecular consequences of altered neuronal cholesterol biosynthesis.
Molecular consequences of altered neuronal cholesterol biosynthesis.
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DOI：
10.1002/jnr.21917
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发表时间：
2009-03
影响因子：
4.2
通讯作者：
Mirnics, Karoly
中科院分区：
文献类型：
--
作者：
Korade, Zeljka;Kenworthy, Anne K.;Mirnics, Karoly
胆固醇从头生物合成的第一个专门步骤从角鲨烯的形成开始，到 7-脱氢胆固醇还原酶 (Dhcr7) 将 7-脱氢胆固醇还原为胆固醇而结束，胆固醇是一种重要的结构和信号分子。 Dhcr7 基因突变会导致 Smith-Lemli-Opitz 综合征 (SLOS)，其特点是发育畸形、髓鞘形成不完全和智力低下。为了更好地了解神经元组织中 Dhcr7 缺乏的分子后果，我们分析了胆固醇缺乏对 Neuro2a 细胞转录组的影响。 siRNA 对 Dhcr7 的瞬时下调导致多个分子的表达发生改变，这些分子在细胞内信号传导或囊泡运输中发挥关键作用，或插入膜筏中（例如 Egr1、Snx 和 Adam19）。在稳定的 Dhrc7-shRNA 转染细胞系中也观察到类似的下调，并通过 qPCR 验证了这一结果。此外，我们研究了 Dhcr7 缺陷细胞和对照细胞中涉及脂质生物合成的几个关键基因的表达。其中，脂肪酸合酶、甾醇调节元件结合蛋白2、SREBF伴侣、位点1蛋白酶和角鲨烯合酶显示出显着的下调，表明在神经元细胞系中，Dhcr7是脂质生物合成的有效调节剂。重要的是，基因表达变化存在于含脂质和缺乏胆固醇的培养基中，这表明内在胆固醇生物合成对于正常神经元功能是必需的，并且不能从外在来源补充。
The first dedicated step in de novo cholesterol biosynthesis begins with formation of squalene and ends with the reduction of 7-dehydrocholesterol by 7-dehydrocholesterol reductase (Dhcr7) into cholesterol, which is an essential structural and signaling molecule. Mutations in the Dhcr7 gene lead to Smith-Lemli-Opitz syndrome (SLOS), which is characterized by developmental deformities, incomplete myelination, and mental retardation. To understand better the molecular consequences of Dhcr7 deficiency in neuronal tissue, we analyzed the effect of cholesterol deficiency on the transcriptome in Neuro2a cells. Transient down-regulation of Dhcr7 by siRNA led to altered expression of multiple molecules that play critical roles in intracellular signaling or vesicular transport or are inserted into membrane rafts (e.g. Egr1, Snx, and Adam19). A similar down-regulation was also observed in stable Dhrc7-shRNA-transfected cell lines, and the findings were verified by qPCR. Furthermore, we investigated the Dhcr7-deficient and control cells for the expression of several critical genes involved in lipid biosynthesis. Among these, fatty acid synthase, sterol-regulatory element binding protein 2, SREBF chaperone, site-1 protease, and squalene synthase showed a significant down-regulation, suggesting that, in a neuronal cell line, Dhcr7 is a potent regulator of lipid biosynthesis. Importantly, the gene expression changes were present in both lipid-containing and cholesterol-deficient media, suggesting that intrinsic cholesterol biosynthesis is necessary for normal neuronal function and cannot be supplemented from extrinsic sources.
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影响因子：
16
作者：
Brown, AJ;Sun, LP;Goldstein, JL
通讯作者：
Goldstein, JL
影响因子：
4.8
作者：
Bae, SH;Lee, JN;Paik, YK
通讯作者：
Paik, YK
影响因子：
6.2
作者：
Chen, Gang;Li, Hai-Min;Duan, Shumin
通讯作者：
Duan, Shumin
DOI：
10.1073/pnas.96.20.11041
发表时间：
1999-09-28
影响因子：
11.1
作者：
Brown, MS;Goldstein, JL
通讯作者：
Goldstein, JL
影响因子：
4.2
作者：
Korade, Zeljka;Mi, Zhiping;Schor, Nina E.
通讯作者：
Schor, Nina E.