Journal of Inherited Metabolic Disease

, Volume 36, Issue 1, pp 113–122

Lipid biomarkers of oxidative stress in a genetic mouse model of Smith-Lemli-Opitz syndrome

  • Zeljka Korade
  • Libin Xu
  • Karoly Mirnics
  • Ned A. Porter
Original Article

DOI: 10.1007/s10545-012-9504-z

Cite this article as:
Korade, Z., Xu, L., Mirnics, K. et al. J Inherit Metab Dis (2013) 36: 113. doi:10.1007/s10545-012-9504-z

Abstract

7-Dehydrocholesterol (7-DHC) accumulates in tissues and fluids of patients with Smith-Lemli-Opitz syndrome (SLOS), which is caused by mutations in the gene encoding 3β-hydroxysterol-Δ7-reductase (DHCR7). We recently reported that 7-DHC is the most reactive lipid molecule toward free radical oxidation (lipid peroxidation) and 14 oxysterols have been identified as products of oxidation of 7-DHC in solution. As the high oxidizability of 7-DHC may lead to systemic oxidative stress in SLOS patients, we report here lipid biomarkers of oxidative stress in a Dhcr7-KO mouse model of SLOS, including oxysterols, isoprostanes (IsoPs), and neuroprostanes (NeuroPs) that are formed from the oxidation of 7-DHC, arachidonic acid and docosahexaenoic acid, respectively. In addition to a previously described oxysterol, 3β,5α-dihydroxycholest-7-en-6-one (DHCEO), we provide evidence for the chemical structures of three new oxysterols in the brain and/or liver tissue of Dhcr7-KO mice, two of which were quantified. We find that levels of IsoPs and NeuroPs are also elevated in brain and/or liver tissues of Dhcr7-KO mice relative to matching WT mice. While IsoPs and NeuroPs have been established as a reliable measurement of lipid peroxidation and oxidative stress in vivo, we show that in this genetic SLOS mouse model, 7-DHC-derived oxysterols are present at much higher levels than IsoPs and NeuroPs and thus are better markers of lipid oxidation and related oxidative stress.

Abbreviations

APCI

atmospheric pressure chemical ionization

BHT

butylated hydroxytoluene

Chol

cholesterol

CYP

cytochrome P450

7-DHC

7-dehydrocholesterol

DHCEO

3β,5α-dihydroxycholest-7-en-6-one

Dhcr7 or DHCR7

7-dehydrocholesterol reductase

EnP(5,8)

5α,8α-epidioxy-cholest-6-en-3β-ol

IsoP

isoprostane

NeuroP

neuroprostane

8-IsoP

8-iso-prostaglandin F (8-iso-PGF)

7-kChol

7-ketocholesterol

KO

knock out

NP

normal phase

4α-OH-7-DHC

4α-hydroxy-7-DHC

4β-OH-7-DHC

4β-hydroxy-7-DHC

24-OH-7-DHC

24-hydroxy-7-DHC

PPh3

triphenylphosphine

SLOS

Smith-Lemli-Opitz syndrome

SRM

selective reaction monitoring

WT

wild type

Copyright information

© SSIEM and Springer 2012

Authors and Affiliations

  • Zeljka Korade
    • 2
  • Libin Xu
    • 1
  • Karoly Mirnics
    • 2
  • Ned A. Porter
    • 1
    • 3
  1. 1.Department of Chemistry and Vanderbilt Institute of Chemical BiologyNashvilleUSA
  2. 2.Department of Psychiatry and Vanderbilt Kennedy Center for Research on Human DevelopmentVanderbilt UniversityNashvilleUSA
  3. 3.Department of Chemistry7962 Stevenson Center, Vanderbilt UniversityNashvilleUSA

Personalised recommendations