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...

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Autores principales:	Sumeet A Khetarpal, Cecilia Vitali, Michael G Levin, Derek Klarin, Joseph Park, Akhil Pampana, John S Millar, Takashi Kuwano, Dhavamani Sugasini, Papasani V Subbaiah, Jeffrey T Billheimer, Pradeep Natarajan, Daniel J Rader
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Genetics QH426-470
Acceso en línea:	https://doaj.org/article/8f70a22c3e124be3bfe8597898cbddf1
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spelling	oai:doaj.org-article:8f70a22c3e124be3bfe8597898cbddf12021-12-02T20:03:19ZEndothelial lipase mediates efficient lipolysis of triglyceride-rich lipoproteins.1553-73901553-740410.1371/journal.pgen.1009802https://doaj.org/article/8f70a22c3e124be3bfe8597898cbddf12021-09-01T00:00:00Zhttps://doi.org/10.1371/journal.pgen.1009802https://doaj.org/toc/1553-7390https://doaj.org/toc/1553-7404Triglyceride-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.Sumeet A KhetarpalCecilia VitaliMichael G LevinDerek KlarinJoseph ParkAkhil PampanaJohn S MillarTakashi KuwanoDhavamani SugasiniPapasani V SubbaiahJeffrey T BillheimerPradeep NatarajanDaniel J RaderPublic Library of Science (PLoS)articleGeneticsQH426-470ENPLoS Genetics, Vol 17, Iss 9, p e1009802 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Genetics QH426-470
spellingShingle	Genetics QH426-470 Sumeet A Khetarpal Cecilia Vitali Michael G Levin Derek Klarin Joseph Park Akhil Pampana John S Millar Takashi Kuwano Dhavamani Sugasini Papasani V Subbaiah Jeffrey T Billheimer Pradeep Natarajan Daniel J Rader Endothelial lipase mediates efficient lipolysis of triglyceride-rich lipoproteins.
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	article
author	Sumeet A Khetarpal Cecilia Vitali Michael G Levin Derek Klarin Joseph Park Akhil Pampana John S Millar Takashi Kuwano Dhavamani Sugasini Papasani V Subbaiah Jeffrey T Billheimer Pradeep Natarajan Daniel J Rader
author_facet	Sumeet A Khetarpal Cecilia Vitali Michael G Levin Derek Klarin Joseph Park Akhil Pampana John S Millar Takashi Kuwano Dhavamani Sugasini Papasani V Subbaiah Jeffrey T Billheimer Pradeep Natarajan Daniel J Rader
author_sort	Sumeet A Khetarpal
title	Endothelial lipase mediates efficient lipolysis of triglyceride-rich lipoproteins.
title_short	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_sort	endothelial lipase mediates efficient lipolysis of triglyceride-rich lipoproteins.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/8f70a22c3e124be3bfe8597898cbddf1
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_version_	1718375671838801920

Endothelial lipase mediates efficient lipolysis of triglyceride-rich lipoproteins.

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