Biological activities of 7-dehydrocholesterol-derived oxysterols: implications for Smith-Lemli-Opitz syndrome.

Abstract

Smith-Lemli-Opitz syndrome (SLOS) is a metabolic and developmental disorder caused by mutations in the gene encoding the enzyme 7-dehydrocholesterol reductase (Dhcr7). This reductase catalyzes the last step in cholesterol biosynthesis, and levels of 7-dehydrocholesterol (7-DHC), the substrate for this enzyme, are elevated in SLOS patients as a result of this defect. Our group has previously shown that 7-DHC is extremely prone to free radical autoxidation, and we identified about a dozen different oxysterols formed from oxidation of 7-DHC. We report here that 7-DHC-derived oxysterols reduce cell viability in a dose- and time-dependent manner, some of the compounds showing activity at sub-micromolar concentrations. The reduction of cell survival is caused by a combination of reduced proliferation and induced differentiation of the Neuro2a cells. The complex 7-DHC oxysterol mixture added to control Neuro2a cells also triggers the gene expression changes that were previously identified in Dhcr7-deficient Neuro2a cells. Based on the identification of overlapping gene expression changes in Dhcr7-deficient and 7-DHC oxysterol-treated Neuro2a cells, we hypothesize that some of the pathophysiological findings in the mouse SLOS model and SLOS patients might be due to accumulated 7-DHC oxysterols.

• Authors: Zeljka Korade, Libin Xu, Richard Shelton, Ned A Porter
• Journal: Journal of lipid research (J Lipid Res) Vol. 51 Issue 11 Pg. 3259-69 (Nov 2010) ISSN: 1539-7262 [Electronic] United States
• PMID: 20702862 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Dehydrocholesterols
• Peroxides
• 7-dehydrocholesterol
• Oxidoreductases Acting on CH-CH Group Donors
• 7-dehydrocholesterol reductase

Topics

• Animals
• Cell Differentiation (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Dehydrocholesterols (metabolism, pharmacology)
• Dose-Response Relationship, Drug
• Gene Expression Profiling
• Mice
• Neurons (cytology, drug effects, metabolism)
• Oxidation-Reduction
• Oxidoreductases Acting on CH-CH Group Donors (deficiency)
• Peroxides (chemistry, toxicity)
• Smith-Lemli-Opitz Syndrome (metabolism, pathology)
• Time Factors