Lipid biomarkers of oxidative stress in a genetic mouse model of Smith-Lemli-Opitz syndrome.
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-Δ(7)-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.
Department of Psychiatry and Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, TN 37235, USA.
Zeljka
Z
Korade
Libin
L
Xu
Karoly
K
Mirnics
Ned A
NA
Porter
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D003684:Dehydrocholesterols / Q000378:metabolism; D004195:Disease Models, Animal; D015227:Lipid Peroxidation; D008099:Liver / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000235:genetics*; D019082:Smith-Lemli-Opitz Syndrome / Q000235:genetics* / Q000378:metabolism*
D015415:Biomarkers; D003684:Dehydrocholesterols; C016705:7-dehydrocholesterol