title: Adaptive responses induced by 24S-hydroxycholesterol through liver X receptor pathway reduce 7-ketocholesterol-caused neuronal cell death.
abstract: Lipid peroxidation products have been known to induce cellular adaptive responses and enhance tolerance against subsequent oxidative stress through up-regulation of antioxidant compounds and enzymes. 24S-hydroxycholesterol (24SOHC) which is endogenously produced oxysterol in the brain plays an important role in maintaining brain cholesterol homeostasis. In this study, we evaluated adaptive responses induced by brain-specific oxysterol 24SOHC in human neuroblastoma SH-SY5Y cells. Cells treated with 24SOHC at sub-lethal concentrations showed significant reduction in cell death induced by subsequent treatment with 7-ketocholesterol (7KC) in both undifferentiated and retinoic acid-differentiated SH-SY5Y cells. These adaptive responses were also induced by other oxysterols such as 25-hydroxycholesterol and 27-hydroxycholesterol which are known to be ligands of liver X receptor (LXR). Co-treatment of 24SOHC with 9-cis retinoic acid, a retinoid X receptor ligand, enhanced the adaptive responses. Knockdown of LXRβ by siRNA diminished the adaptive responses induced by 24SOHC almost completely. The treatment with 24SOHC induced the expression of LXR target genes, such as ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1). The 24SOHC-induced adaptive responses were significantly attenuated by siRNA for ABCG1 but not by siRNA for ABCA1. Taken together, these results strongly suggest that 24SOHC at sub-lethal concentrations induces adaptive responses via transcriptional activation of LXR signaling pathway, thereby protecting neuronal cells from subsequent 7KC-induced cytotoxicity.
authors.affiliation: Systems Life Sciences, Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, 1-3 Miyakodani, Tatara, Kyotanabe, Kyoto 610-0394, Japan.
authors.forename: Akishi
authors.initials: A
authors.lastname: Okabe
authors.affiliation: Systems Life Sciences, 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, Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, 1-3 Miyakodani, Tatara, Kyotanabe, Kyoto 610-0394, Japan.
authors.forename: Sayoko
authors.initials: S
authors.lastname: Itoh
authors.affiliation: Systems Life Sciences, Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, 1-3 Miyakodani, Tatara, Kyotanabe, Kyoto 610-0394, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Suda
authors.affiliation: Systems Life Sciences, Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, 1-3 Miyakodani, Tatara, Kyotanabe, Kyoto 610-0394, Japan.
authors.forename: Rina
authors.initials: R
authors.lastname: Kotani
authors.affiliation: Systems Life Sciences, Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, 1-3 Miyakodani, Tatara, Kyotanabe, Kyoto 610-0394, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Nishimura
authors.affiliation: Systems Life Sciences, 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, Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, 1-3 Miyakodani, Tatara, Kyotanabe, Kyoto 610-0394, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Noguchi
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology*; D007653:Ketocholesterols / Q000494:pharmacology*; D000071518:Liver X Receptors; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D057093:Orphan Nuclear Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C577836:ABCA1 protein, human; C419353:ABCG1 protein, human; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D006888:Hydroxycholesterols; D007653:Ketocholesterols; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D034741:RNA, Small Interfering; C044563:24-hydroxycholesterol; C003001:7-ketocholesterol
keywords: 24S-hydroxycholesterol; 24SOHC, 24S-hydroxycholesterol; 7-ketocholesterol; 7KC, 7-ketocholesterol; 9cRA, 9-cis retinoic acid; ABCA1, ATP-binding cassette transporter A1; ABCG1, ATP-binding cassette transporter G1; AD, Alzheimer's disease; ATP-binding cassette transporter G1; Adaptive responses; CYP46A1, cholesterol 24-hydroxylase; Cell death; FITC, fluorescein isothiocyanate; HDL, high-density lipoprotein; LDH, lactate dehydrogenase; LXR, liver X receptor; Liver X receptor; MAP2, microtubule-associated protein 2; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NC, negative control; PI, propidium iodide; RXR, retinoid X receptor; atRA, all-trans retinoic acid