Abstract
Smith-Lemli-Opitz Syndrome (SLOS) is a recessive human disease caused by defective cholesterol (CHOL) synthesis at the level of DHCR7 (7-dehydrocholesterol reductase), which normally catalyzes the conversion of 7-dehydrocholesterol (7DHC) to CHOL. Formation and abnormal accumulation of 7DHC and 7DHC-derived oxysterols occur in SLOS patients and in rats treated with the DHCR7 inhibitor AY9944. The rat SLOS model exhibits progressive and irreversible retinal dysfunction and degeneration, which is only partially ameliorated by dietary CHOL supplementation. We hypothesized that 7DHC-derived oxysterols are causally involved in this retinal degeneration, and that blocking or reducing their formation should minimize the phenotype. Here, using the SLOS rat model, we demonstrate that combined dietary supplementation with CHOL plus antioxidants (vitamins E and C, plus sodium selenite) provides better outcomes than dietary CHOL supplementation alone with regard to preservation of retinal structure and function and lowering 7DHC-derived oxysterol formation. These proof-of-principle findings provide a translational, pre-clinical framework for designing clinical trials using CHOL-antioxidant combination therapy as an improved therapeutic intervention over the current standard of care for the treatment of SLOS.
Highlights
Smith-Lemli-Opitz Syndrome (SLOS) is a recessive human disease caused by defective cholesterol (CHOL) synthesis at the level of DHCR7 (7-dehydrocholesterol reductase), which normally catalyzes the conversion of 7-dehydrocholesterol (7DHC) to CHOL
The image of the retina from an AY9944-treated rat fed a diet with combined CHOL plus antioxidant supplementation (AY3 group; Fig. 1D) was remarkably similar to that obtained from the untreated control rat
It is important to note that the retinal degeneration observed in this animal model is far more severe than the retinal defects observed in human patients afflicted with SLOS20,44
Summary
Smith-Lemli-Opitz Syndrome (SLOS) is a recessive human disease caused by defective cholesterol (CHOL) synthesis at the level of DHCR7 (7-dehydrocholesterol reductase), which normally catalyzes the conversion of 7-dehydrocholesterol (7DHC) to CHOL. Using the AY9944 rat model of SLOS, we showed that dietary CHOL supplementation (i.e., feeding a rodent chow containing 2%, by wt., CHOL) resulted in a marked preservation of retinal electrophysiological function, for the cone-driven pathway, and a near normalization of the CHOL levels (as well as significant decrease in 7DHC levels) in the retina, but did not significantly abate the histological degeneration[21]. These studies were performed well before the reports regarding the marked susceptibility of 7DHC to oxidation and the structures and cytotoxicity of 7DHC-derived oxysterols were elucidated. The results obtained are consistent with our original hypothesis, and have important translational implications for improving the clinical management of SLOS patients
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