title: Effect of vitamin E on 24(S)-hydroxycholesterol-induced necroptosis-like cell death and apoptosis.
abstract: 24(S)-Hydroxycholesterol (24S-OHC) has diverse physiological and pathological functions. In particular, cytotoxic effects of 24S-OHC in neuronal cells are important in development of neurodegenerative diseases. 24S-OHC induces necroptosis-like cell death in SH-SY5Y cells expressing little caspase-8. In the present study, 24S-OHC was found to induce apoptosis as determined by caspase-3 activation in all-trans-retinoic acid (atRA)-treated SH-SY5Y cells in which expression of caspase-8 was induced. 24S-OHC-induced cell death was inhibited by α-tocopherol (α-Toc) but not by α-tocotrienol (α-Toc3) in SH-SY5Y cells regardless of whether cells were treated with atRA. In contrast, cumene hydroperoxide (CumOOH)-induced cell death was significantly inhibited by α-Toc and α-Toc3. In atRA-treated SH-SY5Y cells, generation of reactive oxygen species (ROS) was induced by stimulation with CumOOH but was not induced by stimulation with 24S-OHC. These results suggest that inhibition of 24S-OHC-induced cell death by α-Toc cannot be explained by its radical scavenging antioxidant activity. Esterification of 24S-OHC followed by lipid droplet (LD) formation due to acyl-CoA:cholesterol acyltransferase 1 (ACAT1) are key events in 24S-OHC-induced cell death in atRA-treated SH-SY5Y cells as demonstrated by inhibition of cell death by ACAT1 inhibitor. LD number was not changed by treatment with either α-Toc or α-Toc3. The different physical properties of α-Toc and α-Toc3 may account for their different inhibitory effects on 24S-OHC-induced cell death.
authors.affiliation: Systems Life Sciences Laboratory, Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, 1-3 Miyakodani, Tatara, Kyotanabe, Kyoto 610-0394, Japan.
authors.forename: Takaya
authors.initials: T
authors.lastname: Nakazawa
authors.affiliation: Systems Life Sciences Laboratory, Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, 1-3 Miyakodani, Tatara, Kyotanabe, Kyoto 610-0394, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Miyanoki
authors.affiliation: Systems Life Sciences Laboratory, Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, 1-3 Miyakodani, Tatara, Kyotanabe, Kyoto 610-0394, Japan.
authors.forename: Yasuomi
authors.initials: Y
authors.lastname: Urano
authors.affiliation: Systems Life Sciences Laboratory, Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, 1-3 Miyakodani, Tatara, Kyotanabe, Kyoto 610-0394, Japan.
authors.forename: Madoka
authors.initials: M
authors.lastname: Uehara
authors.affiliation: Systems Life Sciences Laboratory, Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, 1-3 Miyakodani, Tatara, Kyotanabe, Kyoto 610-0394, Japan.
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Saito
authors.affiliation: Systems Life Sciences Laboratory, Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, 1-3 Miyakodani, Tatara, Kyotanabe, Kyoto 610-0394, Japan. Electronic address: nnoguchi@mail.doshisha.ac.jp.
authors.forename: Noriko
authors.initials: N
authors.lastname: Noguchi
mesh_terms: D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis; D016923:Cell Death; D045744:Cell Line, Tumor; D002470:Cell Survival; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology*; D008055:Lipids / Q000737:chemistry; D008856:Microscopy, Fluorescence; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D024508:Tocotrienols / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology; D014810:Vitamin E / Q000494:pharmacology*; D024502:alpha-Tocopherol / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D006888:Hydroxycholesterols; D008055:Lipids; D017382:Reactive Oxygen Species; D024508:Tocotrienols; D014810:Vitamin E; C044563:24-hydroxycholesterol; D014212:Tretinoin; C082032:tocotrienol, alpha; D024502:alpha-Tocopherol
keywords: 24(S)-hydroxycholesterol; Caspase-8; Cell death; Lipid droplet; α-Tocopherol; α-Tocotrienol