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

Abstract
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.
AuthorsLibin Xu, Wei Liu, Lowell G Sheflin, Steven J Fliesler, Ned A Porter
JournalJournal of lipid research (J Lipid Res) Vol. 52 Issue 10 Pg. 1810-20 (Oct 2011) ISSN: 1539-7262 [Electronic] United States
PMID21817059 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
Chemical References
  • Anticholesteremic Agents
  • Cholestenones
  • Dehydrocholesterols
  • Hydroxycholesterols
  • Ketocholesterols
  • Sterols
  • trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride
  • Cholesterol
  • 7-dehydrocholesterol
  • 7-ketocholesterol
Topics
  • Animals
  • Anticholesteremic Agents (pharmacology)
  • Cholestenones (metabolism)
  • Cholesterol (metabolism)
  • Chromatography, High Pressure Liquid
  • Dehydrocholesterols (metabolism)
  • Disease Models, Animal
  • Hydroxycholesterols (metabolism)
  • Ketocholesterols (metabolism)
  • Lipid Peroxidation (drug effects)
  • Magnetic Resonance Spectroscopy
  • Mass Spectrometry
  • Mice
  • Rats
  • Rats, Sprague-Dawley
  • Smith-Lemli-Opitz Syndrome (drug therapy, metabolism, pathology)
  • Spectrophotometry, Ultraviolet
  • Sterols (metabolism)
  • trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride (pharmacology)

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