期刊
JOURNAL OF LIPID RESEARCH
卷 52, 期 10, 页码 1810-1820出版社
ELSEVIER
DOI: 10.1194/jlr.M018366
关键词
cholesterol; cholesterol/biosynthesis; lipids/peroxidation; 7-dehydrocholesterol
资金
- United States Public Health Service (National Institutes of Health) [ES-013125, HD-064727, EY-007361]
- National Science Foundation [CHE 0717067]
- Research to Prevent Blindness
Treatment of Sprague-Dawley rats with AY9944, an inhibitor of 3 beta-hydroxysterol-Delta(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, 3 beta,5 alpha-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 (4 alpha- and 4 beta-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 4 alpha- and 4 beta-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.-Xu, L., W. Liu, L. G. Sheflin, S. J. Fliesler, and N. A. Porter. Novel oxysterols observed in tissues and fluids of AY9944-treated rats: a model for Smith-Lemli-Opitz syndrome. J. Lipid Res. 2011. 52: 1810-1820.
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