title: Diverse functions of 24(S)-hydroxycholesterol in the brain.
abstract: 24(S)-hydroxycholesterol (24S-OHC) which is enzymatically produced in the brain plays important physiological roles in maintaining brain cholesterol homeostasis. We found that 24S-OHC at sub-lethal concentrations down-regulated amyloid precursor protein (APP) trafficking via enhancement of the complex formation of APP with up-regulated glucose-regulated protein 78, an endoplasmic reticulum chaperone. In accordance with this mechanism, 24S-OHC suppressed amyloid-β production in human neuroblastoma SH-SY5Y cells. Furthermore, 24S-OHC at sub-lethal concentrations induced adaptive responses via transcriptional activation of the liver X receptor signaling pathway, thereby protecting neuronal cells against the forthcoming oxidative stress induced by 7-ketocholesterol. On the other hand, we found that high concentrations of 24S-OHC induced apoptosis in T-lymphoma Jurkat cells which endogenously expressed caspase-8, and induced necroptosis - a form of programmed necrosis - in neuronal SH-SY5Y cells which expressed no caspase-8. In this Article, we show the diverse functions of 24S-OHC and consider the possible importance of controlling 24S-OHC levels in the brain for preventing neurodegenerative diseases.
authors: Systems Life Sciences Laboratory, Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto 610-0394, Japan. Electronic address: nnoguchi@mail.doshisha.ac.jp.
authors: Noriko
authors: N
authors: Noguchi
authors: Systems Life Sciences Laboratory, Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto 610-0394, Japan.
authors: Yoshiro
authors: Y
authors: Saito
authors: Systems Life Sciences Laboratory, Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto 610-0394, Japan.
authors: Yasuomi
authors: Y
authors: Urano
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D053181:Caspase 8 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D006888:Hydroxycholesterols / Q000378:metabolism* / Q000494:pharmacology; D007653:Ketocholesterols / Q000378:metabolism / Q000494:pharmacology; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D006888:Hydroxycholesterols; D007653:Ketocholesterols; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; C044563:24-hydroxycholesterol; D053181:Caspase 8; C003001:7-ketocholesterol
keywords: 24(S)-hydroxycholesterol; 7-Ketocholesterol; Adaptive response; Necroptosis; Neurodegenerative disease