April 2011
Volume 52, Issue 14
Free
ARVO Annual Meeting Abstract  |   April 2011
7-Dehydrocholesterol-Derived Oxysterol Formation and Retinal Degeneration Pathobiology in a Rat Model of Smith-Lemli-Opitz Syndrome
Author Affiliations & Notes
  • Libin Xu
    Chemistry & Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee
  • Wei Liu
    Chemistry & Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee
  • Ned A. Porter
    Chemistry & Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee
  • Lowell G. Sheflin
    VAWNYHS (Research Service), Buffalo, New York
  • Joyce E. Young
    Ophthalmology & Biochemistry, SUNY-Buffalo/SUNY Eye Institute, Buffalo, New York
  • Steven J. Fliesler
    VAWNYHS (Research Service), Buffalo, New York
    Ophthalmology & Biochemistry, SUNY-Buffalo/SUNY Eye Institute, Buffalo, New York
  • Footnotes
    Commercial Relationships  Libin Xu, None; Wei Liu, None; Ned A. Porter, None; Lowell G. Sheflin, None; Joyce E. Young, None; Steven J. Fliesler, None
  • Footnotes
    Support  NIH EY007361 (SJF), RPB Unrestricted Grant (SJF), NIH ES013125 and HD064727 (NAP, LX&WL), NSF CHE 0717067 (NAP, LX&WL)
Investigative Ophthalmology & Visual Science April 2011, Vol.52, 2696. doi:
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      Libin Xu, Wei Liu, Ned A. Porter, Lowell G. Sheflin, Joyce E. Young, Steven J. Fliesler; 7-Dehydrocholesterol-Derived Oxysterol Formation and Retinal Degeneration Pathobiology in a Rat Model of Smith-Lemli-Opitz Syndrome. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2696.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : 7-Dehydrocholesterol (7DHC) accumulates in all tissues in Smith-Lemli-Opitz syndrome (SLOS), and is >200-fold more labile to oxidation than is cholesterol, forming cytotoxic oxysterol products. We examined the presence, types and amounts of 7DHC-derived oxysterols in retinas from the AY9944-induced rat model of SLOS, in comparison to age-matched controls. We also examined the effect of intravitreally injected oxysterol on retinal structure.

Methods: : Sprague-Dawley rats were treated with AY9944 to produce the SLOS model (Fliesler et al., Arch. Ophthalmol. 122:1190, 2004); untreated age-matched rats served as controls. Retinas were harvested at 1, 2, and 3 mo of age, flash frozen in liquid nitrogen, and subsequently analyzed for oxysterols by LC/MS (Xu et al., J. Am. Chem. Soc. 132:1222, 2010). Retinal histology was assessed, in parallel, by analysis of contralateral eyes. 7-Ketocholesterol (7kChol; 0.25 micromol, in 1 microL DMSO) was injected into one eye of an anesthetized adult Sprague-Dawley rat, while DMSO alone was injected into the contralateral eye; one week later, eyes were enucleated, fixed, and subjected to histological analysis.

Results: : Multiple, 7DHC-specific oxysterols were identified in retinas from AY9944-treated rats, but not in control retinas, including 4alpha- and 4beta-hydroxy-7-DHC, and 3beta,5alpha-dihydroxycholest-7-en-6-one. In addition, 7kChol (a known cholesterol oxidation product) was found at levels of ~ 0.5 micromol/retina in AY9944-treated rats at 3 mo, >30-fold higher than in corresponding controls. Progressive AY9944-induced retinal degeneration was confirmed, as previously described. Intravitreal injection of 7kChol resulted in panretinal degeneration and marked gliosis, whereas the vehicle-only control eye appeared histologically normal.

Conclusions: : A variety of 7DHC-derived oxysterols form and accumulate in retinas in the SLOS rat model; some of these are toxic to cells (Korade et al., J Lipid Res. 51:3259, 2010). 7kChol, which may derive either from cholesterol or from 7DHC, formed at levels greater than that sufficient to induce panretinal degeneration when injected intravitreally. These findings implicate 7kChol and other cyototoxic, 7DHC-derived oxysterols in the etiology of retinal degeneration in this SLOS model. Preventing their formation may improve the efficacy of cholesterol supplementation therapy in this and related diseases.

Keywords: retinal degenerations: cell biology • oxidation/oxidative or free radical damage • metabolism 
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