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Endothelial lipase mediates efficient lipolysis of triglyceride-rich lipoproteins
Triglyceride-rich lipoproteins (TRLs) are circulating reservoirs of fatty acids used as vital energy sources for peripheral tissues. Lipoprotein lipase (LPL) is a predominant enzyme mediating triglyceride (TG) lipolysis and TRL clearance to provide fatty acids to tissues in animals. Physiological an...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8483387/ https://www.ncbi.nlm.nih.gov/pubmed/34543263 http://dx.doi.org/10.1371/journal.pgen.1009802 |
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author | Khetarpal, Sumeet A. Vitali, Cecilia Levin, Michael G. Klarin, Derek Park, Joseph Pampana, Akhil Millar, John S. Kuwano, Takashi Sugasini, Dhavamani Subbaiah, Papasani V. Billheimer, Jeffrey T. Natarajan, Pradeep Rader, Daniel J. |
author_facet | Khetarpal, Sumeet A. Vitali, Cecilia Levin, Michael G. Klarin, Derek Park, Joseph Pampana, Akhil Millar, John S. Kuwano, Takashi Sugasini, Dhavamani Subbaiah, Papasani V. Billheimer, Jeffrey T. Natarajan, Pradeep Rader, Daniel J. |
author_sort | Khetarpal, Sumeet A. |
collection | PubMed |
description | Triglyceride-rich lipoproteins (TRLs) are circulating reservoirs of fatty acids used as vital energy sources for peripheral tissues. Lipoprotein lipase (LPL) is a predominant enzyme mediating triglyceride (TG) lipolysis and TRL clearance to provide fatty acids to tissues in animals. Physiological and human genetic evidence support a primary role for LPL in hydrolyzing TRL TGs. We hypothesized that endothelial lipase (EL), another extracellular lipase that primarily hydrolyzes lipoprotein phospholipids may also contribute to TRL metabolism. To explore this, we studied the impact of genetic EL loss-of-function on TRL metabolism in humans and mice. Humans carrying a loss-of-function missense variant in LIPG, p.Asn396Ser (rs77960347), demonstrated elevated plasma TGs and elevated phospholipids in TRLs, among other lipoprotein classes. Mice with germline EL deficiency challenged with excess dietary TG through refeeding or a high-fat diet exhibited elevated TGs, delayed dietary TRL clearance, and impaired TRL TG lipolysis in vivo that was rescued by EL reconstitution in the liver. Lipidomic analyses of postprandial plasma from high-fat fed Lipg(-/-) mice demonstrated accumulation of phospholipids and TGs harboring long-chain polyunsaturated fatty acids (PUFAs), known substrates for EL lipolysis. In vitro and in vivo, EL and LPL together promoted greater TG lipolysis than either extracellular lipase alone. Our data positions EL as a key collaborator of LPL to mediate efficient lipolysis of TRLs in humans and mice. |
format | Online Article Text |
id | pubmed-8483387 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-84833872021-10-01 Endothelial lipase mediates efficient lipolysis of triglyceride-rich lipoproteins Khetarpal, Sumeet A. Vitali, Cecilia Levin, Michael G. Klarin, Derek Park, Joseph Pampana, Akhil Millar, John S. Kuwano, Takashi Sugasini, Dhavamani Subbaiah, Papasani V. Billheimer, Jeffrey T. Natarajan, Pradeep Rader, Daniel J. PLoS Genet Research Article Triglyceride-rich lipoproteins (TRLs) are circulating reservoirs of fatty acids used as vital energy sources for peripheral tissues. Lipoprotein lipase (LPL) is a predominant enzyme mediating triglyceride (TG) lipolysis and TRL clearance to provide fatty acids to tissues in animals. Physiological and human genetic evidence support a primary role for LPL in hydrolyzing TRL TGs. We hypothesized that endothelial lipase (EL), another extracellular lipase that primarily hydrolyzes lipoprotein phospholipids may also contribute to TRL metabolism. To explore this, we studied the impact of genetic EL loss-of-function on TRL metabolism in humans and mice. Humans carrying a loss-of-function missense variant in LIPG, p.Asn396Ser (rs77960347), demonstrated elevated plasma TGs and elevated phospholipids in TRLs, among other lipoprotein classes. Mice with germline EL deficiency challenged with excess dietary TG through refeeding or a high-fat diet exhibited elevated TGs, delayed dietary TRL clearance, and impaired TRL TG lipolysis in vivo that was rescued by EL reconstitution in the liver. Lipidomic analyses of postprandial plasma from high-fat fed Lipg(-/-) mice demonstrated accumulation of phospholipids and TGs harboring long-chain polyunsaturated fatty acids (PUFAs), known substrates for EL lipolysis. In vitro and in vivo, EL and LPL together promoted greater TG lipolysis than either extracellular lipase alone. Our data positions EL as a key collaborator of LPL to mediate efficient lipolysis of TRLs in humans and mice. Public Library of Science 2021-09-20 /pmc/articles/PMC8483387/ /pubmed/34543263 http://dx.doi.org/10.1371/journal.pgen.1009802 Text en © 2021 Khetarpal et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
spellingShingle | Research Article Khetarpal, Sumeet A. Vitali, Cecilia Levin, Michael G. Klarin, Derek Park, Joseph Pampana, Akhil Millar, John S. Kuwano, Takashi Sugasini, Dhavamani Subbaiah, Papasani V. Billheimer, Jeffrey T. Natarajan, Pradeep Rader, Daniel J. Endothelial lipase mediates efficient lipolysis of triglyceride-rich lipoproteins |
title | Endothelial lipase mediates efficient lipolysis of triglyceride-rich lipoproteins |
title_full | Endothelial lipase mediates efficient lipolysis of triglyceride-rich lipoproteins |
title_fullStr | Endothelial lipase mediates efficient lipolysis of triglyceride-rich lipoproteins |
title_full_unstemmed | Endothelial lipase mediates efficient lipolysis of triglyceride-rich lipoproteins |
title_short | Endothelial lipase mediates efficient lipolysis of triglyceride-rich lipoproteins |
title_sort | endothelial lipase mediates efficient lipolysis of triglyceride-rich lipoproteins |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8483387/ https://www.ncbi.nlm.nih.gov/pubmed/34543263 http://dx.doi.org/10.1371/journal.pgen.1009802 |
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