Novel oxysterols observed in tissues and fluids of AY9944-treated rats: a model for Smith-Lemli-Opitz syndrome.

Xu L, Liu W, Sheflin LG, Fliesler SJ, Porter NA
J Lipid Res. 2011 52 (10): 1810-20

PMID: 21817059 · PMCID: PMC3173002 · DOI:10.1194/jlr.M018366

Treatment of Sprague-Dawley rats with AY9944, an inhibitor of 3β-hydroxysterol-Δ(7)-reductase (Dhcr7), leads to elevated levels of 7-dehydrocholesterol (7-DHC) and reduced levels of cholesterol in all biological tissues, mimicking the key biochemical hallmark of Smith-Lemli-Opitz syndrome (SLOS). Fourteen 7-DHC-derived oxysterols previously have been identified as products of free radical oxidation in vitro; one of these oxysterols, 3β,5α-dihydroxycholest-7-en-6-one (DHCEO), was recently identified in Dhcr7-deficient cells and in brain tissues of Dhcr7-null mouse. We report here the isolation and characterization of three novel 7-DHC-derived oxysterols (4α- and 4β-hydroxy-7-DHC and 24-hydroxy-7-DHC) in addition to DHCEO and 7-ketocholesterol (7-kChol) from the brain tissues of AY9944-treated rats. The identities of these five oxysterols were elucidated by HPLC-ultraviolet (UV), HPLC-MS, and 1D- and 2D-NMR. Quantification of 4α- and 4β-hydroxy-7-DHC, DHCEO, and 7-kChol in rat brain, liver, and serum were carried out by HPLC-MS using d(7)-DHCEO as an internal standard. With the exception of 7-kChol, these oxysterols were present only in tissues of AY9944-treated, but not control rats, and 7-kChol levels were markedly (>10-fold) higher in treated versus control rats. These findings are discussed in the context of the potential involvement of 7-DHC-derived oxysterols in the pathogenesis of SLOS.

MeSH Terms (19)

Animals Anticholesteremic Agents Cholestenones Cholesterol Chromatography, High Pressure Liquid Dehydrocholesterols Disease Models, Animal Hydroxycholesterols Ketocholesterols Lipid Peroxidation Magnetic Resonance Spectroscopy Mass Spectrometry Mice Rats Rats, Sprague-Dawley Smith-Lemli-Opitz Syndrome Spectrophotometry, Ultraviolet Sterols trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride

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