Assays of plasma dehydrocholesteryl esters and oxysterols from Smith-Lemli-Opitz syndrome patients[S]

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

Journal of Lipid Research (Jan 2013)

Assays of plasma dehydrocholesteryl esters and oxysterols from Smith-Lemli-Opitz syndrome patients[S]

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

Affiliations

Wei Liu: Department of Chemistry, Vanderbilt Institute of Chemical Biology and Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, TN 37235
Libin Xu: Department of Chemistry, Vanderbilt Institute of Chemical Biology and Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, TN 37235
Connor R. Lamberson: Department of Chemistry, Vanderbilt Institute of Chemical Biology and Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, TN 37235
Louise S. Merkens: Department of Pediatrics, Oregon Health and Science University, Portland, OR 97239
Robert D. Steiner: Departments of Pediatrics and Molecular and Medical Genetics, Child Development and Rehabilitation Center, Doernbecher Children's Hospital, Oregon Health and Science University, Portland, OR 97239
Ellen R. Elias: Department of Pediatrics and Genetics, University of Colorado School of Medicine, The Children's Hospital, Denver, CO 80045; and
Dorothea Haas: University Children's Hospital, Division of Inborn Metabolic Diseases, Im Neuenheimer Feld 430, D-69120 Heidelberg, Germany
Ned A. Porter: To whom correspondence should be addressed. e-mail: [email protected].; Department of Chemistry, Vanderbilt Institute of Chemical Biology and Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, TN 37235; To whom correspondence should be addressed. e-mail: [email protected].

Journal volume & issue: Vol. 54, no. 1
pp. 244 – 253

Abstract

Read online

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.

Published in Journal of Lipid Research

ISSN: 0022-2275 (Print); 1539-7262 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science: Chemistry: Organic chemistry: Biochemistry
Website: https://www.journals.elsevier.com/journal-of-lipid-research

About the journal

Abstract

Keywords