Oxysterol binding protein-related protein 8 mediates the cytotoxicity of 25-hydroxycholesterol.
Oxysterol binding protein-related protein 8 mediates the cytotoxicity of 25-hydroxycholesterol.
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氧甾醇结合蛋白相关蛋白8介导25-羟基胆固醇的细胞毒性
DOI：
10.1194/jlr.m069906
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发表时间：
2016-10
影响因子：
6.5
通讯作者：
Yan D
中科院分区：
文献类型：
--
作者：
Li J;Zheng X;Lou N;Zhong W;Yan D
氧固醇是胆固醇的27-碳氧化衍生物或胆固醇生物合成的副产物，除了许多其他生物作用之外，还可以诱导细胞凋亡。然而，这种细胞毒性的机制尚未完全了解。ORP 8是氧化固醇结合蛋白相关蛋白（ORP）家族的成员，参与细胞脂质稳态、迁移和微管细胞骨架的组织。在这里，我们报告说，25-羟基胆固醇（OHC）诱导凋亡的肝癌细胞系，HepG 2和Huh 7，通过内质网（ER）应激反应途径，和ORP 8过表达导致类似的细胞反应，25-OHC，表明氧化甾醇细胞毒性和ORP 8之间的推定的功能关系。进一步的实验表明，ORP 8过表达显著增强了25-OHC对HepG 2细胞中ER应激和凋亡的作用。缺乏配体结合结构域或密切相关的蛋白质ORP 5的截短的ORP 8构建体缺乏这种活性，证明了所观察到的效应的特异性。重要的是，ORP 8敲低显著抑制了对25-OHC的这种反应。总而言之，本研究表明ORP 8可能介导25-OHC的细胞毒性。
Oxysterols are 27-carbon oxidized derivatives of cholesterol or by-products of cholesterol biosynthesis that can induce cell apoptosis in addition to a number of other bioactions. However, the mechanisms underlying this cytotoxicity are not completely understood. ORP8 is a member of the oxysterol binding protein-related protein (ORP) family, implicated in cellular lipid homeostasis, migration, and organization of the microtubule cytoskeleton. Here, we report that 25-hydroxycholesterol (OHC) induced apoptosis of the hepatoma cell lines, HepG2 and Huh7, via the endoplasmic reticulum (ER) stress response pathway, and ORP8 overexpression resulted in a similar cell response as 25-OHC, indicating a putative functional relationship between oxysterol cytotoxicity and ORP8. Further experiments demonstrated that ORP8 overexpression significantly enhanced the 25-OHC effect on ER stress and apoptosis in HepG2 cells. A truncated ORP8 construct lacking the ligand-binding domain or a closely related protein, ORP5, was devoid of this activity, evidencing for specificity of the observed effects. Importantly, ORP8 knockdown markedly dampened such responses to 25-OHC. Taken together, the present study suggests that ORP8 may mediate the cytotoxicity of 25-OHC.
DOI：
10.1186/1471-2210-1-10
发表时间：
2001
期刊：
BMC pharmacology
影响因子：
--
作者：
Chang JY;Liu LZ
通讯作者：
Liu LZ