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Mutations in lipoprotein lipase that block binding to the endothelial cell transporter GPIHBP1
Journal article   Open access   Peer reviewed

Mutations in lipoprotein lipase that block binding to the endothelial cell transporter GPIHBP1

Constance V Voss, Brandon S. J Davies, Shelly Tat, Peter Gin, Loren G Fong, Christopher Pelletier, Charlene D Mottler, André Bensadoun, Anne P Beigneux and Stephen G Young
Proceedings of the National Academy of Sciences - PNAS, Vol.108(19), pp.7980-7984
05/10/2011
DOI: 10.1073/pnas.1100992108
PMCID: PMC3093490
PMID: 21518912
url
https://doi.org/10.1073/pnas.1100992108View
Published (Version of record) Open Access

Abstract

GPIHBP1, a glycosylphosphatidylinositol-anchored protein of capillary endothelial cells, shuttles lipoprotein lipase (LPL) from subendothelial spaces to the capillary lumen. An absence of GPIHBP1 prevents the entry of LPL into capillaries, blocking LPL-mediated triglyceride hydrolysis and leading to markedly elevated triglyceride levels in the plasma (i.e., chylomicronemia). Earlier studies have established that chylomicronemia can be caused by LPL mutations that interfere with catalytic activity. We hypothesized that some cases of chylomicronemia might be caused by LPL mutations that interfere with LPL's ability to bind to GPIHBP1. Any such mutation would provide insights into LPL sequences required for GPIHBP1 binding. Here, we report that two LPL missense mutations initially identified in patients with chylomicronemia, C418Y and E421K, abolish LPL's ability to bind to GPIHBP1 without interfering with LPL catalytic activity or binding to heparin. Both mutations abolish LPL transport across endothelial cells by GPIHBP1. These findings suggest that sequences downstream from LPL's principal heparin-binding domain (amino acids 403–407) are important for GPIHBP1 binding. In support of this idea, a chicken LPL (cLPL)–specific monoclonal antibody, xCAL 1–11 (epitope, cLPL amino acids 416–435), blocks cLPL binding to GPIHBP1 but not to heparin. Also, changing cLPL residues 421 to 425, 426 to 430, and 431 to 435 to alanine blocks cLPL binding to GPIHBP1 without inhibiting catalytic activity. Together, these data define a mechanism by which LPL mutations could elicit disease and provide insights into LPL sequences required for binding to GPIHBP1.
 hypertriglyceridemia Biological Sciences chylomicron lipid metabolism

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