Antioxidant supplementation ameliorates molecular deficits in smith-lemli-opitz syndrome

Zeljka Korade, Libin Xu, Fiona E. Harrison, Refayat Ahsen, Sarah E. Hart, Oakleigh M. Folkes, Karoly Mirnics, Ned A. Porter

Research output: Contribution to journalArticle

27 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)215-222
Number of pages8
JournalBiological Psychiatry
Volume75
Issue number3
DOIs
StatePublished - Feb 1 2014

Fingerprint

Smith-Lemli-Opitz Syndrome
Antioxidants
Vitamin E
Fibroblasts
coenzyme Q10
Cholesterol
Newborn Infant
Diet
Liver
Brain
Tandem Mass Spectrometry
Oxysterols
7-dehydrocholesterol
Vitamin A
Neuroglia
Transgenic Mice
Ascorbic Acid
Rodentia
Cell Culture Techniques
Western Blotting

Keywords

  • 7-dehydrocholesterol
  • Antioxidants
  • DHCEO
  • Dhcr7
  • Smith-Lemli-Opitz Syndrome
  • oxysterol

ASJC Scopus subject areas

  • Biological Psychiatry

Cite this

Korade, Z., Xu, L., Harrison, F. E., Ahsen, R., Hart, S. E., Folkes, O. M., ... Porter, N. A. (2014). Antioxidant supplementation ameliorates molecular deficits in smith-lemli-opitz syndrome. Biological Psychiatry, 75(3), 215-222. https://doi.org/10.1016/j.biopsych.2013.06.013

Antioxidant supplementation ameliorates molecular deficits in smith-lemli-opitz syndrome. / Korade, Zeljka; Xu, Libin; Harrison, Fiona E.; Ahsen, Refayat; Hart, Sarah E.; Folkes, Oakleigh M.; Mirnics, Karoly; Porter, Ned A.

In: Biological Psychiatry, Vol. 75, No. 3, 01.02.2014, p. 215-222.

Research output: Contribution to journalArticle

Korade, Zeljka ; Xu, Libin ; Harrison, Fiona E. ; Ahsen, Refayat ; Hart, Sarah E. ; Folkes, Oakleigh M. ; Mirnics, Karoly ; Porter, Ned A. / Antioxidant supplementation ameliorates molecular deficits in smith-lemli-opitz syndrome. In: Biological Psychiatry. 2014 ; Vol. 75, No. 3. pp. 215-222.
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AB - 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.

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