title: Oxysterol binding protein-related protein 8 mediates the cytotoxicity of 25-hydroxycholesterol.
abstract: 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.
authors.affiliation: Department of Biotechnology Jinan University, Guangzhou 510632, China; Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Jinan University, Guangzhou 510632, China.
authors.forename: Jiwei
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Biotechnology Jinan University, Guangzhou 510632, China; Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Jinan University, Guangzhou 510632, China.
authors.forename: Xiuting
authors.initials: X
authors.lastname: Zheng
authors.affiliation: State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Lou
authors.affiliation: Department of Biotechnology Jinan University, Guangzhou 510632, China; Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Jinan University, Guangzhou 510632, China.
authors.forename: Wenbin
authors.initials: W
authors.lastname: Zhong
authors.affiliation: Department of Biotechnology Jinan University, Guangzhou 510632, China; Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Jinan University, Guangzhou 510632, China. Electronic address: tydg@jnu.edu.cn.
authors.forename: Daoguang
authors.initials: D
authors.lastname: Yan
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000235:genetics; D056945:Hep G2 Cells; D006801:Humans; D006888:Hydroxycholesterols / Q000633:toxicity*; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D000098825:Oxysterol Binding Proteins
chemical_list: D006888:Hydroxycholesterols; D011987:Receptors, Steroid; D000098825:Oxysterol Binding Proteins; C007997:25-hydroxycholesterol
keywords: apoptosis; cytotoxicity of oxysterols; endoplasmic reticulum stress