Abstract
Deficient cholesterol and/or excessive 7-dehydrocholesterol (7-DHC) may be responsible for the pathology of Smith-Lemli-Opitz syndrome (SLOS). Both high-cholesterol diets given to ameliorate cholesterol deficiency while decreasing 7-DHC and cholesterol-enriched diets plus simvastatin to further decrease sterol synthesis have been used as potential therapies. However, the effect of dietary cholesterol and simvastatin on cholesterol synthesis in SLOS has not been reported. Twelve subjects with SLOS enrolled in the study: Nine had received a high cholesterol diet (HI) for 3 y and three were studied after 4 wk on a low cholesterol diet (LO). Cholesterol fractional synthesis rate (FSR) was measured after oral administration of deuterium oxide, using gas chromatography isotope ratio mass spectrometry. FSR was lower in HI compared with LO (HI: 1.46 ± 0.62%/d; LO: 4.77 ± 0.95%/d; p < 0.001). Three HI subjects were retested after 0.8 y taking simvastatin (HI + ST). Simvastatin tended to reduce FSR and significantly decreased (p < 0.01) plasma 7-DHC compared with cholesterol supplementation alone. The study demonstrates the utility of the deuterium incorporation method to understand the effect of therapeutic interventions in SLOS. The data suggest that dietary cholesterol supplementation reduces cholesterol synthesis in SLOS and further support the rationale for the combined treatment of SLOS with a cholesterol-enriched diet and simvastatin.
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Abbreviations
- 7-DHC:
-
7-dehydrocholesterol
- 8-DHC:
-
8-dehydrocholesterol
- DHCR7:
-
7-dehydrocholesterol reductase
- D2O:
-
deuterium oxide
- FSR:
-
cholesterol fractional synthesis rate
- GC:
-
gas chromatography
- HMG CoA R:
-
3-hydroxy-3-methylglutaryl coenzyme A reductase
- HI:
-
high cholesterol diet group
- HI + ST:
-
high cholesterol diet with simvastatin group
- LO:
-
low cholesterol diet group
- RBC:
-
red blood cells
- SLOS:
-
Smith-Lemli-Opitz syndrome
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Acknowledgements
We thank the staff of the OHSU GCRC (now PCTRC), Dr. Carrie Phillipi for patient care, and the children and their families for participation in this study. We also thank numerous healthcare providers for caring for the subjects who participated in this study and referring them for these research studies.
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Supported by the National Institutes of Health grant no. R01 HL-073980, The Oregon Clinical and Translational Research Institute (OCTRI), grant number UL1 RR024140 from the National Center for Research Resources (NCRR), a component of the National Institutes of Health (NIH), and NIH Roadmap for Medical Research Category of study: Clinical Study.
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Chan, YM., Merkens, L., Connor, W. et al. Effects of Dietary Cholesterol and Simvastatin on Cholesterol Synthesis in Smith-Lemli-Opitz Syndrome. Pediatr Res 65, 681–685 (2009). https://doi.org/10.1203/PDR.0b013e31819ea4eb
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DOI: https://doi.org/10.1203/PDR.0b013e31819ea4eb
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