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Article: A protein of capillary endothelial cells, GPIHBP1, is crucial for plasma triglyceride metabolism

TitleA protein of capillary endothelial cells, GPIHBP1, is crucial for plasma triglyceride metabolism
Authors
Keywordsendothelial cells
lipoprotein lipase
triglycerides
Issue Date29-Aug-2022
PublisherNational Academy of Sciences
Citation
Proceedings of the National Academy of Sciences, 2022, v. 119, n. 36 How to Cite?
Abstract

GPIHBP1, a protein of capillary endothelial cells (ECs), is a crucial partner for lipoprotein lipase (LPL) in the lipolytic processing of triglyceride-rich lipoproteins. GPIHBP1, which contains a three-fingered cysteine-rich LU (Ly6/uPAR) domain and an intrinsically disordered acidic domain (AD), captures LPL from within the interstitial spaces (where it is secreted by parenchymal cells) and shuttles it across ECs to the capillary lumen. Without GPIHBP1, LPL remains stranded within the interstitial spaces, causing severe hypertriglyceridemia (chylomicronemia). Biophysical studies revealed that GPIHBP1 stabilizes LPL structure and preserves LPL activity. That discovery was the key to crystallizing the GPIHBP1-LPL complex. The crystal structure revealed that GPIHBP1's LU domain binds, largely by hydrophobic contacts, to LPL's C-terminal lipid-binding domain and that the AD is positioned to project across and interact, by electrostatic forces, with a large basic patch spanning LPL's lipid-binding and catalytic domains. We uncovered three functions for GPIHBP1's AD. First, it accelerates the kinetics of LPL binding. Second, it preserves LPL activity by inhibiting unfolding of LPL's catalytic domain. Third, by sheathing LPL's basic patch, the ADmakes it possible for LPL tomove across ECs to the capillary lumen. Without the AD, GPIHBP1-bound LPL is trapped by persistent interactions between LPL and negatively charged heparan sulfate proteoglycans (HSPGs) on the abluminal surface of ECs. The AD interrupts the HSPG interactions, freeing LPL-GPIHBP1 complexes to move across ECs to the capillary lumen. GPIHBP1 is medically important; GPIHBP1 mutations cause lifelong chylomicronemia, and GPIHBP1 autoantibodies cause some acquired cases of chylomicronemia.


Persistent Identifierhttp://hdl.handle.net/10722/340305
ISSN
2023 Impact Factor: 9.4
2023 SCImago Journal Rankings: 3.737
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorYoung, SG-
dc.contributor.authorSong, WX-
dc.contributor.authorYang, Y-
dc.contributor.authorBirrane, G-
dc.contributor.authorJiang, HB-
dc.contributor.authorBeigneux, AP-
dc.contributor.authorPloug, M-
dc.contributor.authorFong, LG -
dc.date.accessioned2024-03-11T10:43:09Z-
dc.date.available2024-03-11T10:43:09Z-
dc.date.issued2022-08-29-
dc.identifier.citationProceedings of the National Academy of Sciences, 2022, v. 119, n. 36-
dc.identifier.issn0027-8424-
dc.identifier.urihttp://hdl.handle.net/10722/340305-
dc.description.abstract<p>GPIHBP1, a protein of capillary endothelial cells (ECs), is a crucial partner for lipoprotein lipase (LPL) in the lipolytic processing of triglyceride-rich lipoproteins. GPIHBP1, which contains a three-fingered cysteine-rich LU (Ly6/uPAR) domain and an intrinsically disordered acidic domain (AD), captures LPL from within the interstitial spaces (where it is secreted by parenchymal cells) and shuttles it across ECs to the capillary lumen. Without GPIHBP1, LPL remains stranded within the interstitial spaces, causing severe hypertriglyceridemia (chylomicronemia). Biophysical studies revealed that GPIHBP1 stabilizes LPL structure and preserves LPL activity. That discovery was the key to crystallizing the GPIHBP1-LPL complex. The crystal structure revealed that GPIHBP1's LU domain binds, largely by hydrophobic contacts, to LPL's C-terminal lipid-binding domain and that the AD is positioned to project across and interact, by electrostatic forces, with a large basic patch spanning LPL's lipid-binding and catalytic domains. We uncovered three functions for GPIHBP1's AD. First, it accelerates the kinetics of LPL binding. Second, it preserves LPL activity by inhibiting unfolding of LPL's catalytic domain. Third, by sheathing LPL's basic patch, the ADmakes it possible for LPL tomove across ECs to the capillary lumen. Without the AD, GPIHBP1-bound LPL is trapped by persistent interactions between LPL and negatively charged heparan sulfate proteoglycans (HSPGs) on the abluminal surface of ECs. The AD interrupts the HSPG interactions, freeing LPL-GPIHBP1 complexes to move across ECs to the capillary lumen. GPIHBP1 is medically important; GPIHBP1 mutations cause lifelong chylomicronemia, and GPIHBP1 autoantibodies cause some acquired cases of chylomicronemia.<br></p>-
dc.languageeng-
dc.publisherNational Academy of Sciences-
dc.relation.ispartofProceedings of the National Academy of Sciences-
dc.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subjectendothelial cells-
dc.subjectlipoprotein lipase-
dc.subjecttriglycerides-
dc.titleA protein of capillary endothelial cells, GPIHBP1, is crucial for plasma triglyceride metabolism -
dc.typeArticle-
dc.identifier.doi10.1073/pnas.2211136119-
dc.identifier.scopuseid_2-s2.0-85136859531-
dc.identifier.volume119-
dc.identifier.issue36-
dc.identifier.eissn1091-6490-
dc.identifier.isiWOS:001048523900017-
dc.identifier.issnl0027-8424-

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