Deep sphingolipidomic and metabolomic analyses of ceramide synthase 2 null mice reveal complex pathway-specific effects
The sphingolipidome contains thousands of structurally distinct sphingolipid (SL) species. This enormous diversity is generated by the combination of different long-chain bases (LCBs), N-acyl chains and head groups. In mammals, LCBs are N-acylated with different fatty acids (from C14 to C32, with di...
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Elsevier
2025-07-01
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| Series: | Journal of Lipid Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227525000926 |
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| author | Jeongah Oh Sneha Muralidharan Qing Zhao Johannes Scholz Iris D. Zelnik Shani Blumenreich Tammar Joseph Tamir Dingjan Pradeep Narayanaswamy Hyungwon Choi Heiko Hayen Federico Torta Anthony H. Futerman |
| author_facet | Jeongah Oh Sneha Muralidharan Qing Zhao Johannes Scholz Iris D. Zelnik Shani Blumenreich Tammar Joseph Tamir Dingjan Pradeep Narayanaswamy Hyungwon Choi Heiko Hayen Federico Torta Anthony H. Futerman |
| author_sort | Jeongah Oh |
| collection | DOAJ |
| description | The sphingolipidome contains thousands of structurally distinct sphingolipid (SL) species. This enormous diversity is generated by the combination of different long-chain bases (LCBs), N-acyl chains and head groups. In mammals, LCBs are N-acylated with different fatty acids (from C14 to C32, with different degrees of saturation) by six ceramide synthases (CerS1-6) to generate dihydroceramides (DHCer), with each CerS exhibiting specificity toward acyl-Coenzyme As of defined chain length. CerS2 synthesizes very-long chain dihydroceramide, and mice in which CerS2 has been deleted display a number of pathologies. We now expand previous analyses of the mouse sphingolipidome by examining 259 individual SL species in 18 different tissues, building an extensive SL tissue atlas of WT and CerS2 null mice. Although many of the changes in SL levels were similar to those reported earlier, a number of unexpected findings in CerS2 null mouse tissues were observed, such as the decrease in ceramide 1-phosphate levels in the brain, the increase in C26-SL levels in the lung, and no changes in levels of ceramides containing t18:0-LCBs (phytosphinganine). Furthermore, analysis of levels of other metabolites revealed changes in at least six major metabolic pathways, including some that impinge upon the SL metabolism. Together, these data highlight the complex changes that occur in the lipidome and metabolome upon depletion of CerS2, indicating how sphingolipids are connected to many other pathways and that care must be taken when assigning a relationship between tissue pathology and one or other specific SL species. |
| format | Article |
| id | doaj-art-388986baea7945c78770eff3b90d34e0 |
| institution | DOAJ |
| issn | 0022-2275 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj-art-388986baea7945c78770eff3b90d34e02025-08-20T02:48:49ZengElsevierJournal of Lipid Research0022-22752025-07-0166710083210.1016/j.jlr.2025.100832Deep sphingolipidomic and metabolomic analyses of ceramide synthase 2 null mice reveal complex pathway-specific effectsJeongah Oh0Sneha Muralidharan1Qing Zhao2Johannes Scholz3Iris D. Zelnik4Shani Blumenreich5Tammar Joseph6Tamir Dingjan7Pradeep Narayanaswamy8Hyungwon Choi9Heiko Hayen10Federico Torta11Anthony H. Futerman12Precision Medicine Translational Research Programme and Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; SLING, Singapore Lipidomics Incubator, Life Sciences Institute, National University of Singapore, SingaporePrecision Medicine Translational Research Programme and Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; SLING, Singapore Lipidomics Incubator, Life Sciences Institute, National University of Singapore, SingaporeCardiovascular-Metabolic Disease Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, SingaporeDepartment of Analytical Chemistry, Institute of Inorganic and Analytical Chemistry, University of Münster, Münster, GermanyDepartment of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, IsraelDepartment of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, IsraelDepartment of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, IsraelDepartment of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, IsraelSciex, R&D, SingaporeCardiovascular-Metabolic Disease Translational Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, SingaporeDepartment of Analytical Chemistry, Institute of Inorganic and Analytical Chemistry, University of Münster, Münster, GermanyPrecision Medicine Translational Research Programme and Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; SLING, Singapore Lipidomics Incubator, Life Sciences Institute, National University of Singapore, Singapore; Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore (NUS) Medical School, Singapore; For correspondence: Federico TortaDepartment of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, IsraelThe sphingolipidome contains thousands of structurally distinct sphingolipid (SL) species. This enormous diversity is generated by the combination of different long-chain bases (LCBs), N-acyl chains and head groups. In mammals, LCBs are N-acylated with different fatty acids (from C14 to C32, with different degrees of saturation) by six ceramide synthases (CerS1-6) to generate dihydroceramides (DHCer), with each CerS exhibiting specificity toward acyl-Coenzyme As of defined chain length. CerS2 synthesizes very-long chain dihydroceramide, and mice in which CerS2 has been deleted display a number of pathologies. We now expand previous analyses of the mouse sphingolipidome by examining 259 individual SL species in 18 different tissues, building an extensive SL tissue atlas of WT and CerS2 null mice. Although many of the changes in SL levels were similar to those reported earlier, a number of unexpected findings in CerS2 null mouse tissues were observed, such as the decrease in ceramide 1-phosphate levels in the brain, the increase in C26-SL levels in the lung, and no changes in levels of ceramides containing t18:0-LCBs (phytosphinganine). Furthermore, analysis of levels of other metabolites revealed changes in at least six major metabolic pathways, including some that impinge upon the SL metabolism. Together, these data highlight the complex changes that occur in the lipidome and metabolome upon depletion of CerS2, indicating how sphingolipids are connected to many other pathways and that care must be taken when assigning a relationship between tissue pathology and one or other specific SL species.http://www.sciencedirect.com/science/article/pii/S0022227525000926mass spectrometrysphingolipidsceramidecerebrosidessphingomyelinglycosphingolipids |
| spellingShingle | Jeongah Oh Sneha Muralidharan Qing Zhao Johannes Scholz Iris D. Zelnik Shani Blumenreich Tammar Joseph Tamir Dingjan Pradeep Narayanaswamy Hyungwon Choi Heiko Hayen Federico Torta Anthony H. Futerman Deep sphingolipidomic and metabolomic analyses of ceramide synthase 2 null mice reveal complex pathway-specific effects Journal of Lipid Research mass spectrometry sphingolipids ceramide cerebrosides sphingomyelin glycosphingolipids |
| title | Deep sphingolipidomic and metabolomic analyses of ceramide synthase 2 null mice reveal complex pathway-specific effects |
| title_full | Deep sphingolipidomic and metabolomic analyses of ceramide synthase 2 null mice reveal complex pathway-specific effects |
| title_fullStr | Deep sphingolipidomic and metabolomic analyses of ceramide synthase 2 null mice reveal complex pathway-specific effects |
| title_full_unstemmed | Deep sphingolipidomic and metabolomic analyses of ceramide synthase 2 null mice reveal complex pathway-specific effects |
| title_short | Deep sphingolipidomic and metabolomic analyses of ceramide synthase 2 null mice reveal complex pathway-specific effects |
| title_sort | deep sphingolipidomic and metabolomic analyses of ceramide synthase 2 null mice reveal complex pathway specific effects |
| topic | mass spectrometry sphingolipids ceramide cerebrosides sphingomyelin glycosphingolipids |
| url | http://www.sciencedirect.com/science/article/pii/S0022227525000926 |
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