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

摘要: Abstract Smith–Lemli–Opitz syndrome (SLOS) is a recessive disease characterized by markedly elevated levels of 7-dehydrocholesterol (7-DHC) and reduced cholesterol in tissues fluids affected individuals, due to defective 3β-hydroxysterol-Δ7-reductase (Dhcr7). Treatment Sprague Dawley rats with AY9944 (an inhibitor Dhcr7) leads similar biochemical features as observed SLOS. Eighteen oxysterols previously have been identified oxidation products 7-DHC (most them distinct from (Chol)-derived oxysterols) solution, cells, brains obtained Dhcr7-KO mice AY9944-treated rats, formed either via free radical (peroxidation) or P450-catalyzed enzymatic oxidation. We report here the identification five 7-DHC-derived oxysterols, including 3β,5α-dihydroxycholest-7-en-6-one (DHCEO), 4α- 4β-hydroxy-7-DHC, 24-hydroxy-7-DHC 7-ketocholesterol (7-kChol, an oxysterol that normally derived Chol), retinas comparing retention times mass spectrometric characteristics corresponding synthetic standards HPLC-MS analysis. Levels DHCEO, 7-kChol were quantified using d7-DHCEO internal standard. Among identified, only was control but AY9944-rats 30-fold higher. Intravitreal injection (0.25 μmol) into normal rat eye induced panretinal degeneration within one week; comparison, contralateral (control) eyes injected vehicle alone exhibited histology. These findings are discussed context potential involvement retinal associated SLOS model patients.