title: Antioxidant supplementation ameliorates molecular deficits in Smith-Lemli-Opitz syndrome.
abstract: BACKGROUND
  Smith-Lemli-Opitz syndrome (SLOS) is an inborn error of cholesterol biosynthesis characterized by diminished cholesterol and increased 7-dehydrocholesterol (7-DHC) levels. 7-Dehydrocholesterol is highly reactive, giving rise to biologically active oxysterols.
  
  
  METHODS
  7-DHC-derived oxysterols were measured in fibroblasts from SLOS patients and an in vivo SLOS rodent model using high-performance liquid chromatography tandem mass spectrometry. Expression of lipid biosynthesis genes was ascertained by quantitative polymerase chain reaction and Western blot. The effects of an antioxidant mixture of vitamin A, coenzyme Q10, vitamin C, and vitamin E were evaluated for their potential to reduce formation of 7-DHC oxysterols in fibroblast from SLOS patients. Finally, the effect of maternal feeding of vitamin E enriched diet was ascertained in the brain and liver of newborn SLOS mice.
  
  
  RESULTS
  In cultured human SLOS fibroblasts, the antioxidant mixture led to decreased levels of the 7-DHC-derived oxysterol, 3β,5α-dihydroxycholest-7-en-6-one. Furthermore, gene expression changes in SLOS human fibroblasts were normalized with antioxidant treatment. The active ingredient appeared to be vitamin E, as even at low concentrations, it significantly decreased 3β,5α-dihydroxycholest-7-en-6-one levels. In addition, analyzing a mouse SLOS model revealed that feeding a vitamin E enriched diet to pregnant female mice led to a decrease in oxysterol formation in brain and liver tissues of the newborn Dhcr7-knockout pups.
  
  
  CONCLUSIONS
  Considering the adverse effects of 7-DHC-derived oxysterols in neuronal and glial cultures and the positive effects of antioxidants in patient cell cultures and the transgenic mouse model, we believe that preventing formation of 7-DHC oxysterols is critical for countering the detrimental effects of DHCR7 mutations.
authors.affiliation: Department of Psychiatry, Vanderbilt University, Nashville, Tennessee; Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, Tennessee.
authors.forename: Zeljka
authors.initials: Z
authors.lastname: Korade
authors.affiliation: Department of Chemistry, Vanderbilt University, Nashville, Tennessee; Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee.
authors.forename: Libin
authors.initials: L
authors.lastname: Xu
authors.affiliation: Division of Diabetes, Endocrinology and Metabolism, Vanderbilt University, Nashville, Tennessee; Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, Tennessee.
authors.forename: Fiona E
authors.initials: FE
authors.lastname: Harrison
authors.affiliation: Department of Psychiatry, Vanderbilt University, Nashville, Tennessee.
authors.forename: Refayat
authors.initials: R
authors.lastname: Ahsen
authors.affiliation: Department of Psychiatry, Vanderbilt University, Nashville, Tennessee.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Hart
authors.affiliation: Division of Diabetes, Endocrinology and Metabolism, Vanderbilt University, Nashville, Tennessee.
authors.forename: Oakleigh M
authors.initials: OM
authors.lastname: Folkes
authors.affiliation: Department of Psychiatry, Vanderbilt University, Nashville, Tennessee; Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, Tennessee.
authors.forename: Károly
authors.initials: K
authors.lastname: Mirnics
authors.affiliation: Department of Chemistry, Vanderbilt University, Nashville, Tennessee; Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee; Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, Tennessee. Electronic address: n.porter@vanderbilt.edu.
authors.forename: Ned A
authors.initials: NA
authors.lastname: Porter
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000008:administration & dosage*; D001205:Ascorbic Acid / Q000008:administration & dosage / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002461:Cell Line, Transformed; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics; D019082:Smith-Lemli-Opitz Syndrome / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D014451:Ubiquinone / Q000008:administration & dosage / Q000031:analogs & derivatives; D024502:alpha-Tocopherol / Q000008:administration & dosage / Q000378:metabolism
chemical_list: D000975:Antioxidants; D014451:Ubiquinone; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019995:7-dehydrocholesterol reductase; C024989:coenzyme Q10; D024502:alpha-Tocopherol; D001205:Ascorbic Acid
keywords: 7-dehydrocholesterol; Antioxidants; DHCEO; Dhcr7; Smith-Lemli-Opitz Syndrome; oxysterol
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