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Papers In Press, published online ahead of print November 1, 2003
J. Lipid Res., doi:10.1194/jlr.M300232-JLR200
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Saint Louis University Eye Institute and Ophthalmology, Saint Louis University, Saint Louis, MO 63104-1540
Corresponding Author: fliesler{at}slu.edu
Smith-Lemli-Opitz Syndrome (SLOS) is a recessive disease typified by 7-dehydrocholesterol (7DHC) accumulation and depletion of cholesterol (CHOL). Since CHOL is a primary component of detergent-resistant membrane domains (“rafts”), we examined the compatibility of 7DHC with raft formation. Liposomes containing bovine brain phosphatidylcholine, sphingomyelin, cerebrosides, and either CHOL, 7DHC, or coprostanol (the latter being incompatible with raft formation) were prepared. 7DHC was indistinguishable from CHOL in its ability to become incorporated into membrane rafts, as judged by physical and chemical criteria, whereas coprostanol did not form rafts. The in vivo compatibility of 7DHC with raft formation was evaluated in brains of rats treated with AY9944, which mimics the SLOS biochemical defect. 7DHC/CHOL ratios in rafts and whole brains from AY9944-treated rats were similar, indicating comparable efficiency of 7DHC and CHOL incorporation into brain rafts. In contrast, dolichol (a non-sterol isoprenoid incompatible with raft formation) was greatly depleted in brain rafts, relative to whole brain. Although brain raft fractions prepared from AY9944-treated and control rats yielded similar sterol/protein ratios, their gel electrophoresis profiles exhibited multiple differences, suggesting that altered raft sterol composition perturbs raft protein content. These results are discussed in the context of the SLOS phenotype, particularly as regards the associated central nervous system defects.
Revised on October 10, 2003
Accepted on October 24, 2003
Formation of 7-dehydrocholesterol-containing membrane rafts in vitro and in vivo, with relevance to the Smith-Lemli-Opitz syndrome
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