7-Dehydrocholesterol-derived oxysterols and retinal degeneration in a rat model of Smith-Lemli-Opitz syndrome

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• 作者：Libin Xu^a ; Lowell G. Sheflin^b ; Ned A. Porter^a ; Steven J. Fliesler^b ; ^c ; ^d ; ^{fliesler@buffalo.edu}
• 关键词：APCI ; atmospheric pressure chemical ionization ; BHT ; butylated hydroxytoluene ; Chol ; cholesterol ; Chor ; choroid ; CYP ; cytochrome P450 ; 7-DHC ; 7-dehydrocholesterol ; DHCEO ; 3尾 ; 5伪-dihydroxycholest-7-en-6-one ; Dhcr7 or DHCR7 ; 7-dehydrocholesterol reductase
• 刊名：Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids
• 出版年：2012
• 期刊代码：18_13881981
• 类别：bio
• 出版时间：June, 2012
• 卷：1821
• 期：6
• 页码：877-883
• 文件大小：911 K

摘要

Smith-Lemli-Opitz syndrome (SLOS) is a recessive disease characterized by markedly elevated levels of 7-dehydrocholesterol (7-DHC) and reduced levels of cholesterol in tissues and fluids of affected individuals, due to defective 3尾-hydroxysterol-螖⁷-reductase (Dhcr7). Treatment of Sprague Dawley rats with AY9944 (an inhibitor of Dhcr7) leads to similar biochemical features as observed in SLOS. Eighteen oxysterols previously have been identified as oxidation products of 7-DHC (most of them distinct from cholesterol (Chol)-derived oxysterols) in solution, in cells, and in brains obtained from Dhcr7-KO mice and AY9944-treated rats, formed either via free radical oxidation (peroxidation) or P450-catalyzed enzymatic oxidation. We report here the identification of five 7-DHC-derived oxysterols, including 3尾,5伪-dihydroxycholest-7-en-6-one (DHCEO), 4伪- and 4尾-hydroxy-7-DHC, 24-hydroxy-7-DHC and 7-ketocholesterol (7-kChol, an oxysterol that is normally derived from Chol), in the retinas of AY9944-treated rats by comparing the retention times and mass spectrometric characteristics with corresponding synthetic standards in HPLC-MS analysis. Levels of 4伪- and 4尾-hydroxy-7-DHC, DHCEO, and 7-kChol were quantified using d₇-DHCEO as an internal standard. Among the five oxysterols identified, only 7-kChol was observed in retinas of control rats, but the levels of 7-kChol in retinas of AY9944-rats were 30-fold higher. Intravitreal injection of 7-kChol (0.25 渭mol) into a normal rat eye induced panretinal degeneration within one week; by comparison, contralateral (control) eyes injected with vehicle alone exhibited normal histology. These findings are discussed in the context of the potential involvement of 7-DHC-derived oxysterols in the retinal degeneration associated with the SLOS rat model and in SLOS patients.