Affinage

GPIHBP1

Glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 · UniProt Q8IV16

Length
184 aa
Mass
19.9 kDa
Annotated
2026-04-28
100 papers in source corpus 37 papers cited in narrative 34 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GPIHBP1 is a GPI-anchored endothelial cell-surface protein that serves as the obligate transporter and stabilizer of lipoprotein lipase (LPL) in the intravascular lipolytic system. It captures LPL from subendothelial heparan sulfate proteoglycans via two structurally and functionally distinct domains: an intrinsically disordered, O-sulfated acidic N-terminal domain that accelerates LPL association by >250-fold through electrostatic steering, stabilizes LPL's catalytic domain against unfolding, shields LPL's basic patch from HSPG retention to permit transcytosis, and protects LPL from ANGPTL4-catalyzed inactivation (PMID:26725083, PMID:36037340, PMID:29899144, PMID:27929370); and a disulfide-rich Ly6/LU domain that mediates high-affinity, hydrophobic binding to LPL's C-terminal lipid-binding domain, as resolved by crystal structure (PMID:30559189, PMID:19726683). GPIHBP1 transcytoses LPL across endothelial cells in vesicles to the capillary lumen, where LPL can further detach into the glycocalyx to drive margination and lipolysis of triglyceride-rich lipoproteins; loss of GPIHBP1 in knockout mice causes severe chylomicronemia, and both homozygous missense mutations in the Ly6 domain and autoantibodies against GPIHBP1 cause familial or acquired chylomicronemia in humans (PMID:17620854, PMID:23008484, PMID:37871217, PMID:19304573, PMID:28402248). GPIHBP1 expression in capillary endothelial cells is transcriptionally regulated by PPARγ and by an upstream enhancer element, and is induced by high-glucose/VEGF-Notch signaling in the diabetic heart (PMID:18787041, PMID:30598475, PMID:26586663).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2002 High

    Identification of GPIHBP1 as a GPI-anchored protein with lipid-binding capacity established a new membrane-anchored player in lipoprotein metabolism, though its physiological ligand was initially thought to be HDL.

    Evidence Expression cloning with fluorescent HDL; phospholipase C release and selective lipid uptake assays in transfected cells

    PMID:12496272

    Open questions at the time
    • HDL binding later shown to be secondary; physiological role was not yet connected to LPL or chylomicron metabolism
    • Tissue distribution beyond heart was not characterized
  2. 2007 High

    Knockout mouse studies and binding assays redefined GPIHBP1 as essential for LPL presentation and chylomicron processing at the capillary endothelium, resolving its true physiological role.

    Evidence Gpihbp1−/− mice with severe chylomicronemia (TG ~5000 mg/dL); CHO cell binding assays for LPL and chylomicrons; immunofluorescence localization on luminal capillary endothelium

    PMID:17620854 PMID:18854402

    Open questions at the time
    • Structural basis of LPL binding unknown
    • Transcytosis mechanism not yet demonstrated
  3. 2008 High

    Domain dissection revealed that GPIHBP1 uses two independent structural modules — an acidic N-terminal domain and a cysteine-rich Ly6 domain — to engage LPL through electrostatic interactions, while N-glycosylation at Asn-76 is required for surface trafficking.

    Evidence Alanine substitution of acidic domain residues 38–48; peptide competition; cysteine mutagenesis; N-glycosylation site mutagenesis with immunofluorescence and binding assays

    PMID:18340083 PMID:18713736

    Open questions at the time
    • Relative contribution of each domain to binding kinetics not quantified
    • Whether the two domains bind the same or different regions of LPL was unknown
  4. 2008 High

    Demonstrating that PPARγ directly regulates GPIHBP1 transcription in endothelial cells established a metabolic signaling axis controlling LPL platform expression.

    Evidence PPARγ agonist treatment; functional PPAR binding site in Gpihbp1 promoter by luciferase assay; endothelial-specific PPARγ conditional knockout reducing Gpihbp1 mRNA

    PMID:18787041

    Open questions at the time
    • Other transcription factors contributing to tissue-specific expression not identified
    • Post-transcriptional regulation not explored
  5. 2009 High

    Human mutations in GPIHBP1's Ly6 domain cysteines and Q115 causing familial chylomicronemia, combined with the finding that GPIHBP1 protects LPL from ANGPTL4-mediated inactivation, defined GPIHBP1 as both a genetically validated disease gene and a functional shield for LPL.

    Evidence Genetic screening of chylomicronemia patients; CHO cell and cell-free binding assays for Q115P, C65S, C68G mutants; in vitro LPL activity assays with ANGPTL4; Angptl4−/−/Gpihbp1−/− double-knockout mice

    PMID:19304573 PMID:19542565 PMID:20026666

    Open questions at the time
    • Structural basis of ANGPTL4 protection by GPIHBP1 not yet resolved
    • Quantitative contribution of ANGPTL4 regulation to the chylomicronemia phenotype not separated from transport defects
  6. 2011 High

    Alanine scanning of the Ly6 domain and LPL C-terminal mutagenesis mapped the binding interface to finger 2 of GPIHBP1 and LPL residues ~418–435, and transcytosis assays demonstrated that GPIHBP1 physically transports LPL across endothelial cells.

    Evidence Systematic alanine scanning mutagenesis; LPL C418Y/E421K mutations abolishing GPIHBP1 binding but not catalytic activity; endothelial transcytosis assays

    PMID:21478160 PMID:21518912

    Open questions at the time
    • Atomic-resolution structure of the interface not available
    • Whether LPL monomer or dimer binds GPIHBP1 was debated
  7. 2012 High

    Demonstrating that GPIHBP1 transcytoses LPL bidirectionally in vesicles via a dynamin-dependent, caveolin-1-independent mechanism resolved the cellular transport pathway, while showing that LPL's isolated C-terminal domain suffices for GPIHBP1 binding clarified the minimal binding unit.

    Evidence Bidirectional transcytosis assays; dynasore/genistein inhibition; caveolin-1 KO cells; EM tomography showing GPIHBP1/LPL in vesicles; LPL domain deletion constructs

    PMID:22493000 PMID:23008484

    Open questions at the time
    • Specific vesicular machinery mediating GPIHBP1 transcytosis not identified
    • Sorting signals for basolateral-to-apical directionality unknown
  8. 2014 High

    In vivo imaging showed that GPIHBP1-bound LPL — not HSPG-bound LPL — is the primary determinant of triglyceride-rich lipoprotein margination along capillaries, establishing GPIHBP1 as the functional platform for intravascular lipolysis.

    Evidence Fluorescence and infrared-dye microscopy of TRL margination in Gpihbp1−/− vs wild-type hearts; endothelial LPL expression rescue failing to restore margination without GPIHBP1

    PMID:24726386

    Open questions at the time
    • Mechanism by which luminal LPL–GPIHBP1 complex captures TRLs not structurally resolved
    • Role of apoC-II in this context not dissected
  9. 2016 High

    Biophysical studies using HDX-MS and SPR revealed the dual mechanism of GPIHBP1's two domains: the LU domain binds LPL's C-terminal domain via hydrophobic contacts, while the intrinsically disordered acidic domain stabilizes LPL's catalytic domain against ANGPTL4-catalyzed unfolding, establishing molecular-level understanding of GPIHBP1's chaperone-like function.

    Evidence Hydrogen-deuterium exchange mass spectrometry; surface plasmon resonance; zero-length cross-linking; ANGPTL4 unfolding protection assays with domain-specific mutants

    PMID:26725083 PMID:27929370

    Open questions at the time
    • Whether acidic domain protection is stoichiometric or catalytic was unclear
    • Structural model of acidic domain–basic patch interaction at atomic level not available
  10. 2017 High

    Discovery that autoantibodies against GPIHBP1 block LPL binding and cause acquired chylomicronemia in patients established an autoimmune etiology for hypertriglyceridemia, paralleling the genetic loss-of-function phenotype.

    Evidence Immunoassays and LPL–GPIHBP1 blocking assays with plasma from six patients; clinical characterization

    PMID:28402248

    Open questions at the time
    • Epitope specificity of autoantibodies beyond Ly6 vs acidic domain not mapped
    • Prevalence in the broader chylomicronemia population unknown
  11. 2018 High

    The crystal structure of the LPL–GPIHBP1 complex at 2.5–3.0 Å confirmed that monomeric LPL forms a 1:1 complex with GPIHBP1's LU domain via hydrophobic interactions with LPL's C-terminal lipid-binding domain, while LPL's basic patch faces outward, poised to interact with the acidic domain and lipoproteins. O-sulfation of a conserved tyrosine in the acidic domain was shown to enhance binding kinetics and protective function.

    Evidence X-ray crystallography; mass spectrometry identification of O-sulfation; SPR kinetics

    PMID:29899144 PMID:30559189 PMID:31072929

    Open questions at the time
    • Structure of the full complex including the acidic domain is missing (disordered in crystal)
    • How GPIHBP1-bound LPL engages triglyceride-rich lipoproteins structurally is unresolved
  12. 2022 High

    The acidic domain was shown to serve three mechanistically separable functions — accelerating LPL capture, stabilizing LPL structure, and shielding LPL's basic patch from HSPGs to enable transcytosis — resolving the longstanding question of why the acidic domain is essential despite not being the primary LPL-binding domain.

    Evidence Domain-specific mutant GPIHBP1 constructs; transcytosis assays; HSPG interaction studies; biophysical binding measurements

    PMID:36037340

    Open questions at the time
    • Structural visualization of acidic domain sheathing the basic patch not achieved
    • Whether HSPG retention in the absence of the acidic domain is the sole cause of transport failure was not independently confirmed
  13. 2023 High

    Demonstrating that LPL detaches from GPIHBP1 after transcytosis and enters the endothelial glycocalyx where it actively processes TRLs revealed a previously unknown post-transport phase of GPIHBP1-mediated lipolysis.

    Evidence Conformation-specific monoclonal antibody (88B8) detecting free but not GPIHBP1-bound LPL; confocal and immunogold EM; NanoSIMS imaging of lipid delivery

    PMID:37871217

    Open questions at the time
    • Mechanism of LPL release from GPIHBP1 in the lumen not defined
    • Whether GPIHBP1 recycles after LPL release is unknown
    • Relative contribution of glycocalyx-associated vs GPIHBP1-bound LPL to total intravascular lipolysis not quantified

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include: how GPIHBP1 directs vesicular transcytosis (sorting machinery unknown), the structural basis of the acidic domain's interaction with LPL's basic patch (disordered in available crystals), the mechanism by which LPL dissociates from GPIHBP1 in the capillary lumen, and whether GPIHBP1 recycles after LPL delivery.
  • Vesicular sorting signals and trafficking machinery for GPIHBP1 transcytosis not identified
  • Atomic structure of acidic domain–basic patch interaction lacking
  • LPL release mechanism from GPIHBP1 in the lumen undefined
  • GPIHBP1 recycling or turnover after LPL delivery not characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 5 GO:0060090 molecular adaptor activity 5 GO:0098772 molecular function regulator activity 4 GO:0038024 cargo receptor activity 3
Localization
GO:0005886 plasma membrane 4 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-1430728 Metabolism 5 R-HSA-9609507 Protein localization 3 R-HSA-5653656 Vesicle-mediated transport 2
Partners
ANGPTL3ANGPTL4APOA5APOC3LPL

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 GPIHBP1 (GPI-HBP1) was identified as a novel GPI-anchored protein that binds HDL with high affinity (Kd = 2-3 µg/mL) and mediates selective lipid uptake but not the protein component of HDL; it lacks HDL-dependent cholesterol efflux activity. Highest expression was found in heart. Expression cloning with fluorescent-labeled HDL; phosphatidylinositol-specific phospholipase C treatment; selective lipid uptake assays The Journal of biological chemistry High 12496272
2007 GPIHBP1 is expressed on the luminal surface of capillary endothelial cells in heart, adipose tissue, and skeletal muscle, and cells transfected with GPIHBP1 bind both lipoprotein lipase (LPL) and chylomicrons avidly. GPIHBP1 knockout mice develop severe chylomicronemia (plasma TG up to 5000 mg/dL), establishing GPIHBP1 as essential for lipolytic processing of triglyceride-rich lipoproteins. Gpihbp1 knockout mouse model; transfected CHO cell binding assays; immunofluorescence microscopy for localization Current opinion in lipidology High 17620854 18854402
2008 The acidic N-terminal domain of GPIHBP1 (amino acids 24–48, enriched in aspartate and glutamate) is essential for binding LPL and chylomicrons. Polyaspartate/polyglutamate peptides, an antiserum against the acidic domain, and alanine substitution of residues 38–48 each abolished LPL and chylomicron binding. Mutation of the positively charged heparin-binding domains in LPL and apoAV also abolished binding to GPIHBP1, indicating electrostatic interactions are key. CHO cell-based binding assays; peptide competition; site-directed mutagenesis; antibody blocking The Journal of biological chemistry High 18713736
2008 N-glycosylation of mouse GPIHBP1 at Asn-76 is critical for trafficking of GPIHBP1 to the cell surface; mutating this site causes accumulation in the endoplasmic reticulum and loss of LPL and chylomicron binding. N-glycosidase/endoglycosidase digestion; site-directed mutagenesis; immunofluorescence microscopy; cell-based binding assays Journal of lipid research High 18340083
2008 GPIHBP1 expression in endothelial cells is regulated by PPARγ; a PPARγ agonist increases Gpihbp1 expression in adipose tissue, heart, and skeletal muscle. An upstream PPAR binding site in the Gpihbp1 promoter is functional in a luciferase reporter assay, and conditional knockout of PPARγ in endothelial cells reduces Gpihbp1 transcript levels in vivo. Luciferase reporter assay; PPARγ agonist treatment; endothelial PPARγ conditional knockout mice; RT-PCR Molecular endocrinology (Baltimore, Md.) High 18787041
2008 In Gpihbp1-/- mice, heparin-induced LPL release into plasma is markedly delayed and reduced compared to wild-type, and Intralipid injection releases LPL in wild-type but not Gpihbp1-/- mice, demonstrating that GPIHBP1 is a major in vivo binding site for LPL in capillaries. Intravenous heparin injection in Gpihbp1-/- vs wild-type mice; plasma LPL kinetics; Intralipid challenge The Journal of biological chemistry High 18845532
2009 All 10 conserved cysteines in the Ly6 domain of GPIHBP1 are required for LPL binding; cysteine-to-alanine mutants reach the cell surface but cannot bind LPL in cell-based and cell-free assays, demonstrating the Ly6 domain is essential for GPIHBP1 function. Site-directed mutagenesis; CHO cell surface binding assays; cell-free LPL-binding bead assay; phospholipase C release assay The Journal of biological chemistry High 19726683
2009 A homozygous missense mutation in GPIHBP1 (Q115P) in a patient with chylomicronemia abolishes the ability of GPIHBP1 to bind LPL and chylomicrons without affecting cell-surface localization, establishing that Q115 in the Ly6 domain is critical for LPL binding. Patient genetic screening; CHO cell-based binding assays; cell-surface expression studies Arteriosclerosis, thrombosis, and vascular biology High 19304573
2009 GPIHBP1 stabilizes LPL activity and prevents inhibition of LPL by ANGPTL4 and ANGPTL3 in vitro; GPIHBP1-stabilized LPL is largely refractory to ANGPTL4 inactivation, unlike free or heparin-bound LPL. Genetic epistasis in Angptl4-/-/Gpihbp1-/- mice confirms ANGPTL4 acts upstream of GPIHBP1-bound LPL in vivo. In vitro LPL activity assays; double-knockout mouse models; neutralizing antibody treatment Journal of lipid research High 19542565
2009 Compound heterozygous mutations in conserved cysteines of the GPIHBP1 Ly6 domain (C65S and C68G) cause familial chylomicronemia; these mutant proteins reach the cell surface but are defective in LPL binding, demonstrating the C65-C89 disulfide bond region is critical for LPL binding. Family genetic sequencing; CHO cell-based and cell-free LPL binding assays; adipose tissue biopsy LPL analysis Journal of lipid research High 20026666
2010 GPIHBP1's acidic domain binds LPL avidly (fast on/off kinetics, electrostatically dependent), while the Ly6 domain binds LPL through a distinct site (slower kinetics, salt-resistant, heparin-resistant). These are two functionally independent binding sites for LPL on GPIHBP1; LPL's interaction with lipoproteins is supported when LPL is bound to the acidic domain but not when bound to the Ly6 domain. Surface plasmon resonance; peptide competition binding assays with isolated acidic peptide and Ly6 domain; salt and heparin dissociation experiments The Journal of biological chemistry (inferred; published 2015 per PMID 25873395) High 25873395
2010 GPIHBP1 is found on capillary endothelial cells not only in heart, skeletal muscle, and adipose tissue but also prominently in lung and liver, as revealed by PET scanning with radiolabeled antibodies; LPL produced in muscle can be captured by GPIHBP1 in the lung. Positron emission tomography with radiolabeled GPIHBP1-specific antibodies; immunofluorescence microscopy; Gpihbp1-/- and Lpl-/- mouse models The Journal of biological chemistry High 20889497
2010 GPIHBP1 specifically binds LPL but not other lipase family members (endothelial lipase, hepatic lipase, pancreatic lipase). GPIHBP1 binds apoAV via its acidic domain independently of the Ly6 domain. Chylomicron binding to GPIHBP1-expressing CHO cells is dependent on LPL captured from the medium, not a direct interaction. Cell-based and cell-free binding assays with lipase family members and apoAV-phospholipid disks; mutant GPIHBP1 constructs Arteriosclerosis, thrombosis, and vascular biology High 20966398
2011 Nine amino acid residues clustered in finger 2 of GPIHBP1's three-fingered Ly6 domain (beyond the conserved cysteines) are important for LPL binding and for transport of LPL across endothelial cells from basolateral to apical surface. Systematic alanine scanning mutagenesis of the Ly6 domain; immunofluorescence microscopy binding assay; Western blot binding assay; endothelial transcytosis assay The Journal of biological chemistry High 21478160
2011 LPL missense mutations C418Y and E421K abolish LPL binding to GPIHBP1 without affecting LPL catalytic activity or heparin binding, and prevent LPL transport across endothelial cells. Sequences in LPL's C-terminal domain (residues ~421–435) are critical for GPIHBP1 binding. Cell-based and cell-free LPL-GPIHBP1 binding assays; LPL catalytic activity assays; endothelial transcytosis assays; monoclonal antibody epitope mapping Proceedings of the National Academy of Sciences of the United States of America High 21518912
2011 GPIHBP1 picks up LPL in the subendothelial spaces and transports it bidirectionally across endothelial cells to the capillary lumen in vesicles; this transport is inhibited by dynasore and genistein (consistent with vesicular/endocytic mechanism) and does not require caveolin-1. EM tomography confirmed GPIHBP1 and LPL in membrane invaginations and vesicles. Bidirectional transcytosis assays in cultured endothelial cells and live mice; dynasore/genistein inhibition; caveolin-1 KO cells; transmission EM and dual-axis EM tomography Journal of lipid research High 23008484
2012 LPL's C-terminal domain (residues 298–448) is sufficient for GPIHBP1 binding and does not require full-length LPL homodimers. After proteolytic cleavage at residue 297, the isolated C-terminal fragment binds GPIHBP1 avidly; this binding is abolished by C418Y or E421K mutations. LPL domain deletion and mutagenesis; cell-based and cell-free GPIHBP1 binding assays; refolding experiment after denaturing conditions Human molecular genetics High 22493000
2014 Triglyceride-rich lipoproteins (TRLs) marginate along heart capillaries in wild-type but not Gpihbp1-/- mice, and this margination requires LPL bound to GPIHBP1. Expression of LPL by endothelial cells in Gpihbp1-/- mice (bound to HSPGs) does not restore TRL margination, demonstrating GPIHBP1-bound LPL is the primary determinant of TRL margination. Fluorescence microscopy; quantitative assay with infrared-dye-labeled lipoproteins; EM tomography; in vivo and cell-culture studies in Gpihbp1-/- mice Cell metabolism High 24726386
2014 Many GPIHBP1 missense mutations (including those in patients with chylomicronemia) cause formation of disulfide-linked GPIHBP1 dimers and multimers; only GPIHBP1 monomers are capable of binding LPL. Residue W109 plays a more direct role in LPL binding as W109S abolishes LPL binding without promoting multimerization. Expression of mutant GPIHBP1 in CHO, rat/human endothelial cells, and Drosophila S2 cells; non-reducing SDS-PAGE; cell-based and cell-free LPL binding assays Circulation research High 25387803
2015 ANGPTL4 can bind and inactivate LPL that is complexed to GPIHBP1 on the surface of endothelial cells. Once inactivated by ANGPTL4, LPL dissociates from GPIHBP1, and ANGPTL4-inactivated LPL is incapable of binding GPIHBP1. ANGPTL4 binding to LPL at 4°C is not sufficient for inactivation, indicating binding and inactivation are separable steps. Cell-based binding and activity assays with LPL-GPIHBP1 complexes on endothelial cells; temperature-dependent experiments; N-terminal fragment vs full-length ANGPTL4 comparison The Journal of biological chemistry High 25809481
2016 GPIHBP1's intrinsically disordered acidic N-terminal domain stabilizes LPL catalytic activity by preventing global unfolding of LPL's catalytic domain. The Ly6/LU domain binds LPL's C-terminal domain. The acidic domain and LU domain serve distinct roles: the LU domain mediates LPL binding kinetics while the acidic domain preserves LPL structure/activity. Hydrogen-deuterium exchange/mass spectrometry; surface plasmon resonance; zero-length cross-linking; LPL activity assays eLife High 26725083
2016 ANGPTL4 inactivates LPL by catalytically unfolding its hydrolase domain; GPIHBP1 binding renders LPL largely refractory to this ANGPTL4-catalyzed unfolding. Both the LU domain and the intrinsically disordered acidic domain of GPIHBP1 are required for protection against ANGPTL4. A clinically relevant ANGPTL4 polymorphism (E40K) is less efficient at catalyzing LPL unfolding due to destabilization of its N-terminal α-helix. Hydrogen-deuterium exchange/mass spectrometry; LPL unfolding assays; ANGPTL4 variant functional assays; GPIHBP1 domain mutants eLife High 27929370
2016 HSPG-bound LPL in the interstitial spaces is mobile and can detach from HSPGs to move to GPIHBP1 on capillary endothelial cells. This movement requires the Ly6 domain of GPIHBP1 (W109S mutation blocks it) but not the acidic domain. In vivo, GPIHBP1-coated beads injected into adipose tissue capture HSPG-bound LPL from adipocytes. Cell-culture LPL transfer assays; GPIHBP1-coated bead injection in Gpihbp1-/- mice; domain mutant GPIHBP1 constructs Journal of lipid research High 27811232
2017 Autoantibodies against GPIHBP1 in patients with chylomicronemia block the binding of LPL to GPIHBP1, preventing LPL transport to the capillary lumen and causing low plasma LPL levels and severe hypertriglyceridemia. This defines a new acquired form of chylomicronemia. Immunoassays; Western blot; immunocytochemistry; LPL-GPIHBP1 blocking assays with patient plasma The New England journal of medicine High 28402248
2017 ApoC-III inhibits triglyceride hydrolysis by GPIHBP1-bound LPL more potently than free LPL. TRLs from APOC3 transgenic mice bind normally to GPIHBP1-bound LPL but are hydrolyzed more slowly. A mutant apoC-III (p.A23T) associated with low plasma TG displayed reduced inhibition of GPIHBP1-bound LPL. In vitro lipolysis assays with LPL bound to GPIHBP1 on agarose beads and cultured cells; APOC3 transgenic mouse TRL binding assays; in vivo heart perfusion Journal of lipid research High 28694296
2017 Monoclonal antibodies against GPIHBP1's Ly6 domain (RE3, RG3) abolish LPL binding, whereas antibodies against the acidic domain (RF4) do not, confirming the Ly6 domain is the principal structural determinant for LPL binding. Human GPIHBP1 is expressed exclusively in capillary endothelial cells. Monoclonal antibody panel; LPL binding assays; immunohistochemistry of human tissues Journal of lipid research High 27875259
2018 GPIHBP1's intrinsically disordered acidic domain contains a conserved tyrosine that is posttranslationally modified by O-sulfation; this sulfation increases the affinity of GPIHBP1–LPL interactions and enhances GPIHBP1's ability to protect LPL against ANGPTL4-catalyzed unfolding. The acidic IDR increases the LPL association rate (kon) by >250-fold via electrostatic steering. Mass spectrometry identification of O-sulfation; surface plasmon resonance; ANGPTL4 unfolding protection assays; biophysical binding kinetics Proceedings of the National Academy of Sciences of the United States of America High 29899144
2018 Crystal structure of LPL in complex with GPIHBP1 was solved; GPIHBP1's LU domain binds LPL's C-terminal lipid-binding domain primarily by hydrophobic interactions. LPL contains a large basic patch spanning its N- and C-terminal domains that is positioned to interact with GPIHBP1's acidic domain. The structure reveals LPL can be active as a monomeric 1:1 complex with GPIHBP1. X-ray crystallography of LPL-GPIHBP1 complex (2.5–3.0 Å); biochemical characterization; co-expression with LMF1 chaperone Proceedings of the National Academy of Sciences of the United States of America High 30559189 31072929
2015 High glucose induces GPIHBP1 expression in endothelial cells through heparanase-mediated release of PDGF, amplifying LPL shuttling across endothelial cells. In diabetes, VEGF from cardiomyocytes activates endothelial Notch signaling (via DLL4 and nuclear translocation of NICD) to upregulate GPIHBP1 expression and thereby increase LPL-derived fatty acid delivery to cardiomyocytes. EC high-glucose exposure; heparanase treatment; VEGF neutralization; Notch signaling inhibition; coculture with cardiomyocytes; in vivo diabetic heart perfusion Arteriosclerosis, thrombosis, and vascular biology Medium 24735886 26586663
2016 An upstream enhancer element ~3.6 kb from exon 1 of mouse Gpihbp1 regulates tissue-specific expression; deletion of the enhancer by CRISPR/Cas9 reduces Gpihbp1 expression >90% in liver and ~50% in heart and brown adipose tissue, with partial LPL mislocalization in compound heterozygotes. CRISPR/Cas9 enhancer deletion; RT-PCR; immunohistochemistry for LPL localization Journal of lipid research Medium 30598475
2019 GPIHBP1 is expressed in capillaries of mouse and human gliomas (but absent from normal brain capillaries) and captures locally produced LPL, enabling margination of TRLs along glioma capillaries and uptake of TRL-derived lipid nutrients by surrounding glioma cells as shown by NanoSIMS imaging. Immunohistochemistry; NanoSIMS isotope imaging of TRL-derived lipid uptake; in vivo glioma model eLife High 31169500
2020 ANGPTL4 and ANGPTL3-ANGPTL8 complexes disrupt LPL-GPIHBP1 binding on endothelial cells, whereas exogenous LPL blockers (tyloxapol, poloxamer-407, tetrahydrolipstatin) do not. Chylomicrons and fatty acids produced during lipolysis can also dissociate LPL from GPIHBP1. NanoBiT split-luciferase real-time binding assay on endothelial cells; pharmacological inhibitor testing; ANGPTL protein addition Journal of lipid research High 32029511
2022 GPIHBP1's acidic domain (AD) serves three distinct functions: (1) it accelerates LPL binding kinetics; (2) it stabilizes LPL structure by preventing unfolding of LPL's catalytic domain; (3) by sheathing LPL's basic patch, the AD prevents persistent HSPG interactions on the abluminal EC surface, thereby freeing GPIHBP1-LPL complexes to transcytose to the capillary lumen. Without the AD, GPIHBP1-bound LPL is trapped by HSPG interactions and cannot reach the lumen. Biophysical studies; domain-specific mutant GPIHBP1; transcytosis assays; HSPG interaction studies Proceedings of the National Academy of Sciences of the United States of America High 36037340
2023 After GPIHBP1 transports LPL into capillaries, LPL can detach from GPIHBP1 and enter the endothelial cell glycocalyx, distant from GPIHBP1 on the plasma membrane. This glycocalyx-associated LPL mediates margination of TRLs along capillaries and performs active TRL processing, delivering lipoprotein-derived lipids to adjacent parenchymal cells. LPL-specific monoclonal antibody (88B8) that cannot detect GPIHBP1-bound LPL; confocal microscopy; immunogold electron microscopy; NanoSIMS imaging Proceedings of the National Academy of Sciences of the United States of America High 37871217

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2012 Mutations in LPL, APOC2, APOA5, GPIHBP1 and LMF1 in patients with severe hypertriglyceridaemia. Journal of internal medicine 201 22239554
2014 The GPIHBP1-LPL complex is responsible for the margination of triglyceride-rich lipoproteins in capillaries. Cell metabolism 130 24726386
2009 Chylomicronemia with a mutant GPIHBP1 (Q115P) that cannot bind lipoprotein lipase. Arteriosclerosis, thrombosis, and vascular biology 128 19304573
2017 Autoantibodies against GPIHBP1 as a Cause of Hypertriglyceridemia. The New England journal of medicine 123 28402248
2019 GPIHBP1 and Lipoprotein Lipase, Partners in Plasma Triglyceride Metabolism. Cell metabolism 111 31269429
2016 The angiopoietin-like protein ANGPTL4 catalyzes unfolding of the hydrolase domain in lipoprotein lipase and the endothelial membrane protein GPIHBP1 counteracts this unfolding. eLife 109 27929370
2009 GPIHBP1 stabilizes lipoprotein lipase and prevents its inhibition by angiopoietin-like 3 and angiopoietin-like 4. Journal of lipid research 105 19542565
2009 Mutation of conserved cysteines in the Ly6 domain of GPIHBP1 in familial chylomicronemia. Journal of lipid research 102 20026666
2016 The acidic domain of the endothelial membrane protein GPIHBP1 stabilizes lipoprotein lipase activity by preventing unfolding of its catalytic domain. eLife 93 26725083
2010 Chylomicronemia with low postheparin lipoprotein lipase levels in the setting of GPIHBP1 defects. Circulation. Cardiovascular genetics 92 20124439
2011 GPIHBP1, an endothelial cell transporter for lipoprotein lipase. Journal of lipid research 85 21844202
2002 Expression cloning and characterization of a novel glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein, GPI-HBP1. The Journal of biological chemistry 82 12496272
2018 Structure of the lipoprotein lipase-GPIHBP1 complex that mediates plasma triglyceride hydrolysis. Proceedings of the National Academy of Sciences of the United States of America 81 30559189
2011 Deletion of GPIHBP1 causing severe chylomicronemia. Journal of inherited metabolic disease 80 22008945
2008 The acidic domain of GPIHBP1 is important for the binding of lipoprotein lipase and chylomicrons. The Journal of biological chemistry 79 18713736
2009 Highly conserved cysteines within the Ly6 domain of GPIHBP1 are crucial for the binding of lipoprotein lipase. The Journal of biological chemistry 68 19726683
2016 GPIHBP1 and Plasma Triglyceride Metabolism. Trends in endocrinology and metabolism: TEM 67 27185325
2012 Linking nutritional regulation of Angptl4, Gpihbp1, and Lmf1 to lipoprotein lipase activity in rodent adipose tissue. BMC physiology 67 23176178
2007 GPIHBP1: an endothelial cell molecule important for the lipolytic processing of chylomicrons. Current opinion in lipidology 67 17620854
2008 Abnormal patterns of lipoprotein lipase release into the plasma in GPIHBP1-deficient mice. The Journal of biological chemistry 65 18845532
2012 Assessing mechanisms of GPIHBP1 and lipoprotein lipase movement across endothelial cells. Journal of lipid research 64 23008484
2007 Homozygous missense mutation (G56R) in glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPI-HBP1) in two siblings with fasting chylomicronemia (MIM 144650). Lipids in health and disease 62 17883852
2010 Modulation of plasma TG lipolysis by Angiopoietin-like proteins and GPIHBP1. Biochimica et biophysica acta 61 20056168
2015 Angiopoietin-like 4 Modifies the Interactions between Lipoprotein Lipase and Its Endothelial Cell Transporter GPIHBP1. The Journal of biological chemistry 58 25809481
2018 A disordered acidic domain in GPIHBP1 harboring a sulfated tyrosine regulates lipoprotein lipase. Proceedings of the National Academy of Sciences of the United States of America 56 29899144
2011 Childhood-onset chylomicronaemia with reduced plasma lipoprotein lipase activity and mass: identification of a novel GPIHBP1 mutation. Journal of internal medicine 56 21314738
2011 GPIHBP1 C89F neomutation and hydrophobic C-terminal domain G175R mutation in two pedigrees with severe hyperchylomicronemia. The Journal of clinical endocrinology and metabolism 54 21816778
2019 Structure of lipoprotein lipase in complex with GPIHBP1. Proceedings of the National Academy of Sciences of the United States of America 52 31072929
2011 Mutations in lipoprotein lipase that block binding to the endothelial cell transporter GPIHBP1. Proceedings of the National Academy of Sciences of the United States of America 51 21518912
2011 Assessing the role of the glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1) three-finger domain in binding lipoprotein lipase. The Journal of biological chemistry 50 21478160
2014 GPIHBP1 missense mutations often cause multimerization of GPIHBP1 and thereby prevent lipoprotein lipase binding. Circulation research 49 25387803
2008 The expression of GPIHBP1, an endothelial cell binding site for lipoprotein lipase and chylomicrons, is induced by peroxisome proliferator-activated receptor-gamma. Molecular endocrinology (Baltimore, Md.) 49 18787041
2008 GPIHBP1, a GPI-anchored protein required for the lipolytic processing of triglyceride-rich lipoproteins. Journal of lipid research 48 18854402
2017 Apolipoprotein C-III inhibits triglyceride hydrolysis by GPIHBP1-bound LPL. Journal of lipid research 47 28694296
2014 Multimerization of glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1) and familial chylomicronemia from a serine-to-cysteine substitution in GPIHBP1 Ly6 domain. The Journal of biological chemistry 47 24847059
2011 Lipoprotein lipase deficiency in chronic kidney disease is accompanied by down-regulation of endothelial GPIHBP1 expression. Clinical and experimental nephrology 43 22009636
2010 Binding preferences for GPIHBP1, a glycosylphosphatidylinositol-anchored protein of capillary endothelial cells. Arteriosclerosis, thrombosis, and vascular biology 43 20966398
2020 Chylomicronemia from GPIHBP1 autoantibodies. Journal of lipid research 41 32948662
2016 Mobility of "HSPG-bound" LPL explains how LPL is able to reach GPIHBP1 on capillaries. Journal of lipid research 37 27811232
2007 Normal binding of lipoprotein lipase, chylomicrons, and apo-AV to GPIHBP1 containing a G56R amino acid substitution. Biochimica et biophysica acta 36 17997385
2015 Cardiomyocyte VEGF Regulates Endothelial Cell GPIHBP1 to Relocate Lipoprotein Lipase to the Coronary Lumen During Diabetes Mellitus. Arteriosclerosis, thrombosis, and vascular biology 33 26586663
2010 Unexpected expression pattern for glycosylphosphatidylinositol-anchored HDL-binding protein 1 (GPIHBP1) in mouse tissues revealed by positron emission tomography scanning. The Journal of biological chemistry 33 20889497
2014 Familial chylomicronemia syndrome and response to medium-chain triglyceride therapy in an infant with novel mutations in GPIHBP1. Journal of clinical lipidology 32 25499947
2021 GPIHBP1 and ANGPTL4 Utilize Protein Disorder to Orchestrate Order in Plasma Triglyceride Metabolism and Regulate Compartmentalization of LPL Activity. Frontiers in cell and developmental biology 29 34336854
2017 GPIHBP1 autoantibodies in a patient with unexplained chylomicronemia. Journal of clinical lipidology 29 28666713
2011 Reciprocal metabolic perturbations in the adipose tissue and liver of GPIHBP1-deficient mice. Arteriosclerosis, thrombosis, and vascular biology 28 22173228
2008 Glycosylation of Asn-76 in mouse GPIHBP1 is critical for its appearance on the cell surface and the binding of chylomicrons and lipoprotein lipase. Journal of lipid research 28 18340083
2013 Novel combined GPIHBP1 mutations in a patient with hypertriglyceridemia associated with CAD. Journal of atherosclerosis and thrombosis 27 23831619
2009 GPIHBP1 and lipolysis: an update. Current opinion in lipidology 27 19369870
2015 Novel mutations in the GPIHBP1 gene identified in 2 patients with recurrent acute pancreatitis. Journal of clinical lipidology 26 26892125
2014 A 3-day-old neonate with severe hypertriglyceridemia from novel mutations of the GPIHBP1 gene. Journal of clinical lipidology 24 25911085
2022 A protein of capillary endothelial cells, GPIHBP1, is crucial for plasma triglyceride metabolism. Proceedings of the National Academy of Sciences of the United States of America 23 36037340
2016 Clinical and genetic features of 3 patients with familial chylomicronemia due to mutations in GPIHBP1 gene. Journal of clinical lipidology 23 27578123
2012 Chylomicronemia mutations yield new insights into interactions between lipoprotein lipase and GPIHBP1. Human molecular genetics 23 22493000
2017 An enzyme-linked immunosorbent assay for measuring GPIHBP1 levels in human plasma or serum. Journal of clinical lipidology 22 29246728
2014 Whole-exome sequencing reveals GPIHBP1 mutations in infantile colitis with severe hypertriglyceridemia. Journal of pediatric gastroenterology and nutrition 20 24614124
2023 The lipoprotein lipase that is shuttled into capillaries by GPIHBP1 enters the glycocalyx where it mediates lipoprotein processing. Proceedings of the National Academy of Sciences of the United States of America 19 37871217
2021 A novel GPIHBP1 mutation related to familial chylomicronemia syndrome: A series of cases. Atherosclerosis 19 33706081
2020 Intermittent chylomicronemia caused by intermittent GPIHBP1 autoantibodies. Journal of clinical lipidology 19 32107180
2018 GPIHBP1 autoantibody syndrome during interferon β1a treatment. Journal of clinical lipidology 19 30514621
2011 Comparative studies of glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1: evidence for a eutherian mammalian origin for the GPIHBP1 gene from an LY6-like gene. 3 Biotech 19 22582156
2018 Lipoprotein lipase transporter GPIHBP1 and triglyceride-rich lipoprotein metabolism. Clinica chimica acta; international journal of clinical chemistry 17 30218660
2020 A novel NanoBiT-based assay monitors the interaction between lipoprotein lipase and GPIHBP1 in real time. Journal of lipid research 16 32029511
2017 Mutating a conserved cysteine in GPIHBP1 reduces amounts of GPIHBP1 in capillaries and abolishes LPL binding. Journal of lipid research 16 28476858
2016 Type 1 hyperlipoproteinemia in a child with large homozygous deletion encompassing GPIHBP1. Journal of clinical lipidology 16 27578137
2016 Monoclonal antibodies that bind to the Ly6 domain of GPIHBP1 abolish the binding of LPL. Journal of lipid research 16 27875259
2019 GPIHBP1 expression in gliomas promotes utilization of lipoprotein-derived nutrients. eLife 15 31169500
2015 Evidence for Two Distinct Binding Sites for Lipoprotein Lipase on Glycosylphosphatidylinositol-anchored High Density Lipoprotein-binding Protein 1 (GPIHBP1). The Journal of biological chemistry 15 25873395
2014 Endothelial cells respond to hyperglycemia by increasing the LPL transporter GPIHBP1. American journal of physiology. Endocrinology and metabolism 15 24735886
2012 Localization of lipoprotein lipase and GPIHBP1 in mouse pancreas: effects of diet and leptin deficiency. BMC physiology 15 23186339
2022 GPIHBP1 autoantibody is an independent risk factor for the recurrence of hypertriglyceridemia-induced acute pancreatitis. Journal of clinical lipidology 14 36064883
2014 Type 1 hyperlipoproteinemia due to a novel deletion of exons 3 and 4 in the GPIHBP1 gene. Atherosclerosis 14 24589565
2019 Gpihbp1 deficiency accelerates atherosclerosis and plaque instability in diabetic Ldlr-/- mice. Atherosclerosis 13 30721842
2020 Management of a pregnant patient with chylomicronemia from a novel mutation in GPIHBP1: a case report. BMC pregnancy and childbirth 12 32375710
2018 Impaired thermogenesis and sharp increases in plasma triglyceride levels in GPIHBP1-deficient mice during cold exposure. Journal of lipid research 12 29449313
2017 Lipoprotein lipase reaches the capillary lumen in chickens despite an apparent absence of GPIHBP1. JCI insight 12 29046479
2023 AAV-mediated hepatic LPL expression ameliorates severe hypertriglyceridemia and acute pancreatitis in Gpihbp1 deficient mice and rats. Molecular therapy : the journal of the American Society of Gene Therapy 11 37974401
2016 An LPL-specific monoclonal antibody, 88B8, that abolishes the binding of LPL to GPIHBP1. Journal of lipid research 11 27494936
2014 Equivalent binding of wild-type lipoprotein lipase (LPL) and S447X-LPL to GPIHBP1, the endothelial cell LPL transporter. Biochimica et biophysica acta 11 24704550
2018 A novel mutation in GPIHBP1 causes familial chylomicronemia syndrome. Journal of clinical lipidology 10 29452893
2018 An ELISA for quantifying GPIHBP1 autoantibodies and making a diagnosis of the GPIHBP1 autoantibody syndrome. Clinica chimica acta; international journal of clinical chemistry 10 30287259
2017 A 1-month-old infant with chylomicronemia due to GPIHBP1 gene mutation treated by plasmapheresis. Annals of pediatric endocrinology & metabolism 10 28443263
2017 Functional validation of GPIHBP1 and identification of a functional mutation in GPIHBP1 for milk fat traits in dairy cattle. Scientific reports 10 28819221
2019 Association between skeletal muscle mass and serum concentrations of lipoprotein lipase, GPIHBP1, and hepatic triglyceride lipase in young Japanese men. Lipids in health and disease 9 30947712
2019 Genetic variants in the LPL and GPIHBP1 genes, in patients with severe hypertriglyceridaemia, detected with high resolution melting analysis. Clinica chimica acta; international journal of clinical chemistry 9 31669931
2018 Novel GPIHBP1-independent pathway for clearance of plasma TGs in Angptl4-/-Gpihbp1-/- mice. Journal of lipid research 7 29739862
2018 An upstream enhancer regulates Gpihbp1 expression in a tissue-specific manner. Journal of lipid research 7 30598475
2009 Some things just have to be done in vivo: GPIHBP1, caloric delivery, and the generation of remnant lipoproteins. Arteriosclerosis, thrombosis, and vascular biology 7 19458350
2017 The effect of combined diet and exercise intervention on body weight and the serum GPIHBP1 concentration in overweight/obese middle-aged women. Clinica chimica acta; international journal of clinical chemistry 6 29056530
2023 The GPIHBP1-LPL complex and its role in plasma triglyceride metabolism: Insights into chylomicronemia. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 5 37951027
2023 Molecular genetic testing and measurement of levels of GPIHBP1 autoantibodies in patients with severe hypertriglyceridemia: The importance of identifying the underlying cause of hypertriglyceridemia. Journal of clinical lipidology 5 37981531
2022 A case of hyperchylomicronemia associated with GPIHBP1 autoantibodies and fluctuating thyroid autoimmune disease. Journal of clinical lipidology 5 36402671
2018 Decreased GPIHBP1 protein levels in visceral adipose tissue partly underlie the hypertriglyceridemic phenotype in insulin resistance. PloS one 5 30408040
2022 Circulating GPIHBP1 levels and microvascular complications in patients with type 2 diabetes: A cross-sectional study. Journal of clinical lipidology 4 35101360
2022 A homozygous variant in the GPIHBP1 gene in a child with severe hypertriglyceridemia and a systematic literature review. Frontiers in genetics 4 36051701
2022 Biochemical, Clinical, and Genetic Characteristics of Mexican Patients with Primary Hypertriglyceridemia, Including the First Case of Hyperchylomicronemia Syndrome Due to GPIHBP1 Deficiency. International journal of molecular sciences 4 36613909
2020 The antagonic behavior of GPIHBP1 between EAT and circulation does not reflect lipolytic enzymes levels in the tissue and serum from coronary patients. Clinica chimica acta; international journal of clinical chemistry 4 32771483
2025 KLF13 promotes esophageal cancer progression and regulates triacylglyceride and free fatty acid metabolism through GPIHBP1. Cell death & disease 3 40450000
2023 Severe hypertriglyceridemia caused by Gpihbp1 deficiency facilitates vascular remodeling through increasing endothelial activation and oxidative stress. Biochimica et biophysica acta. Molecular and cell biology of lipids 3 37172802
2022 Anti-GPIHBP1 Antibody-Positive Autoimmune Hyperchylomicronemia and Immune Thrombocytopenia. Journal of atherosclerosis and thrombosis 3 35185060