Oxidized phospholipids induce ceramide accumulation in RAW 264.7 macrophages: role of ceramide synthases.
Oxidized phospholipids (OxPLs), including 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine (PGPC) and 1-palmitoyl-2-oxovaleroyl-sn-glycero-3-phosphocholine (POVPC) are among several biologically active derivatives that are generated during oxidation of low-density lipoproteins (LDLs). These OxPLs...
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Public Library of Science (PLoS)
2013-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0070002 |
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| author | Lingaraju M Halasiddappa Harald Koefeler Anthony H Futerman Albin Hermetter |
| author_facet | Lingaraju M Halasiddappa Harald Koefeler Anthony H Futerman Albin Hermetter |
| author_sort | Lingaraju M Halasiddappa |
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| description | Oxidized phospholipids (OxPLs), including 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine (PGPC) and 1-palmitoyl-2-oxovaleroyl-sn-glycero-3-phosphocholine (POVPC) are among several biologically active derivatives that are generated during oxidation of low-density lipoproteins (LDLs). These OxPLs are factors contributing to pro-atherogenic effects of oxidized LDLs (OxLDLs), including inflammation, proliferation and death of vascular cells. OxLDL also elicits formation of the lipid messenger ceramide (Cer) which plays a pivotal role in apoptotic signaling pathways. Here we report that both PGPC and POVPC are cytotoxic to cultured macrophages and induce apoptosis in these cells which is associated with increased cellular ceramide levels after several hours. In addition, exposure of RAW 264.7 cells to POVPC and PGPC under the same conditions resulted in a significant increase in ceramide synthase activity, whereas, acid or neutral sphingomyelinase activities were not affected. PGPC is not only more toxic than POVPC, but also a more potent inducer of ceramide formation by activating a limited subset of CerS isoforms. The stimulated CerS activities are in line with the C16-, C22-, and C24:0-Cer species that are generated under the influence of the OxPL. Fumonisin B1, a specific inhibitor of CerS, suppressed OxPL-induced ceramide generation, demonstrating that OxPL-induced CerS activity in macrophages is responsible for the accumulation of ceramide. OxLDL elicits the same cellular ceramide and CerS effects. Thus, it is concluded that PGPC and POVPC are active components that contribute to the capacity of this lipoprotein to elevate ceramide levels in macrophages. |
| format | Article |
| id | doaj-art-6576751216524f3fbd8f955fe77d4e4c |
| institution | OA Journals |
| issn | 1932-6203 |
| language | English |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS ONE |
| spelling | doaj-art-6576751216524f3fbd8f955fe77d4e4c2025-08-20T02:22:28ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0187e7000210.1371/journal.pone.0070002Oxidized phospholipids induce ceramide accumulation in RAW 264.7 macrophages: role of ceramide synthases.Lingaraju M HalasiddappaHarald KoefelerAnthony H FutermanAlbin HermetterOxidized phospholipids (OxPLs), including 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine (PGPC) and 1-palmitoyl-2-oxovaleroyl-sn-glycero-3-phosphocholine (POVPC) are among several biologically active derivatives that are generated during oxidation of low-density lipoproteins (LDLs). These OxPLs are factors contributing to pro-atherogenic effects of oxidized LDLs (OxLDLs), including inflammation, proliferation and death of vascular cells. OxLDL also elicits formation of the lipid messenger ceramide (Cer) which plays a pivotal role in apoptotic signaling pathways. Here we report that both PGPC and POVPC are cytotoxic to cultured macrophages and induce apoptosis in these cells which is associated with increased cellular ceramide levels after several hours. In addition, exposure of RAW 264.7 cells to POVPC and PGPC under the same conditions resulted in a significant increase in ceramide synthase activity, whereas, acid or neutral sphingomyelinase activities were not affected. PGPC is not only more toxic than POVPC, but also a more potent inducer of ceramide formation by activating a limited subset of CerS isoforms. The stimulated CerS activities are in line with the C16-, C22-, and C24:0-Cer species that are generated under the influence of the OxPL. Fumonisin B1, a specific inhibitor of CerS, suppressed OxPL-induced ceramide generation, demonstrating that OxPL-induced CerS activity in macrophages is responsible for the accumulation of ceramide. OxLDL elicits the same cellular ceramide and CerS effects. Thus, it is concluded that PGPC and POVPC are active components that contribute to the capacity of this lipoprotein to elevate ceramide levels in macrophages.https://doi.org/10.1371/journal.pone.0070002 |
| spellingShingle | Lingaraju M Halasiddappa Harald Koefeler Anthony H Futerman Albin Hermetter Oxidized phospholipids induce ceramide accumulation in RAW 264.7 macrophages: role of ceramide synthases. PLoS ONE |
| title | Oxidized phospholipids induce ceramide accumulation in RAW 264.7 macrophages: role of ceramide synthases. |
| title_full | Oxidized phospholipids induce ceramide accumulation in RAW 264.7 macrophages: role of ceramide synthases. |
| title_fullStr | Oxidized phospholipids induce ceramide accumulation in RAW 264.7 macrophages: role of ceramide synthases. |
| title_full_unstemmed | Oxidized phospholipids induce ceramide accumulation in RAW 264.7 macrophages: role of ceramide synthases. |
| title_short | Oxidized phospholipids induce ceramide accumulation in RAW 264.7 macrophages: role of ceramide synthases. |
| title_sort | oxidized phospholipids induce ceramide accumulation in raw 264 7 macrophages role of ceramide synthases |
| url | https://doi.org/10.1371/journal.pone.0070002 |
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