Lipid Biomarkers of Oxidative Stress in a Genetic Mouse Model of Smith-Lemli-Opitz Syndrome

Overview

Journal J Inherit Metab Dis

Publisher Wiley

Date 2012 Jun 22

PMID 22718275

Citations 39

Authors

Zeljka Korade

Libin Xu

Karoly Mirnics

Ned A Porter

Affiliations

Soon will be listed here.

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-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.

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References

Yoritaka A, Hattori N, Uchida K, Tanaka M, Stadtman E, Mizuno Y . Immunohistochemical detection of 4-hydroxynonenal protein adducts in Parkinson disease. Proc Natl Acad Sci U S A. 1996; 93(7):2696-701. PMC: 39693. DOI: 10.1073/pnas.93.7.2696. View

Montine K, Quinn J, Zhang J, Fessel J, Roberts 2nd L, Morrow J . Isoprostanes and related products of lipid peroxidation in neurodegenerative diseases. Chem Phys Lipids. 2004; 128(1-2):117-24. DOI: 10.1016/j.chemphyslip.2003.10.010. View

Porter F, Scherrer D, Lanier M, Langmade S, Molugu V, Gale S . Cholesterol oxidation products are sensitive and specific blood-based biomarkers for Niemann-Pick C1 disease. Sci Transl Med. 2010; 2(56):56ra81. PMC: 3170139. DOI: 10.1126/scitranslmed.3001417. View

Vaughan D, Peachey N, Richards M, Buchan B, Fliesler S . Light-induced exacerbation of retinal degeneration in a rat model of Smith-Lemli-Opitz syndrome. Exp Eye Res. 2005; 82(3):496-504. PMC: 2844790. DOI: 10.1016/j.exer.2005.08.008. View

Yin H, Xu L, Porter N . Free radical lipid peroxidation: mechanisms and analysis. Chem Rev. 2011; 111(10):5944-72. DOI: 10.1021/cr200084z. View

Bukelis I, Porter F, Zimmerman A, Tierney E . Smith-Lemli-Opitz syndrome and autism spectrum disorder. Am J Psychiatry. 2007; 164(11):1655-61. DOI: 10.1176/appi.ajp.2007.07020315. View

Miller W, Gaylor J . Investigation of the component reactions of oxidative sterol demethylation. Oxidation of a 4 alpha-methyl sterol to a 4 alpha-carboxylic acid during cholesterol biosynthesis. J Biol Chem. 1970; 245(20):5369-74. View

Milne G, Yin H, Hardy K, Davies S, Roberts 2nd L . Isoprostane generation and function. Chem Rev. 2011; 111(10):5973-96. PMC: 3192249. DOI: 10.1021/cr200160h. View

Porter F, Herman G . Malformation syndromes caused by disorders of cholesterol synthesis. J Lipid Res. 2010; 52(1):6-34. PMC: 2999931. DOI: 10.1194/jlr.R009548. View

10.

Breuer O, Dzeletovic S, Lund E, Diczfalusy U . The oxysterols cholest-5-ene-3 beta,4 alpha-diol, cholest-5-ene-3 beta,4 beta-diol and cholestane-3 beta,5 alpha,6 alpha-triol are formed during in vitro oxidation of low density lipoprotein, and are present in human atherosclerotic plaques. Biochim Biophys Acta. 1996; 1302(2):145-52. DOI: 10.1016/0005-2760(96)00052-5. View

11.

Janowski B, Willy P, Devi T, Falck J, Mangelsdorf D . An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha. Nature. 1996; 383(6602):728-31. DOI: 10.1038/383728a0. View

12.

Valencia A, Kochevar I . Ultraviolet A induces apoptosis via reactive oxygen species in a model for Smith-Lemli-Opitz syndrome. Free Radic Biol Med. 2006; 40(4):641-50. DOI: 10.1016/j.freeradbiomed.2005.09.036. View

13.

Shinkyo R, Xu L, Tallman K, Cheng Q, Porter N, Guengerich F . Conversion of 7-dehydrocholesterol to 7-ketocholesterol is catalyzed by human cytochrome P450 7A1 and occurs by direct oxidation without an epoxide intermediate. J Biol Chem. 2011; 286(38):33021-8. PMC: 3190903. DOI: 10.1074/jbc.M111.282434. View

14.

Tint G, Seller M, Batta A, SHEFER S, Genest D, Irons M . Markedly increased tissue concentrations of 7-dehydrocholesterol combined with low levels of cholesterol are characteristic of the Smith-Lemli-Opitz syndrome. J Lipid Res. 1995; 36(1):89-95. View

15.

Vejux A, Lizard G . Cytotoxic effects of oxysterols associated with human diseases: Induction of cell death (apoptosis and/or oncosis), oxidative and inflammatory activities, and phospholipidosis. Mol Aspects Med. 2009; 30(3):153-70. DOI: 10.1016/j.mam.2009.02.006. View

16.

Agus D, Gambhir S, Pardridge W, Spielholz C, Baselga J, Vera J . Vitamin C crosses the blood-brain barrier in the oxidized form through the glucose transporters. J Clin Invest. 1998; 100(11):2842-8. PMC: 508490. DOI: 10.1172/JCI119832. View

17.

Charman C, Ryan A, Tyrrell R, Pearse A, Arlett C, Kurwa H . Photosensitivity associated with the Smith-Lemli-Opitz syndrome. Br J Dermatol. 1998; 138(5):885-8. DOI: 10.1046/j.1365-2133.1998.02231.x. View

18.

Roberts 2nd L, Montine T, Markesbery W, Tapper A, Hardy P, Chemtob S . Formation of isoprostane-like compounds (neuroprostanes) in vivo from docosahexaenoic acid. J Biol Chem. 1998; 273(22):13605-12. DOI: 10.1074/jbc.273.22.13605. View

19.

Xu L, Sheflin L, Porter N, Fliesler S . 7-Dehydrocholesterol-derived oxysterols and retinal degeneration in a rat model of Smith-Lemli-Opitz syndrome. Biochim Biophys Acta. 2012; 1821(6):877-83. PMC: 3340457. DOI: 10.1016/j.bbalip.2012.03.001. View

20.

Miller W, Gaylor J . Investigation of the component reactions of oxidative sterol demethylation. Oxidation of a 4,4-dimethyl sterol to a 4 beta-methyl-4 alpha-carboxylic acid during cholesterol biosynthesis. J Biol Chem. 1970; 245(20):5375-81. View