Treatment of Sprague-Dawley rats with AY9944, an inhibitor of 3 β -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 identifi ed as products of free radical oxidation in vitro; one of these oxysterols, 3 β,5 α - dihydroxycholest-7-en-6-one (DHCEO), was recently identifi ed in Dhcr7-defi cient 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 fi ve oxysterols were elucidated by HPLC-ultraviolet (UV), HPLC-MS, and 1D- and 2D-NMR. Quantifi cation of 4 α - and 4 β -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 fi ndings are discussed in the context of the potential involvement of 7-DHC-derived oxysterols in the pathogenesis of SLOS.
CITATION STYLE
Xu, L., Liu, W., Shefli, L. G., Fliesler, S. J., & Porter, N. A. (2011). Novel oxysterols observed in tissues and fluids of AY9944-treated rats: A model for Smith-Lemli-Opitz syndrome. Journal of Lipid Research, 52(10), 1810–1820. https://doi.org/10.1194/jlr.M018366
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