The origin of long-chain fatty acids required for de novo ether lipid/plasmalogen synthesis
Peroxisomes are single-membrane bounded organelles that in humans play a dual role in lipid metabolism, including the degradation of very long-chain fatty acids and the synthesis of ether lipids/plasmalogens. The first step in de novo ether lipid synthesis is mediated by the peroxisomal enzyme glyce...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-05-01
|
| Series: | Journal of Lipid Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227523000378 |
| _version_ | 1827942731773640704 |
|---|---|
| author | Serhii Chornyi Rob Ofman Janet Koster Hans R. Waterham |
| author_facet | Serhii Chornyi Rob Ofman Janet Koster Hans R. Waterham |
| author_sort | Serhii Chornyi |
| collection | DOAJ |
| description | Peroxisomes are single-membrane bounded organelles that in humans play a dual role in lipid metabolism, including the degradation of very long-chain fatty acids and the synthesis of ether lipids/plasmalogens. The first step in de novo ether lipid synthesis is mediated by the peroxisomal enzyme glyceronephosphate O-acyltransferase, which has a strict substrate specificity reacting only with the long-chain acyl-CoAs. The aim of this study was to determine the origin of these long-chain acyl-CoAs. To this end, we developed a sensitive method for the measurement of de novo ether phospholipid synthesis in cells and, by CRISPR-Cas9 genome editing, generated a series of HeLa cell lines with deficiencies of proteins involved in peroxisomal biogenesis, beta-oxidation, ether lipid synthesis, or metabolite transport. Our results show that the long-chain acyl-CoAs required for the first step of ether lipid synthesis can be imported from the cytosol by the peroxisomal ABCD proteins, in particular ABCD3. Furthermore, we show that these acyl-CoAs can be produced intraperoxisomally by chain shortening of CoA esters of very long-chain fatty acids via beta-oxidation. Our results demonstrate that peroxisomal beta-oxidation and ether lipid synthesis are intimately connected and that the peroxisomal ABC transporters play a crucial role in de novo ether lipid synthesis. |
| first_indexed | 2024-03-13T10:03:39Z |
| format | Article |
| id | doaj.art-d3dbfee03d5e473f9f7dfc2fe5820712 |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-03-13T10:03:39Z |
| publishDate | 2023-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-d3dbfee03d5e473f9f7dfc2fe58207122023-05-23T04:20:36ZengElsevierJournal of Lipid Research0022-22752023-05-01645100364The origin of long-chain fatty acids required for de novo ether lipid/plasmalogen synthesisSerhii Chornyi0Rob Ofman1Janet Koster2Hans R. Waterham3Amsterdam UMC - University of Amsterdam, Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, AZ Amsterdam, the Netherlands; Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the NetherlandsAmsterdam UMC - University of Amsterdam, Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, AZ Amsterdam, the Netherlands; Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the NetherlandsAmsterdam UMC - University of Amsterdam, Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, AZ Amsterdam, the NetherlandsAmsterdam UMC - University of Amsterdam, Department of Clinical Chemistry, Laboratory Genetic Metabolic Diseases, AZ Amsterdam, the Netherlands; Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands; Amsterdam Reproduction & Development, Amsterdam, the Netherlands; For correspondence: Hans R. WaterhamPeroxisomes are single-membrane bounded organelles that in humans play a dual role in lipid metabolism, including the degradation of very long-chain fatty acids and the synthesis of ether lipids/plasmalogens. The first step in de novo ether lipid synthesis is mediated by the peroxisomal enzyme glyceronephosphate O-acyltransferase, which has a strict substrate specificity reacting only with the long-chain acyl-CoAs. The aim of this study was to determine the origin of these long-chain acyl-CoAs. To this end, we developed a sensitive method for the measurement of de novo ether phospholipid synthesis in cells and, by CRISPR-Cas9 genome editing, generated a series of HeLa cell lines with deficiencies of proteins involved in peroxisomal biogenesis, beta-oxidation, ether lipid synthesis, or metabolite transport. Our results show that the long-chain acyl-CoAs required for the first step of ether lipid synthesis can be imported from the cytosol by the peroxisomal ABCD proteins, in particular ABCD3. Furthermore, we show that these acyl-CoAs can be produced intraperoxisomally by chain shortening of CoA esters of very long-chain fatty acids via beta-oxidation. Our results demonstrate that peroxisomal beta-oxidation and ether lipid synthesis are intimately connected and that the peroxisomal ABC transporters play a crucial role in de novo ether lipid synthesis.http://www.sciencedirect.com/science/article/pii/S0022227523000378PhospholipidsBiosynthesisMetabolismZellweger syndromeFatty acidTransport |
| spellingShingle | Serhii Chornyi Rob Ofman Janet Koster Hans R. Waterham The origin of long-chain fatty acids required for de novo ether lipid/plasmalogen synthesis Journal of Lipid Research Phospholipids Biosynthesis Metabolism Zellweger syndrome Fatty acid Transport |
| title | The origin of long-chain fatty acids required for de novo ether lipid/plasmalogen synthesis |
| title_full | The origin of long-chain fatty acids required for de novo ether lipid/plasmalogen synthesis |
| title_fullStr | The origin of long-chain fatty acids required for de novo ether lipid/plasmalogen synthesis |
| title_full_unstemmed | The origin of long-chain fatty acids required for de novo ether lipid/plasmalogen synthesis |
| title_short | The origin of long-chain fatty acids required for de novo ether lipid/plasmalogen synthesis |
| title_sort | origin of long chain fatty acids required for de novo ether lipid plasmalogen synthesis |
| topic | Phospholipids Biosynthesis Metabolism Zellweger syndrome Fatty acid Transport |
| url | http://www.sciencedirect.com/science/article/pii/S0022227523000378 |
| work_keys_str_mv | AT serhiichornyi theoriginoflongchainfattyacidsrequiredfordenovoetherlipidplasmalogensynthesis AT robofman theoriginoflongchainfattyacidsrequiredfordenovoetherlipidplasmalogensynthesis AT janetkoster theoriginoflongchainfattyacidsrequiredfordenovoetherlipidplasmalogensynthesis AT hansrwaterham theoriginoflongchainfattyacidsrequiredfordenovoetherlipidplasmalogensynthesis AT serhiichornyi originoflongchainfattyacidsrequiredfordenovoetherlipidplasmalogensynthesis AT robofman originoflongchainfattyacidsrequiredfordenovoetherlipidplasmalogensynthesis AT janetkoster originoflongchainfattyacidsrequiredfordenovoetherlipidplasmalogensynthesis AT hansrwaterham originoflongchainfattyacidsrequiredfordenovoetherlipidplasmalogensynthesis |