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Christopher Goulah, Eduard Struys, Erwin Jansen, Steven Fliesler; Metabolomic Analysis of a Rat Model of the Smith-Lemli-Opitz Syndrome (SLOS). Invest. Ophthalmol. Vis. Sci. 2013;54(15):710.
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© ARVO (1962-2015); The Authors (2016-present)
Smith-Lemli-Opitz syndrome (SLOS) is a developmental disorder resulting from mutations in the DHCR7 gene, which encodes the final enzyme (7-dehydrocholesterol reductase) in cholesterol biosynthesis. The phenotypic range is broad, and involves multiple dysmorphologies, cognitive and behavioral deficits, and failure to thrive. Recent evidence suggests the disease mechanism goes well beyond the initial defect in cholesterol biosynthesis. Here, we conducted metabolomics profiling of tissues from a SLOS rat model vs. age-matched controls, assessing changes in multiple biochemical pathways simultaneously.
A pharmacologically-induced rat model of SLOS was generated by treating Sprague-Dawley rats with AY9944, a DHCR7 inhibitor (Fliesler et al., 2004). Retina, brain, liver and serum were harvested from experimental and untreated control animals (N=5 each) at 61 days post-natal (p61). Small-molecule tissue extracts from retina, liver and brain were subjected to GC/MS and LC/MS/MS analysis (Metabolon®: www.metabolon.com); serum was subjected to GC/MS analysis (VU Univ. Med. Ctr. Amsterdam). The present dataset comprises a total of 238 compounds of known identity in brain, 293 in liver, and 208 in retina. Data were subjected to Welch’s two-sample t-test to identify analytes that differed significantly between groups.
Multiple, treatment-induced changes were observed in compounds relevant to bile acid metabolism, membrane dynamics, amino acid catabolism, the urea cycle, polyamine synthesis, glucose utilization, and antioxidant mobilization, in addition to the expected changes in cholesterol metabolism. Levels of the branched chain amino acids (BCAA) were significantly lower in treated retinas, compared to controls, while BCAA catabolites were higher, suggesting increased BCAA degradation. Pipecolate, a pro-apoptotic catabolite of lysine degradation, was elevated 3-4 fold in brain and retina and >5 fold in the serum of treated animals, compared to controls.
These results confirm that multiple biochemical pathways are dysregulated in this rat model of SLOS, beyond the AY9944-targeted disruption of cholesterol biosynthesis. This is consistent with the complexity and broad phenotype of SLOS. The mechanisms underlying elevated pipecolate levels and dysregulation of other non-sterol pathways remain to be determined.
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