Metabolism of oxysterols derived from nonenzymatic oxidation of 7-dehydrocholesterol in cells[S]
Recent studies suggest that 7-dehydrocholesterol (7-DHC)-derived oxysterols play important roles in the pathophysiology of Smith-Lemli-Opitz syndrome (SLOS), a metabolic disorder that is caused by defective 3β-hydroxysterol-Δ7-reductase (DHCR7). Although 14 oxysterols have been identified as the pri...
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| Format: | Article |
| Language: | English |
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Elsevier
2013-04-01
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| Series: | Journal of Lipid Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520422163 |
| _version_ | 1818740550525779968 |
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| author | Libin Xu Zeljka Korade Dale A. Rosado, Jr. Karoly Mirnics Ned A. Porter |
| author_facet | Libin Xu Zeljka Korade Dale A. Rosado, Jr. Karoly Mirnics Ned A. Porter |
| author_sort | Libin Xu |
| collection | DOAJ |
| description | Recent studies suggest that 7-dehydrocholesterol (7-DHC)-derived oxysterols play important roles in the pathophysiology of Smith-Lemli-Opitz syndrome (SLOS), a metabolic disorder that is caused by defective 3β-hydroxysterol-Δ7-reductase (DHCR7). Although 14 oxysterols have been identified as the primary products of 7-DHC autoxidation in organic solution, the metabolic fate of these oxysterols in a biological environment has not yet been elucidated. Therefore, we incubated these primary 7-DHC oxysterols in control Neuro2a and control human fibroblast cells and identified metabolites of these oxysterols by HPLC-MS. We also incubated Dhcr7-deficient Neuro2a cells and fibroblasts from SLOS patients with isotopically labeled 7-DHC (d7-7-DHC). The observation of matching d0- and d7 peaks in HPLC-MS confirmed the presence of true metabolites of 7-DHC after excluding the possibility of ex vivo oxidation. The metabolites of primary 7-DHC oxysterols were found to contribute to the majority of the metabolic profile of 7-DHC in cells. Furthermore, based on this new data, we identified three new 7-DHC-derived metabolites in the brain of Dhcr7-KO mice. Our studies suggest that 7-DHC peroxidation is a major source of oxysterols observed in cells and in vivo and that the stable metabolites of primary 7-DHC oxysterols can be used as markers of 7-DHC peroxidation in these biological systems. |
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| id | doaj.art-f1fe4d6a1c0a43b4969ee2bac7b88015 |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-18T01:42:31Z |
| publishDate | 2013-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-f1fe4d6a1c0a43b4969ee2bac7b880152022-12-21T21:25:16ZengElsevierJournal of Lipid Research0022-22752013-04-0154411351143Metabolism of oxysterols derived from nonenzymatic oxidation of 7-dehydrocholesterol in cells[S]Libin Xu0Zeljka Korade1Dale A. Rosado, Jr.2Karoly Mirnics3Ned A. Porter4To whom correspondence should be addressed. (L.X.) libin.xu@vanderbilt.edu; Department of Chemistry and Vanderbilt Institute of Chemical Biology and, Vanderbilt University, Nashville, TN 37235; To whom correspondence should be addressed. (L.X.) libin.xu@vanderbilt.eduDepartment of Psychiatry and Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, TN 37235Department of Chemistry and Vanderbilt Institute of Chemical Biology and, Vanderbilt University, Nashville, TN 37235Department of Psychiatry and Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, TN 37235To whom correspondence should be addressed. (N.A.P.) n.porter@vanderbilt.edu; Department of Chemistry and Vanderbilt Institute of Chemical Biology and, Vanderbilt University, Nashville, TN 37235; To whom correspondence should be addressed. (L.X.) libin.xu@vanderbilt.eduRecent studies suggest that 7-dehydrocholesterol (7-DHC)-derived oxysterols play important roles in the pathophysiology of Smith-Lemli-Opitz syndrome (SLOS), a metabolic disorder that is caused by defective 3β-hydroxysterol-Δ7-reductase (DHCR7). Although 14 oxysterols have been identified as the primary products of 7-DHC autoxidation in organic solution, the metabolic fate of these oxysterols in a biological environment has not yet been elucidated. Therefore, we incubated these primary 7-DHC oxysterols in control Neuro2a and control human fibroblast cells and identified metabolites of these oxysterols by HPLC-MS. We also incubated Dhcr7-deficient Neuro2a cells and fibroblasts from SLOS patients with isotopically labeled 7-DHC (d7-7-DHC). The observation of matching d0- and d7 peaks in HPLC-MS confirmed the presence of true metabolites of 7-DHC after excluding the possibility of ex vivo oxidation. The metabolites of primary 7-DHC oxysterols were found to contribute to the majority of the metabolic profile of 7-DHC in cells. Furthermore, based on this new data, we identified three new 7-DHC-derived metabolites in the brain of Dhcr7-KO mice. Our studies suggest that 7-DHC peroxidation is a major source of oxysterols observed in cells and in vivo and that the stable metabolites of primary 7-DHC oxysterols can be used as markers of 7-DHC peroxidation in these biological systems.http://www.sciencedirect.com/science/article/pii/S0022227520422163Smith-Lemli-Opitz syndromelipid peroxidation autoxidationNeuro2afibroblastmass spectrometry |
| spellingShingle | Libin Xu Zeljka Korade Dale A. Rosado, Jr. Karoly Mirnics Ned A. Porter Metabolism of oxysterols derived from nonenzymatic oxidation of 7-dehydrocholesterol in cells[S] Journal of Lipid Research Smith-Lemli-Opitz syndrome lipid peroxidation autoxidation Neuro2a fibroblast mass spectrometry |
| title | Metabolism of oxysterols derived from nonenzymatic oxidation of 7-dehydrocholesterol in cells[S] |
| title_full | Metabolism of oxysterols derived from nonenzymatic oxidation of 7-dehydrocholesterol in cells[S] |
| title_fullStr | Metabolism of oxysterols derived from nonenzymatic oxidation of 7-dehydrocholesterol in cells[S] |
| title_full_unstemmed | Metabolism of oxysterols derived from nonenzymatic oxidation of 7-dehydrocholesterol in cells[S] |
| title_short | Metabolism of oxysterols derived from nonenzymatic oxidation of 7-dehydrocholesterol in cells[S] |
| title_sort | metabolism of oxysterols derived from nonenzymatic oxidation of 7 dehydrocholesterol in cells s |
| topic | Smith-Lemli-Opitz syndrome lipid peroxidation autoxidation Neuro2a fibroblast mass spectrometry |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520422163 |
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