Biological activities of 7-dehydrocholesterol-derived oxysterols: implications for Smith-Lemli-Opitz syndrome
Biological activities of 7-dehydrocholesterol-derived oxysterols: implications for Smith-Lemli-Opitz syndrome
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DOI：
10.1194/jlr.m009365
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发表时间：
2010-11-01
影响因子：
6.5
通讯作者：
Porter, Ned A.
中科院分区：
文献类型：
--
作者：
Korade, Zeljka;Xu, Libin;Porter, Ned A.
Smith-Lemli-Opitz 综合征 (SLOS) 是一种代谢和发育障碍，由编码 7-脱氢胆固醇还原酶 (Dhcr7) 的基因突变引起。这种还原酶催化胆固醇生物合成的最后一步，并且由于这种缺陷，SLOS 患者的 7-脱氢胆固醇 (7-DHC)（这种酶的底物）水平升高。我们的小组之前已经表明，7-DHC 极易发生自由基自氧化，并且我们鉴定了大约十几种由 7-DHC 氧化形成的不同氧甾醇。我们在此报道，7-DHC 衍生的氧甾醇以剂量和时间依赖性方式降低细胞活力，其中一些化合物在亚微摩尔浓度下显示出活性。细胞存活率的降低是由 Neuro2a 细胞增殖减少和诱导分化共同引起的。添加到对照 Neuro2a 细胞中的复杂 7-DHC 氧化甾醇混合物也会触发先前在 Dhcr7 缺陷型 Neuro2a 细胞中发现的基因表达变化。基于 Dhcr7 缺陷和 7-DHC 氧化甾醇处理的 Neuro2a 细胞中重叠基因表达变化的鉴定，我们假设小鼠 SLOS 模型和 SLOS 患者的一些病理生理学发现可能是由于 7-DHC 氧化甾醇的积累所致。-Korade, Z., L. Xu, R. Shelton 和 N. A. Porter。 7-脱氢胆固醇衍生的氧甾醇的生物活性：对 Smith-Lemli-Opitz 综合征的影响。 J.脂质研究。 51：3259-3269。
Smith-Lemli-Opitz syndrome (SLOS) is a metabolic and developmental disorder caused by mutations in the gene encoding the enzyme 7-dehydrocholesterol reductase (Dhcr7). This reductase catalyzes the last step in cholesterol biosynthesis, and levels of 7-dehydrocholesterol (7-DHC), the substrate for this enzyme, are elevated in SLOS patients as a result of this defect. Our group has previously shown that 7-DHC is extremely prone to free radical autoxidation, and we identified about a dozen different oxysterols formed from oxidation of 7-DHC. We report here that 7-DHC-derived oxysterols reduce cell viability in a dose-and time-dependent manner, some of the compounds showing activity at sub-micromolar concentrations. The reduction of cell survival is caused by a combination of reduced proliferation and induced differentiation of the Neuro2a cells. The complex 7-DHC oxysterol mixture added to control Neuro2a cells also triggers the gene expression changes that were previously identified in Dhcr7-deficient Neuro2a cells. Based on the identification of overlapping gene expression changes in Dhcr7-deficient and 7-DHC oxysteroltreated Neuro2a cells, we hypothesize that some of the pathophysiological findings in the mouse SLOS model and SLOS patients might be due to accumulated 7-DHC oxysterols.-Korade, Z., L. Xu, R. Shelton, and N. A. Porter. Biological activities of 7-dehydrocholesterol-derived oxysterols: implications for Smith-Lemli-Opitz syndrome. J. Lipid Res. 51: 3259-3269.