Metabolism of oxysterols derived from nonenzymatic oxidation of 7-dehydrocholesterol in cells

Libin Xu, Zeljka Korade, Dale A. Rosado, Karoly Mirnics, Ned A. Porter

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

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 3 α -hydroxysterol- δ 7 -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.

Original languageEnglish (US)
Pages (from-to)1135-1143
Number of pages9
JournalJournal of Lipid Research
Volume54
Issue number4
DOIs
StatePublished - Apr 2013

Keywords

  • Fibroblast
  • Lipid peroxidation autoxidation
  • Mass spectrometry
  • Neuro2a
  • Smith -Lemli-Opitz syndrome

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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