Assays of plasma dehydrocholesteryl esters and oxysterols from Smith-Lemli-Opitz syndrome patient

Wei Liu, Libin Xu, Connor R. Lamberson, Louise S. Merkens, Robert D. Steiner, Ellen R. Elias, Dorothea Haas, Ned A. Porter

Research output: Contribution to journalArticlepeer-review

26 Scopus citations

Abstract

Smith-Lemli-Opitz syndrome (SLOS) is caused by mutations in the gene encoding 3β-hydroxysterol-Δ7 -reductase and as a result of this defect, 7-dehydrocholesterol (7-DHC) and 8-dehydrocholesterol (8-DHC) accumulate in the fluids and tissues of patients with this syndrome. Both 7- and 8-DHC are susceptible to peroxidation reactions, and several biologically active DHC oxysterols are found in cell and animal models of SLOS. Ex vivo oxidation of DHCs can be a confounding factor in the analysis of these sterols and their esters, and we developed HPLC/MS methods that permit the direct analysis of cholesterol, 7-DHC, 8-DHC, and their esters in human plasma, thus avoiding ex vivo oxidation. In addition, three oxysterols were classified as endogenously formed products by the use of an isotopically-labeled 7-DHC (d7-7-DHC) added to the sample before workup, followed by MS analysis of products formed. Analysis of 17 SLOS plasma samples shows that 8-DHC linoleate correlates better with the SLOS severity score of the patients than other sterols or metabolites, including cholesterol and 7-DHC. Levels of 7-ketocholesterol also correlate with the SLOS severity score. 8-DHC esters should have utility as surrogate markers of severity in SLOS for prognostication and as endpoints in clinical trials.

Original languageEnglish (US)
Pages (from-to)244-253
Number of pages10
JournalJournal of lipid research
Volume54
Issue number1
DOIs
StatePublished - Jan 2013

Keywords

  • 7-Dehydrocholesterol
  • 8-Dehydrocholesterol
  • Acyl-CoA:cholesterol acyltransferase
  • Free radical oxidation
  • Lecithin: Cholesterol acyl transferase
  • Lipid peroxidation
  • Oxysterol
  • Sterol ester

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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