The acidic domain of GPIHBP1 is important for the binding of lipoprotein lipase and chylomicrons.
Open accessAbstract
GPIHBP1, a glycosylphosphatidylinositol-anchored endothelial cell protein of the lymphocyte antigen 6 (Ly6) family, plays a key role in the lipolysis of triglyceride-rich lipoproteins (e.g. chylomicrons). GPIHBP1 is expressed along the luminal surface of endothelial cells of heart, skeletal muscle, and adipose tissue, and GPIHBP1-expressing cells bind lipoprotein lipase (LPL) and chylomicrons avidly. GPIHBP1 contains an amino-terminal acidic domain (amino acids 24-48) that is enriched in aspartate and glutamate residues, and we previously speculated that this domain might be important in binding ligands. To explore the functional importance of the acidic domain, we tested the ability of polyaspartate or polyglutamate peptides to block the binding of ligands to pgsA-745 Chinese hamster ovary cells that overexpress GPIHBP1. Both polyaspartate and polyglutamate blocked LPL and chylomicron binding to GPIHBP1. Also, a rabbit antiserum against the acidic domain of GPIHBP1 blocked LPL and chylomicron binding to GPIHBP1-expressing cells. Replacing the acidic amino acids within GPIHBP1 residues 38-48 with alanine eliminated the ability of GPIHBP1 to bind LPL and chylomicrons. Finally, mutation of the positively charged heparin-binding domains within LPL and apolipoprotein AV abolished the ability of these proteins to bind to GPIHBP1. These studies indicate that the acidic domain of GPIHBP1 is important and that electrostatic interactions play a key role in ligand binding.
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Defective lipolysis occurs with genetic defects in LpL; defects in apoC-II; defective association of LpL with the vascular wall due to antibodies to heparin or defects in GPIHBP1; or defective intracellular LpL processing due to mutated lipase maturation factor 1.
“Defective lipolysis occurs with genetic defects in LpL; defects in apoC-II; defective association of LpL with the vascular wall due to antibodies to heparin or defects in glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1, an LpL-binding protein (75, 76); or defective intracellular LpL processing due to mutated lipase maturation factor 1 (77).”
From Evaluation and Treatment of Hypertriglyceridemia: An Endocrine Society Clinical Practice Guideline (2012) · cites this paper as [75]
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Evaluation and Treatment of Hypertriglyceridemia: An Endocrine Society Clinical Practice Guideline
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“Defective lipolysis occurs with genetic defects in LpL; defects in apoC-II; defective association of LpL with the vascular wall due to antibodies to heparin or defects in glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1, an LpL-binding protein (75, 76); or defective intracellular LpL pr…”
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“Because expression of GPIHBP1 in Chinese hamster ovary (CHO) cells confers the ability to bind LPL (Beigneux et al., 2007, 2009a, 2009b; Gin et al., 2008), we hypothesized that at least some of the LPL in mouse tissues might colocalize with GPIHBP1 in capillaries.”
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“In addition to LPL, GPIHBP1 binds apo-AV (Beigneux et al. 2007; Gin et al. 2007, 2008, 2011), another heparin- binding protein with a key role in plasma TG metabolism (Pennacchio et al. 2001, 2002).”
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“In fact, replacement of the acidic residues completely eliminates the capacity of GPIHBP1 to bind LPL and chylomicrons.[50] Moreover, mutations in the heparin-binding domain of both LPL and apo-AV abolished the binding of these proteins to GPIHBP1.”
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“Mutations in the acidic and Ly6 domains interfere with the ability of GPIHBP1 to bind LPL and chylomicrons (Beigneux et al. 2009c; Gin et al. 2008).”
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“A small glyco-protein, GPIHBP1 has high affinity for LPL and has recently been shown to be responsible for the transendothelial transport of LPL from the parenchymal cells to the capillary lumen where it is postulated to provide a platform for lipolysis [25–27].”
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“in which residues R233, K234, K238 and K240 were simultaneously replaced by glutamic acid or glutamine residues (56-58).”
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“This mutation also resulted in loss of GPIHBP1 binding [35], validating the concept that coordination of GPIHBP1, LPL and apoA-V are a prerequisite for maintaining normal plasma triacylglycerol levels.”
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“It is the N-terminal acidic domain of GPIHBP1 that can electrostatically interact with LPL [43].”
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“1) and the acidic domain in GPIHBP1 are both required for binding [19].”
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“For example, when the acidic domain was expressed in the context of CD59’s LU domain, there was no LPL binding (45), and single amino acid substitutions in the LU domain eliminated LPL binding—”
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Self-citationSong, W., Beigneux, A. P., Weston, T. A., Chen, K., Yang, Y., Nguyen, L. P., Guagliardo, P. R., Jung, H., Tran, A. P., Tu, Y., et al. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2313825120 · Cited by 25 · see citing works
“…iii ) electrostatic interactions between GPIHBP1’s acidic domain and LPL’s large basic patch increase the affinity of these interactions (3, 4, 11, 42); iv ) mis sense mutations that disrupt LPL–GPIHBP1 interactions pre vent LPL transport and cause hypertriglyceridemia (3, 43–46); v ) GPIHBP1…”
Self-citationReimund, M., Larsson, M., Kovrov, O., Kasvandik, S., Olivecrona, G., & Lõokene, A. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.634626 · Cited by 22 · see citing works
“Both domains contribute to the interaction of GPIHBP1 with LPL as evidenced by deletion, mutation, or replacement of one of the two domains that significantly reduce the ability of GPIHBP1 to associate with LPL (5, 16, 17).”
BackgroundInfluentialLipoprotein lipase as a target for obesity/diabetes related cardiovascular disease
Shang, R., & Rodrigues, B. B. (2024) · Journal of Pharmacy & Pharmaceutical Sciences · doi:10.3389/jpps.2024.13199 · Cited by 21 · see citing works
Sharma, V., Witkowski, A., Witkowska, H. E., Dykstra, A. B., Simonsen, J. B., Nelbach, L., Beckstead, J. A., Pullinger, C. R., Kane, J. P., Malloy, M. J., et al. (2014) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.114.304027 · Cited by 21 · see citing works
“When associated with triacylglycerol-rich lipoproteins, WT apoA-V directs these particles to GPIHBP1 via a specific binding interaction.(20) A positively charged sequence motif, located between residues 186 to 227 in apoA-V, mediates interaction with the highly acidic N-terminal segment of GPIHBP1, effectively sequest…”
BackgroundSelf-citationMZF-1/Elk-1 Complex Binds to Protein Kinase Cα Promoter and Is Involved in Hepatocellular Carcinoma
Yue, C.-H., Huang, C., Tsai, J.-H., Hsu, C.-W., Hsieh, Y., Lin, H., & Liu, J.-Y. (2015) · PLoS ONE · doi:10.1371/journal.pone.0127420 · Cited by 19 · see citing works
“This domain probably functions as a transcriptional activation domain, which is a common feature of various transcriptional factors [24, 25], and is important in the binding with positively charged heparin-binding domains [26].”
BackgroundLee, C. J., Hsu, L., Yue, C.-H., Lin, H., Chiu, Y.-W., Lin, Y.-Y., Huang, C., Hung, M., & Liu, J.-Y. (2016) · Oncotarget · doi:10.18632/oncotarget.11337 · Cited by 19 · see citing works
“The acidic domain is important for interaction with the positively charged heparin-binding domain [23].”
BackgroundThe Role of Cdkn1A-Interacting Zinc Finger Protein 1 (CIZ1) in DNA Replication and Pathophysiology
Liu, Q., Niu, N., Wada, Y., & Liu, J. (2016) · International Journal of Molecular Sciences · doi:10.3390/ijms17020212 · Cited by 19 · see citing works
Monoclonal antibodies that bind to the Ly6 domain of GPIHBP1 abolish the binding of LPL
Hu, X., Sleeman, M. W., Miyashita, K., Linton, M. F., Allan, C. M., He, C. H., Larsson, M., Tu, Y., Sandoval, N. P., Jung, R. S., et al. (2016) · Journal of Lipid Research · doi:10.1194/jlr.m072462 · Cited by 18 · see citing works
“Expression vectors for S-protein–tagged CD59 and a GPIHBP1–CD59 chimeric protein were described previously (16).”
MethodSelf-citationType 1 hyperlipoproteinemia in a child with large homozygous deletion encompassing GPIHBP1
Patni, N., Brothers, J. A., Xing, C., & Garg, A. (2016) · Journal of clinical lipidology · doi:10.1016/j.jacl.2016.04.001 · Cited by 18 · see citing works
Lipoprotein lipase transporter GPIHBP1 and triglyceride-rich lipoprotein metabolism
Liu, C., Li, L., Guo, D., Lv, Y.-C., Zheng, X., Mo, Z., & Xie, W. (2018) · Clinica Chimica Acta · doi:10.1016/j.cca.2018.09.020 · Cited by 18 · see citing works
Takanashi, M., Kimura, T., Li, C., Tanaka, M., Matsuhashi, A., Yoshida, H., Noda, A., Xu, P., Takase, S., Okazaki, S., et al. (2019) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.118.311931 · Cited by 18 · see citing works
Apolipoprotein A5, a unique modulator of fasting and postprandial triglycerides
Zhang, L., Liu, M., Black, D. D., & Tso, P. (2022) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2022.159185 · Cited by 17 · see citing works
GPIHBP1 and the processing of triglyceride-rich lipoproteins
Beigneux, A. P. (2010) · Clinical Lipidology · doi:10.2217/clp.10.43 · Cited by 17 · see citing works
Self-citationAllan, C. M., Jung, C. J., Larsson, M., Heizer, P. J., Tu, Y., Sandoval, N. P., Dang, T. L. P., Jung, R. S., Beigneux, A. P., de Jong, P. J., et al. (2017) · Journal of Lipid Research · doi:10.1194/jlr.m076943 · Cited by 17 · see citing works
“An early report suggested that the acidic domain played an important role in LPL binding (5), but recent studies with more refined LPL– GPIHBP1 binding assays showed that the Ly6 domain is primarily responsible for LPL binding, with the acidic domain playing a smaller, accessory role (3).”
BackgroundSelf-citationYang, J., Liu, X. E., Wang, D., Ning, C., Wang, H., Zhang, Q., & Jiang, L. (2017) · Scientific Reports · doi:10.1038/s41598-017-08668-6 · Cited by 17 · see citing works
Type 1 hyperlipoproteinemia due to a novel deletion of exons 3 and 4 in the GPIHBP1 gene
Berge, K. E., Retterstøl, K., Romeo, S., Pirazzi, C., & Leren, T. P. (2014) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2014.02.005 · Cited by 17 · see citing works
Lipoprotein Lipase: Structure, Function, and Genetic Variation
Perera, S. D., Wang, J., McIntyre, A. D., & Hegele, R. A. (2025) · Genes · doi:10.3390/genes16010055 · Cited by 16 · see citing works
“…in more detail in the “Protein Structure of LPL” section of this review) [29,30] and TRL-bound apo A-V, another essential cofactor of LPL, binding to GPIHBP1 [31,32], which enhances the association of apo A-V containing lipoproteins with the endothelial cell surface features associated with LPL.”
Kurooka, N., Eguchi, J., & Wada, J. (2023) · Journal of Diabetes Investigation · doi:10.1111/jdi.14056 · Cited by 17 · see citing works
“The replacement of the LU domain of GPIHBP1 with that of CD59 and mutation of any of the 10 cysteines abolished the LPL binding 20 (Figure 2).”
Yuan, C., Yao, X., Lu, G., Hu, Y., Mao, W., Ke, L., Tong, Z., Xia, Y., Ma, S., Dong, X., et al. (2023) · Molecular Therapy · doi:10.1016/j.ymthe.2023.11.018 · Cited by 16 · see citing works
Shetty, S. K., Walzem, R. L., & Davies, B. S. J. (2020) · Journal of Lipid Research · doi:10.1194/jlr.d119000388 · Cited by 16 · see citing works
“Heparin is known to release LPL from GPIHBP1, likely by competing with the acidic domain of GPIHBP1 for binding to the heparin binding domain of LPL (1, 48).”
BackgroundSelf-citationBril, F., Berg, G. A., Barchuk, M., & Nogueira, J. P. (2025) · Journal of Lipid and Atherosclerosis · doi:10.12997/jla.2025.14.1.5 · Cited by 15 · see citing works
A novel mutation in GPIHBP1 causes familial chylomicronemia syndrome
Paquette, M., Hegele, R. A., Paré, G., & Baass, A. W. (2018) · Journal of clinical lipidology · doi:10.1016/j.jacl.2018.01.011 · Cited by 14 · see citing works
Turlo, K. A., Leung, C. S., Seo, J. J., Goulbourne, C. N., Adeyo, O., Gin, P., Voss, C. V., Bensadoun, A., Fong, L. G., Young, S. G., et al. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2014.03.011 · Cited by 13 · see citing works
“The binding of internally tagged WT-LPL and S447X-LPL to soluble GPIHBP1 (lacking the GPI anchor) was assessed with a cell-free assay [37, 38].”
MethodSelf-citationCardiomyocyte-endothelial cell control of lipoprotein lipase
Chiu, A. P., Wan, A., & Rodrigues, B. B. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2016.03.016 · Cited by 13 · see citing works
Lipoprotein lipase reaches the capillary lumen in chickens despite an apparent absence of GPIHBP1
He, C. H., Hu, X., Jung, R. S., Larsson, M., Tu, Y., Duarte‐Vogel, S., Kim, P., Sandoval, N. P., Price, T. R., Allan, C. M., et al. (2017) · JCI Insight · doi:10.1172/jci.insight.96783 · Cited by 13 · see citing works
“The sequences for the mature proteins were amplified and subcloned into the pTriEx-4 mammalian expression vector (Novagen) as described for expression vectors for human GPIHBP1 or human CD59 (48).”
MethodSelf-citationGenetic variation in apolipoprotein A-V in hypertriglyceridemia
Perera, S. D., & Hegele, R. A. (2023) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000916 · Cited by 12 · see citing works
Jiang, S., Ren, Z., Yang, Y., Liu, Q., Zhou, S., & Xiao, Y. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.115874 · Cited by 12 · see citing works
Vallerie, S. N., & Bornfeldt, K. (2015) · Circulation Research · doi:10.1161/circresaha.115.305819 · Cited by 9 · see citing works
“The lymphocyte antigen 6 motif also contains a N-linked glycosylation site (Asn-78 in human and, Asn-76 in mouse) that is critical for trafficking of GPIHBP1 to the cell surface and for binding LpL. GPIHBP1 is tethered to the surface of the plasma membrane by its GPI anchor, which can be cleaved by a phosphatidylinosi…”
BackgroundInfluentialSümegi, K., Duga, B., Melegh, B., Bánfai, Z., Kövesdi, E., Maász, A., & Melegh, B. (2017) · Pathology & Oncology Research · doi:10.1007/s12253-017-0197-3 · Cited by 7 · see citing works
Yang, P., Zhu, B., Cui, H., Yu, Y., Yu, Q., Kong, L., Sun, M., Liu, Y., Han, B., & Chen, S. (2025) · Cell Death and Disease · doi:10.1038/s41419-025-07709-7 · Cited by 4 · see citing works
“The acidic domain is highly enriched in aspartic and glutamic acid residues and mediates the binding of LPL and Apo-AV [50].”
Role of GPIHBP1 in regulating milk protein traits in dairy cattle
Dong, W., Yang, J., Zhang, Q., & Jiang, L. (2018) · Animal Biotechnology · doi:10.1080/10495398.2018.1536064 · Cited by 4 · see citing works
Changes in Lipoprotein Lipase in the Heart Following Diabetes Onset
Lee, C. S., Zhai, Y., & Rodrigues, B. B. (2022) · Engineering · doi:10.1016/j.eng.2022.06.013 · Cited by 3 · see citing works
New insights in regulation factors of lipoprotein lipase
Jiang, Y., Shu-Hua, X. I. N. G., Cen, W., Chen, J., & Li, X. (2013) · Hereditas (Beijing) · doi:10.3724/sp.j.1005.2013.00830 · Cited by 3 · see citing works
“DOI [21] Gin P, Yin LY, Davies BSJ, Weinstein MM, Ryan RO, Bensadoun A, Fong LG, Young SG, Beigneux AP.”
BackgroundSylvers-Davie, K. L., & Davies, B. S. J. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-819460-7.00125-0 · Cited by 2 · see citing works
Self-citationLipids, Lipoproteins, and Cardiovascular Outcomes
Sakers, A. P., Mszar, R., & Soffer, D. E. (2024) · Contemporary cardiology · doi:10.1007/978-3-031-54960-1_9 · Cited by 1 · see citing works
Stabilizing lipoprotein lipase
Kersten, S., & Bensadoun, A. (2009) · Journal of Lipid Research · doi:10.1194/jlr.e000703 · Cited by 1 · see citing works
Self-citationIdentification and quantitative mRNA analysis of a novel splice variant of GPIHBP1 in dairy cattle
Yang, J., Liu, X. E., Zhang, Q., & Jiang, L. (2014) · Journal of Animal Science and Biotechnology/Journal of animal science and biotechnology · doi:10.1186/2049-1891-5-50 · Cited by 1 · see citing works
“Abbreviations GPIHBP1: Glycosylphosphatidylinositol-anchored HDL binding protein1; LPL: Lipoprotein lipase; UTR: Untranslated region; ORF: Open reading frame; NMD: Nonsense-mediated decay; ESEs: Exonic splicing enhancers; ESSs: Exonic splicing silencers; ISEs: Intronic splicing enhancers; ISSs: Intronic splicing silen…”
BackgroundInfluential(2009) · Current Opinion in Lipidology · doi:10.1097/mol.0b013e32832cef8f · Cited by 1 · see citing works
Sümegi, K. (2019) · Pesci Egyetemi Archivum (University of Pécs)
Bril, F., Berg, G. A., Barchuk, M., & Nogueira, J. P. (2025) · Journal of Lipid and Atherosclerosis · doi:10.12997/jla.2025.14.1.69
GPIHBP1 on oligodendrocytes binds lipoprotein lipase within the human brain
Liu, M., Hung, M., Kozlov, E., Hung, M., Colaço-Gaspar, M., Roy, S., Tu, Y., Magaki, S., Williams, C. K., Mäe, M. A., et al. (2026) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2610646123
“GPIHBP1’s ability to bind LPL depends on two structural domains—a folded three - fingered LU (Ly6/uPAR) domain and an intrinsically disordered N - terminal acidic tail (6, 7).”
Self-citation
- Authors
- Gin, P., Yin, L., Davies, B. S. J., Weinstein, M. M., Ryan, R. O., Bensadoun, A., Fong, L. G., Young, S. G., & Beigneux, A. P.
- Affiliations
- University of California, Los Angeles (US)
- Cornell University (US)
- Corresponding author
- Beigneux, Anne P.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2008-10
- Volume
- 283
- Issue
- 43
- Pages
- 29554-29562
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2662032
- OpenAlex
- W1976037677
- Cited by
- 85
- References
- 27
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 2 · 2023: 5 · 2022: 3 · 2021: 2 · 2020: 1 · 2019: 3 · 2018: 4 · 2017: 5 · 2016: 11 · 2015: 3 · 2014: 7 · 2013: 4 · 2012: 6
- FWCI
- 5.84
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Heart, Lung, and Blood Institute (HL073061, R01HL087228, HL-66600, R01HL073061, HL-66621, U01HL066621, U01HL066600)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Health Sciences › Medicine › Surgery › Lymphatic Disorders and Treatments
- Keywords
- GPIHBP1, acidic domain, lipoprotein lipase, chylomicrons, ligand binding, electrostatic interactions, polyaspartate, poly-γ-glutamic acid, heparin-binding domain, triglyceride-rich lipoproteins, lipolysis, endothelial cells, GPI-anchored proteins
- MeSH terms
- Animals, Carrier Proteins, Chylomicrons, Cricetulus, Cricetinae, Humans, Hydrogen-Ion Concentration, Ligands, Lipoprotein Lipase, Peptides, Polyglutamic Acid, Protein Binding, CHO Cells, Protein Structure, Tertiary, Receptors, Lipoprotein, Mice
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