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A. M. Siddiqui, M. J. Richards, S. J. Fliesler; Effect of Cholesterol Supplementation on the Retinal Gene Transcriptome in a Rat Model of Smith-Lemli-Opitz Syndrome. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4152.
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© ARVO (1962-2015); The Authors (2016-present)
Smith-Lemli-Opitz syndrome (SLOS) is a hereditary disease caused by defective cholesterol biosynthesis. Previously (Siddiqui et al., ARVO 2007, 2008), we reported time-dependent retinal gene transcription changes in a rat model of SLOS, compared to age-matched controls. Here we studied the effects of dietary cholesterol supplementation on the retinal transcription profile in normal vs. high-cholesterol fed SLOS rats, and in age-matched controls.
Sprague Dawley rats were treated with AY9944 to generate the SLOS rat model (Fliesler et al. Arch. Ophthalmol. 122:1190, 2004): NC (normal chow) group; HC (2% (w/w) cholesterol chow) group, starting at weaning and continuing to 3-mo postnatal. C (control) group: normal chow, no drug. At 1, 2, and 3 mo postnatal, total RNA was extracted from individual retinas; mRNA was amplified, labeled, and hybridized to Affymetrix GeneChip Rat Genome 230 2.0 arrays. Data were normalized using gcRMA algorithms. Retinas from NC vs. C groups were compared (N=3 per age/treatment); 2-way ANOVA (FDR ≤ 0.01) was performed to assess gene expression variability, re: AY9944 Rx and age. The cholesterol supplementation effect was determined by comparing 3-mo old NC, HC, and C retinas (1-way ANOVA; FDR ≤ 0.01). Differentially expressed genes of interest (reciprocally regulated, NC vs. HC) were identified, and functional category enrichment for each gene profile group was statistically analyzed (2x2 Fisher’s Exact Test).
681 genes were differentially regulated at 3 mo; of these, 192 were negatively (104) or positively (88) regulated by cholesterol. The negatively-regulated genes included those involved in apoptosis and complement activation, whereas the positively-regulated group included those implicated in visual transduction. Notably, the sterol metabolism genes (Srebp1 & Abcg1) which were down-regulated at all ages (NC vs. C) were up-regulated to near control levels in the HC group.
Dietary cholesterol supplementation dramatically impacts the differential regulation of multiple genes in the SLOS rat model. The partial amelioration of retinal degeneration in this model afforded by cholesterol supplementation may, in part, be due to down-regulating expression of genes involved in apoptosis and complement activation.
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