文章基本信息

标题：Metabolism of oxysterols derived from nonenzymatic oxidation of 7-dehydrocholesterol in cells
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作者：Libin Xu ; Zeljka Korade ; Dale A. Rosado 等
期刊名称：JLR Papers In Press
印刷版ISSN：0022-2275
电子版ISSN：1539-7262
出版年度：2013
卷号：54
期号：4
页码：1135-1143
DOI：10.1194/jlr.M035733
语种：English
出版社：American Society for Biochemistry and Molecular Biology
摘要：Recent studies suggest that 7-dehydrocholesterol (7-DHC)-derived oxysterols play important roles in the pathophysiology of Smith-Lemli-Opitz syndrome (SLOS), a metabolic disorder that is caused by defective 3β-hydroxysterol-Δ⁷-reductase (DHCR7). Although 14 oxysterols have been identified as the primary products of 7-DHC autoxidation in organic solution, the metabolic fate of these oxysterols in a biological environment has not yet been elucidated. Therefore, we incubated these primary 7-DHC oxysterols in control Neuro2a and control human fibroblast cells and identified metabolites of these oxysterols by HPLC-MS. We also incubated Dhcr7 -deficient Neuro2a cells and fibroblasts from SLOS patients with isotopically labeled 7-DHC ( d ₇-7-DHC). The observation of matching d ₀- and d ₇ peaks in HPLC-MS confirmed the presence of true metabolites of 7-DHC after excluding the possibility of ex vivo oxidation. The metabolites of primary 7-DHC oxysterols were found to contribute to the majority of the metabolic profile of 7-DHC in cells. Furthermore, based on this new data, we identified three new 7-DHC-derived metabolites in the brain of Dhcr7 -KO mice. Our studies suggest that 7-DHC peroxidation is a major source of oxysterols observed in cells and in vivo and that the stable metabolites of primary 7-DHC oxysterols can be used as markers of 7-DHC peroxidation in these biological systems.
关键词：Smith-Lemli-Opitz syndrome ; lipid peroxidation autoxidation ; Neuro2a ; fibroblast ; mass spectrometry