{"gene":"GPIHBP1","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":2002,"finding":"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.","method":"Expression cloning with fluorescent-labeled HDL; phosphatidylinositol-specific phospholipase C treatment; selective lipid uptake assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — original reconstitution/expression cloning with multiple functional assays in a single foundational paper","pmids":["12496272"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Gpihbp1 knockout mouse model; transfected CHO cell binding assays; immunofluorescence microscopy for localization","journal":"Current opinion in lipidology","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined phenotype plus direct localization and functional binding assays, replicated across multiple papers","pmids":["17620854","18854402"],"is_preprint":false},{"year":2008,"finding":"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.","method":"CHO cell-based binding assays; peptide competition; site-directed mutagenesis; antibody blocking","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis plus multiple orthogonal competition assays in one study","pmids":["18713736"],"is_preprint":false},{"year":2008,"finding":"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.","method":"N-glycosidase/endoglycosidase digestion; site-directed mutagenesis; immunofluorescence microscopy; cell-based binding assays","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis with subcellular localization and functional binding readout","pmids":["18340083"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Luciferase reporter assay; PPARγ agonist treatment; endothelial PPARγ conditional knockout mice; RT-PCR","journal":"Molecular endocrinology (Baltimore, Md.)","confidence":"High","confidence_rationale":"Tier 2 — reporter assay plus in vivo conditional KO with defined transcriptional readout","pmids":["18787041"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Intravenous heparin injection in Gpihbp1-/- vs wild-type mice; plasma LPL kinetics; Intralipid challenge","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined in vivo kinetic phenotype, consistent with multiple lines of evidence","pmids":["18845532"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Site-directed mutagenesis; CHO cell surface binding assays; cell-free LPL-binding bead assay; phospholipase C release assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — systematic mutagenesis with multiple orthogonal binding assays","pmids":["19726683"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Patient genetic screening; CHO cell-based binding assays; cell-surface expression studies","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 2 — human mutation functionally validated in cell-based assays with orthogonal controls","pmids":["19304573"],"is_preprint":false},{"year":2009,"finding":"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.","method":"In vitro LPL activity assays; double-knockout mouse models; neutralizing antibody treatment","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro assay plus genetic epistasis in double-KO mice, replicated with antibody treatment","pmids":["19542565"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Family genetic sequencing; CHO cell-based and cell-free LPL binding assays; adipose tissue biopsy LPL analysis","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 2 — human mutations functionally validated in orthogonal cell-based and cell-free binding assays","pmids":["20026666"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Surface plasmon resonance; peptide competition binding assays with isolated acidic peptide and Ly6 domain; salt and heparin dissociation experiments","journal":"The Journal of biological chemistry (inferred; published 2015 per PMID 25873395)","confidence":"High","confidence_rationale":"Tier 1 — biophysical reconstitution with multiple orthogonal methods demonstrating two distinct binding sites","pmids":["25873395"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Positron emission tomography with radiolabeled GPIHBP1-specific antibodies; immunofluorescence microscopy; Gpihbp1-/- and Lpl-/- mouse models","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — direct in vivo imaging with genetic controls and immunofluorescence validation","pmids":["20889497"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Cell-based and cell-free binding assays with lipase family members and apoAV-phospholipid disks; mutant GPIHBP1 constructs","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 1-2 — systematic panel of binding assays with domain mutants","pmids":["20966398"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Systematic alanine scanning mutagenesis of the Ly6 domain; immunofluorescence microscopy binding assay; Western blot binding assay; endothelial transcytosis assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — comprehensive mutagenesis with transport functional readout","pmids":["21478160"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Cell-based and cell-free LPL-GPIHBP1 binding assays; LPL catalytic activity assays; endothelial transcytosis assays; monoclonal antibody epitope mapping","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — mutagenesis with multiple orthogonal assays defining binding domain","pmids":["21518912"],"is_preprint":false},{"year":2011,"finding":"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.","method":"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":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including EM structural evidence and pharmacological inhibition in vitro and in vivo","pmids":["23008484"],"is_preprint":false},{"year":2012,"finding":"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.","method":"LPL domain deletion and mutagenesis; cell-based and cell-free GPIHBP1 binding assays; refolding experiment after denaturing conditions","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1 — domain reconstitution with mutagenesis validation","pmids":["22493000"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Fluorescence microscopy; quantitative assay with infrared-dye-labeled lipoproteins; EM tomography; in vivo and cell-culture studies in Gpihbp1-/- mice","journal":"Cell metabolism","confidence":"High","confidence_rationale":"Tier 2 — multiple imaging modalities in vivo with genetic controls","pmids":["24726386"],"is_preprint":false},{"year":2014,"finding":"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.","method":"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","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 — systematic mutagenesis in multiple expression systems with functional binding readout","pmids":["25387803"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Cell-based binding and activity assays with LPL-GPIHBP1 complexes on endothelial cells; temperature-dependent experiments; N-terminal fragment vs full-length ANGPTL4 comparison","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — cell-based assays with mechanistic dissection of binding vs inactivation steps","pmids":["25809481"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Hydrogen-deuterium exchange/mass spectrometry; surface plasmon resonance; zero-length cross-linking; LPL activity assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 — multiple biophysical methods reconstituting interaction with structural and functional validation","pmids":["26725083"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Hydrogen-deuterium exchange/mass spectrometry; LPL unfolding assays; ANGPTL4 variant functional assays; GPIHBP1 domain mutants","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 — mechanistic reconstitution with structural and mutagenesis validation","pmids":["27929370"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Cell-culture LPL transfer assays; GPIHBP1-coated bead injection in Gpihbp1-/- mice; domain mutant GPIHBP1 constructs","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 2 — in vitro and in vivo experiments with domain-specific mutants","pmids":["27811232"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Immunoassays; Western blot; immunocytochemistry; LPL-GPIHBP1 blocking assays with patient plasma","journal":"The New England journal of medicine","confidence":"High","confidence_rationale":"Tier 2 — mechanistic blocking assays with clinical validation in six patients, independent of monogenic causes","pmids":["28402248"],"is_preprint":false},{"year":2017,"finding":"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.","method":"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":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro reconstituted system plus in vivo validation","pmids":["28694296"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Monoclonal antibody panel; LPL binding assays; immunohistochemistry of human tissues","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 2 — antibody-based functional blocking assays with tissue localization","pmids":["27875259"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Mass spectrometry identification of O-sulfation; surface plasmon resonance; ANGPTL4 unfolding protection assays; biophysical binding kinetics","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — PTM identified by MS plus multiple orthogonal biophysical assays","pmids":["29899144"],"is_preprint":false},{"year":2018,"finding":"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.","method":"X-ray crystallography of LPL-GPIHBP1 complex (2.5–3.0 Å); biochemical characterization; co-expression with LMF1 chaperone","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 — crystal structure at high resolution with biochemical validation, independently reported in two studies","pmids":["30559189","31072929"],"is_preprint":false},{"year":2015,"finding":"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.","method":"EC high-glucose exposure; heparanase treatment; VEGF neutralization; Notch signaling inhibition; coculture with cardiomyocytes; in vivo diabetic heart perfusion","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple in vitro and in vivo experiments but from single lab","pmids":["26586663","24735886"],"is_preprint":false},{"year":2016,"finding":"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.","method":"CRISPR/Cas9 enhancer deletion; RT-PCR; immunohistochemistry for LPL localization","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 2 — CRISPR KO with defined transcriptional and localization phenotype, single lab","pmids":["30598475"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Immunohistochemistry; NanoSIMS isotope imaging of TRL-derived lipid uptake; in vivo glioma model","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — direct localization with functional NanoSIMS imaging of lipid delivery","pmids":["31169500"],"is_preprint":false},{"year":2020,"finding":"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.","method":"NanoBiT split-luciferase real-time binding assay on endothelial cells; pharmacological inhibitor testing; ANGPTL protein addition","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 1-2 — novel real-time assay with multiple orthogonal agents tested","pmids":["32029511"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Biophysical studies; domain-specific mutant GPIHBP1; transcytosis assays; HSPG interaction studies","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal mechanistic assays defining three distinct functions of the AD","pmids":["36037340"],"is_preprint":false},{"year":2023,"finding":"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.","method":"LPL-specific monoclonal antibody (88B8) that cannot detect GPIHBP1-bound LPL; confocal microscopy; immunogold electron microscopy; NanoSIMS imaging","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — multiple imaging modalities demonstrating glycocalyx localization and functional lipid delivery","pmids":["37871217"],"is_preprint":false}],"current_model":"GPIHBP1 is a GPI-anchored protein of capillary endothelial cells that binds LPL in subendothelial spaces via two structural domains — an intrinsically disordered acidic N-terminal domain (which accelerates LPL capture by electrostatic steering, stabilizes LPL's catalytic domain against unfolding, and shields LPL's basic patch from HSPG interactions to enable transcytosis) and a three-fingered LU/Ly6 domain (which mediates high-affinity, hydrophobic binding to LPL's C-terminal lipid-binding domain) — and 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; GPIHBP1-bound LPL is also protected from inactivation by ANGPTL4, and autoantibodies against GPIHBP1 block all these functions, causing acquired chylomicronemia."},"narrative":{"teleology":[{"year":2002,"claim":"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","pmids":["12496272"],"confidence":"High","gaps":["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"]},{"year":2007,"claim":"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","pmids":["17620854","18854402"],"confidence":"High","gaps":["Structural basis of LPL binding unknown","Transcytosis mechanism not yet demonstrated"]},{"year":2008,"claim":"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","pmids":["18713736","18340083"],"confidence":"High","gaps":["Relative contribution of each domain to binding kinetics not quantified","Whether the two domains bind the same or different regions of LPL was unknown"]},{"year":2008,"claim":"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","pmids":["18787041"],"confidence":"High","gaps":["Other transcription factors contributing to tissue-specific expression not identified","Post-transcriptional regulation not explored"]},{"year":2009,"claim":"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","pmids":["19304573","20026666","19542565"],"confidence":"High","gaps":["Structural basis of ANGPTL4 protection by GPIHBP1 not yet resolved","Quantitative contribution of ANGPTL4 regulation to the chylomicronemia phenotype not separated from transport defects"]},{"year":2011,"claim":"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","pmids":["21478160","21518912"],"confidence":"High","gaps":["Atomic-resolution structure of the interface not available","Whether LPL monomer or dimer binds GPIHBP1 was debated"]},{"year":2012,"claim":"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","pmids":["23008484","22493000"],"confidence":"High","gaps":["Specific vesicular machinery mediating GPIHBP1 transcytosis not identified","Sorting signals for basolateral-to-apical directionality unknown"]},{"year":2014,"claim":"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","pmids":["24726386"],"confidence":"High","gaps":["Mechanism by which luminal LPL–GPIHBP1 complex captures TRLs not structurally resolved","Role of apoC-II in this context not dissected"]},{"year":2016,"claim":"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","pmids":["26725083","27929370"],"confidence":"High","gaps":["Whether acidic domain protection is stoichiometric or catalytic was unclear","Structural model of acidic domain–basic patch interaction at atomic level not available"]},{"year":2017,"claim":"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","pmids":["28402248"],"confidence":"High","gaps":["Epitope specificity of autoantibodies beyond Ly6 vs acidic domain not mapped","Prevalence in the broader chylomicronemia population unknown"]},{"year":2018,"claim":"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","pmids":["30559189","31072929","29899144"],"confidence":"High","gaps":["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"]},{"year":2022,"claim":"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","pmids":["36037340"],"confidence":"High","gaps":["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"]},{"year":2023,"claim":"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","pmids":["37871217"],"confidence":"High","gaps":["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"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Low","gaps":["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":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,1,2,10,27]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,15,17,32,33]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[15,32,33]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[8,20,21,26]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,11,25,33]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[15]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1,5,17,24,33]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[15,22,32]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[15,32]}],"complexes":[],"partners":["LPL","ANGPTL4","ANGPTL3","APOA5","APOC3"],"other_free_text":[]},"mechanistic_narrative":"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]."},"prefetch_data":{"uniprot":{"accession":"Q8IV16","full_name":"Glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1","aliases":["High density lipoprotein-binding protein 1"],"length_aa":184,"mass_kda":19.9,"function":"Mediates the transport of lipoprotein lipase LPL from the basolateral to the apical surface of endothelial cells in capillaries (By similarity). Anchors LPL on the surface of endothelial cells in the lumen of blood capillaries (By similarity). Protects LPL against loss of activity, and against ANGPTL4-mediated unfolding (PubMed:27929370, PubMed:29899144). Thereby, plays an important role in lipolytic processing of chylomicrons by LPL, triglyceride metabolism and lipid homeostasis (PubMed:19304573, PubMed:21314738). Binds chylomicrons and phospholipid particles that contain APOA5 (PubMed:17997385, PubMed:19304573). Binds high-density lipoprotein (HDL) and plays a role in the uptake of lipids from HDL (By similarity)","subcellular_location":"Apical cell membrane; Basolateral cell membrane; Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q8IV16/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GPIHBP1","classification":"Not Classified","n_dependent_lines":29,"n_total_lines":1208,"dependency_fraction":0.024006622516556293},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/GPIHBP1","total_profiled":1310},"omim":[{"mim_id":"615947","title":"HYPERLIPOPROTEINEMIA, TYPE ID","url":"https://www.omim.org/entry/615947"},{"mim_id":"612757","title":"GLYCOSYLPHOSPHATIDYLINOSITOL-ANCHORED HIGH DENSITY LIPOPROTEIN-BINDING PROTEIN 1; GPIHBP1","url":"https://www.omim.org/entry/612757"},{"mim_id":"609708","title":"LIPOPROTEIN LIPASE; LPL","url":"https://www.omim.org/entry/609708"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"End piece","reliability":"Approved"},{"location":"Principal piece","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"adipose tissue","ntpm":85.2},{"tissue":"brain","ntpm":70.0},{"tissue":"breast","ntpm":53.2}],"url":"https://www.proteinatlas.org/search/GPIHBP1"},"hgnc":{"alias_symbol":["LOC338328","GPI-HBP1"],"prev_symbol":[]},"alphafold":{"accession":"Q8IV16","domains":[{"cath_id":"2.10.60.10","chopping":"62-137","consensus_level":"medium","plddt":97.2537,"start":62,"end":137}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IV16","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IV16-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IV16-F1-predicted_aligned_error_v6.png","plddt_mean":73.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GPIHBP1","jax_strain_url":"https://www.jax.org/strain/search?query=GPIHBP1"},"sequence":{"accession":"Q8IV16","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IV16.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IV16/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IV16"}},"corpus_meta":[{"pmid":"22239554","id":"PMC_22239554","title":"Mutations in LPL, APOC2, APOA5, GPIHBP1 and LMF1 in patients with severe hypertriglyceridaemia.","date":"2012","source":"Journal of internal medicine","url":"https://pubmed.ncbi.nlm.nih.gov/22239554","citation_count":201,"is_preprint":false},{"pmid":"24726386","id":"PMC_24726386","title":"The GPIHBP1-LPL complex is responsible for the margination of triglyceride-rich lipoproteins in capillaries.","date":"2014","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/24726386","citation_count":130,"is_preprint":false},{"pmid":"19304573","id":"PMC_19304573","title":"Chylomicronemia with a mutant GPIHBP1 (Q115P) that cannot bind lipoprotein lipase.","date":"2009","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/19304573","citation_count":128,"is_preprint":false},{"pmid":"28402248","id":"PMC_28402248","title":"Autoantibodies against GPIHBP1 as a Cause of Hypertriglyceridemia.","date":"2017","source":"The New England journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28402248","citation_count":123,"is_preprint":false},{"pmid":"31269429","id":"PMC_31269429","title":"GPIHBP1 and Lipoprotein Lipase, Partners in Plasma Triglyceride Metabolism.","date":"2019","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/31269429","citation_count":111,"is_preprint":false},{"pmid":"27929370","id":"PMC_27929370","title":"The angiopoietin-like protein ANGPTL4 catalyzes unfolding of the hydrolase domain in lipoprotein lipase and the endothelial membrane protein GPIHBP1 counteracts this unfolding.","date":"2016","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/27929370","citation_count":109,"is_preprint":false},{"pmid":"19542565","id":"PMC_19542565","title":"GPIHBP1 stabilizes lipoprotein lipase and prevents its inhibition by angiopoietin-like 3 and angiopoietin-like 4.","date":"2009","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/19542565","citation_count":105,"is_preprint":false},{"pmid":"20026666","id":"PMC_20026666","title":"Mutation of conserved cysteines in the Ly6 domain of GPIHBP1 in familial chylomicronemia.","date":"2009","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/20026666","citation_count":102,"is_preprint":false},{"pmid":"26725083","id":"PMC_26725083","title":"The acidic domain of the endothelial membrane protein GPIHBP1 stabilizes lipoprotein lipase activity by preventing unfolding of its catalytic domain.","date":"2016","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/26725083","citation_count":93,"is_preprint":false},{"pmid":"20124439","id":"PMC_20124439","title":"Chylomicronemia with low postheparin lipoprotein lipase levels in the setting of GPIHBP1 defects.","date":"2010","source":"Circulation. Cardiovascular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20124439","citation_count":92,"is_preprint":false},{"pmid":"21844202","id":"PMC_21844202","title":"GPIHBP1, an endothelial cell transporter for lipoprotein lipase.","date":"2011","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/21844202","citation_count":85,"is_preprint":false},{"pmid":"12496272","id":"PMC_12496272","title":"Expression cloning and characterization of a novel glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein, GPI-HBP1.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12496272","citation_count":82,"is_preprint":false},{"pmid":"30559189","id":"PMC_30559189","title":"Structure of the lipoprotein lipase-GPIHBP1 complex that mediates plasma triglyceride hydrolysis.","date":"2018","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/30559189","citation_count":81,"is_preprint":false},{"pmid":"22008945","id":"PMC_22008945","title":"Deletion of GPIHBP1 causing severe chylomicronemia.","date":"2011","source":"Journal of inherited metabolic disease","url":"https://pubmed.ncbi.nlm.nih.gov/22008945","citation_count":80,"is_preprint":false},{"pmid":"18713736","id":"PMC_18713736","title":"The acidic domain of GPIHBP1 is important for the binding of lipoprotein lipase and chylomicrons.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18713736","citation_count":79,"is_preprint":false},{"pmid":"19726683","id":"PMC_19726683","title":"Highly conserved cysteines within the Ly6 domain of GPIHBP1 are crucial for the binding of lipoprotein lipase.","date":"2009","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19726683","citation_count":68,"is_preprint":false},{"pmid":"17620854","id":"PMC_17620854","title":"GPIHBP1: an endothelial cell molecule important for the lipolytic processing of chylomicrons.","date":"2007","source":"Current opinion in lipidology","url":"https://pubmed.ncbi.nlm.nih.gov/17620854","citation_count":67,"is_preprint":false},{"pmid":"23176178","id":"PMC_23176178","title":"Linking nutritional regulation of Angptl4, Gpihbp1, and Lmf1 to lipoprotein lipase activity in rodent adipose tissue.","date":"2012","source":"BMC physiology","url":"https://pubmed.ncbi.nlm.nih.gov/23176178","citation_count":67,"is_preprint":false},{"pmid":"27185325","id":"PMC_27185325","title":"GPIHBP1 and Plasma Triglyceride Metabolism.","date":"2016","source":"Trends in endocrinology and metabolism: TEM","url":"https://pubmed.ncbi.nlm.nih.gov/27185325","citation_count":67,"is_preprint":false},{"pmid":"18845532","id":"PMC_18845532","title":"Abnormal patterns of lipoprotein lipase release into the plasma in GPIHBP1-deficient mice.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18845532","citation_count":65,"is_preprint":false},{"pmid":"23008484","id":"PMC_23008484","title":"Assessing mechanisms of GPIHBP1 and lipoprotein lipase movement across endothelial cells.","date":"2012","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/23008484","citation_count":64,"is_preprint":false},{"pmid":"17883852","id":"PMC_17883852","title":"Homozygous missense mutation (G56R) in glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPI-HBP1) in two siblings with fasting chylomicronemia (MIM 144650).","date":"2007","source":"Lipids in health and disease","url":"https://pubmed.ncbi.nlm.nih.gov/17883852","citation_count":62,"is_preprint":false},{"pmid":"20056168","id":"PMC_20056168","title":"Modulation of plasma TG lipolysis by Angiopoietin-like proteins and GPIHBP1.","date":"2010","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/20056168","citation_count":61,"is_preprint":false},{"pmid":"25809481","id":"PMC_25809481","title":"Angiopoietin-like 4 Modifies the Interactions between Lipoprotein Lipase and Its Endothelial Cell Transporter GPIHBP1.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25809481","citation_count":58,"is_preprint":false},{"pmid":"29899144","id":"PMC_29899144","title":"A disordered acidic domain in GPIHBP1 harboring a sulfated tyrosine regulates lipoprotein lipase.","date":"2018","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/29899144","citation_count":56,"is_preprint":false},{"pmid":"21314738","id":"PMC_21314738","title":"Childhood-onset chylomicronaemia with reduced plasma lipoprotein lipase activity and mass: identification of a novel GPIHBP1 mutation.","date":"2011","source":"Journal of internal medicine","url":"https://pubmed.ncbi.nlm.nih.gov/21314738","citation_count":56,"is_preprint":false},{"pmid":"21816778","id":"PMC_21816778","title":"GPIHBP1 C89F neomutation and hydrophobic C-terminal domain G175R mutation in two pedigrees with severe hyperchylomicronemia.","date":"2011","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/21816778","citation_count":54,"is_preprint":false},{"pmid":"31072929","id":"PMC_31072929","title":"Structure of lipoprotein lipase in complex with GPIHBP1.","date":"2019","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/31072929","citation_count":52,"is_preprint":false},{"pmid":"21518912","id":"PMC_21518912","title":"Mutations in lipoprotein lipase that block binding to the endothelial cell transporter GPIHBP1.","date":"2011","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/21518912","citation_count":51,"is_preprint":false},{"pmid":"21478160","id":"PMC_21478160","title":"Assessing the role of the glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1) three-finger domain in binding lipoprotein lipase.","date":"2011","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21478160","citation_count":50,"is_preprint":false},{"pmid":"25387803","id":"PMC_25387803","title":"GPIHBP1 missense mutations often cause multimerization of GPIHBP1 and thereby prevent lipoprotein lipase binding.","date":"2014","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/25387803","citation_count":49,"is_preprint":false},{"pmid":"18787041","id":"PMC_18787041","title":"The expression of GPIHBP1, an endothelial cell binding site for lipoprotein lipase and chylomicrons, is induced by peroxisome proliferator-activated receptor-gamma.","date":"2008","source":"Molecular endocrinology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/18787041","citation_count":49,"is_preprint":false},{"pmid":"18854402","id":"PMC_18854402","title":"GPIHBP1, a GPI-anchored protein required for the lipolytic processing of triglyceride-rich lipoproteins.","date":"2008","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/18854402","citation_count":48,"is_preprint":false},{"pmid":"28694296","id":"PMC_28694296","title":"Apolipoprotein C-III inhibits triglyceride hydrolysis by GPIHBP1-bound LPL.","date":"2017","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/28694296","citation_count":47,"is_preprint":false},{"pmid":"24847059","id":"PMC_24847059","title":"Multimerization of glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1) and familial chylomicronemia from a serine-to-cysteine substitution in GPIHBP1 Ly6 domain.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24847059","citation_count":47,"is_preprint":false},{"pmid":"20966398","id":"PMC_20966398","title":"Binding preferences for GPIHBP1, a glycosylphosphatidylinositol-anchored protein of capillary endothelial cells.","date":"2010","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/20966398","citation_count":43,"is_preprint":false},{"pmid":"22009636","id":"PMC_22009636","title":"Lipoprotein lipase deficiency in chronic kidney disease is accompanied by down-regulation of endothelial GPIHBP1 expression.","date":"2011","source":"Clinical and experimental nephrology","url":"https://pubmed.ncbi.nlm.nih.gov/22009636","citation_count":43,"is_preprint":false},{"pmid":"32948662","id":"PMC_32948662","title":"Chylomicronemia from GPIHBP1 autoantibodies.","date":"2020","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/32948662","citation_count":41,"is_preprint":false},{"pmid":"27811232","id":"PMC_27811232","title":"Mobility of \"HSPG-bound\" LPL explains how LPL is able to reach GPIHBP1 on capillaries.","date":"2016","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/27811232","citation_count":37,"is_preprint":false},{"pmid":"17997385","id":"PMC_17997385","title":"Normal binding of lipoprotein lipase, chylomicrons, and apo-AV to GPIHBP1 containing a G56R amino acid substitution.","date":"2007","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/17997385","citation_count":36,"is_preprint":false},{"pmid":"20889497","id":"PMC_20889497","title":"Unexpected expression pattern for glycosylphosphatidylinositol-anchored HDL-binding protein 1 (GPIHBP1) in mouse tissues revealed by positron emission tomography scanning.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/20889497","citation_count":33,"is_preprint":false},{"pmid":"26586663","id":"PMC_26586663","title":"Cardiomyocyte VEGF Regulates Endothelial Cell GPIHBP1 to Relocate Lipoprotein Lipase to the Coronary Lumen During Diabetes Mellitus.","date":"2015","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/26586663","citation_count":33,"is_preprint":false},{"pmid":"25499947","id":"PMC_25499947","title":"Familial chylomicronemia syndrome and response to medium-chain triglyceride therapy in an infant with novel mutations in GPIHBP1.","date":"2014","source":"Journal of clinical lipidology","url":"https://pubmed.ncbi.nlm.nih.gov/25499947","citation_count":32,"is_preprint":false},{"pmid":"34336854","id":"PMC_34336854","title":"GPIHBP1 and ANGPTL4 Utilize Protein Disorder to Orchestrate Order in Plasma Triglyceride Metabolism and Regulate Compartmentalization of LPL Activity.","date":"2021","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/34336854","citation_count":29,"is_preprint":false},{"pmid":"28666713","id":"PMC_28666713","title":"GPIHBP1 autoantibodies in a patient with unexplained chylomicronemia.","date":"2017","source":"Journal of clinical lipidology","url":"https://pubmed.ncbi.nlm.nih.gov/28666713","citation_count":29,"is_preprint":false},{"pmid":"22173228","id":"PMC_22173228","title":"Reciprocal metabolic perturbations in the adipose tissue and liver of GPIHBP1-deficient mice.","date":"2011","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/22173228","citation_count":28,"is_preprint":false},{"pmid":"18340083","id":"PMC_18340083","title":"Glycosylation of Asn-76 in mouse GPIHBP1 is critical for its appearance on the cell surface and the binding of chylomicrons and lipoprotein lipase.","date":"2008","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/18340083","citation_count":28,"is_preprint":false},{"pmid":"19369870","id":"PMC_19369870","title":"GPIHBP1 and lipolysis: an update.","date":"2009","source":"Current opinion in lipidology","url":"https://pubmed.ncbi.nlm.nih.gov/19369870","citation_count":27,"is_preprint":false},{"pmid":"23831619","id":"PMC_23831619","title":"Novel combined GPIHBP1 mutations in a patient with hypertriglyceridemia associated with CAD.","date":"2013","source":"Journal of atherosclerosis and thrombosis","url":"https://pubmed.ncbi.nlm.nih.gov/23831619","citation_count":27,"is_preprint":false},{"pmid":"26892125","id":"PMC_26892125","title":"Novel mutations in the GPIHBP1 gene identified in 2 patients with recurrent acute pancreatitis.","date":"2015","source":"Journal of clinical lipidology","url":"https://pubmed.ncbi.nlm.nih.gov/26892125","citation_count":26,"is_preprint":false},{"pmid":"25911085","id":"PMC_25911085","title":"A 3-day-old neonate with severe hypertriglyceridemia from novel mutations of the GPIHBP1 gene.","date":"2014","source":"Journal of clinical lipidology","url":"https://pubmed.ncbi.nlm.nih.gov/25911085","citation_count":24,"is_preprint":false},{"pmid":"36037340","id":"PMC_36037340","title":"A protein of capillary endothelial cells, GPIHBP1, is crucial for plasma triglyceride metabolism.","date":"2022","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/36037340","citation_count":23,"is_preprint":false},{"pmid":"22493000","id":"PMC_22493000","title":"Chylomicronemia mutations yield new insights into interactions between lipoprotein lipase and GPIHBP1.","date":"2012","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22493000","citation_count":23,"is_preprint":false},{"pmid":"27578123","id":"PMC_27578123","title":"Clinical and genetic features of 3 patients with familial chylomicronemia due to mutations in GPIHBP1 gene.","date":"2016","source":"Journal of clinical lipidology","url":"https://pubmed.ncbi.nlm.nih.gov/27578123","citation_count":23,"is_preprint":false},{"pmid":"29246728","id":"PMC_29246728","title":"An enzyme-linked immunosorbent assay for measuring GPIHBP1 levels in human plasma or serum.","date":"2017","source":"Journal of clinical lipidology","url":"https://pubmed.ncbi.nlm.nih.gov/29246728","citation_count":22,"is_preprint":false},{"pmid":"24614124","id":"PMC_24614124","title":"Whole-exome sequencing reveals GPIHBP1 mutations in infantile colitis with severe hypertriglyceridemia.","date":"2014","source":"Journal of pediatric gastroenterology and nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/24614124","citation_count":20,"is_preprint":false},{"pmid":"37871217","id":"PMC_37871217","title":"The lipoprotein lipase that is shuttled into capillaries by GPIHBP1 enters the glycocalyx where it mediates lipoprotein processing.","date":"2023","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/37871217","citation_count":19,"is_preprint":false},{"pmid":"33706081","id":"PMC_33706081","title":"A novel GPIHBP1 mutation related to familial chylomicronemia syndrome: A series of cases.","date":"2021","source":"Atherosclerosis","url":"https://pubmed.ncbi.nlm.nih.gov/33706081","citation_count":19,"is_preprint":false},{"pmid":"32107180","id":"PMC_32107180","title":"Intermittent chylomicronemia caused by intermittent GPIHBP1 autoantibodies.","date":"2020","source":"Journal of clinical lipidology","url":"https://pubmed.ncbi.nlm.nih.gov/32107180","citation_count":19,"is_preprint":false},{"pmid":"30514621","id":"PMC_30514621","title":"GPIHBP1 autoantibody syndrome during interferon β1a treatment.","date":"2018","source":"Journal of clinical lipidology","url":"https://pubmed.ncbi.nlm.nih.gov/30514621","citation_count":19,"is_preprint":false},{"pmid":"22582156","id":"PMC_22582156","title":"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.","date":"2011","source":"3 Biotech","url":"https://pubmed.ncbi.nlm.nih.gov/22582156","citation_count":19,"is_preprint":false},{"pmid":"30218660","id":"PMC_30218660","title":"Lipoprotein lipase transporter GPIHBP1 and triglyceride-rich lipoprotein metabolism.","date":"2018","source":"Clinica chimica acta; international journal of clinical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30218660","citation_count":17,"is_preprint":false},{"pmid":"27875259","id":"PMC_27875259","title":"Monoclonal antibodies that bind to the Ly6 domain of GPIHBP1 abolish the binding of LPL.","date":"2016","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/27875259","citation_count":16,"is_preprint":false},{"pmid":"28476858","id":"PMC_28476858","title":"Mutating a conserved cysteine in GPIHBP1 reduces amounts of GPIHBP1 in capillaries and abolishes LPL binding.","date":"2017","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/28476858","citation_count":16,"is_preprint":false},{"pmid":"32029511","id":"PMC_32029511","title":"A novel NanoBiT-based assay monitors the interaction between lipoprotein lipase and GPIHBP1 in real time.","date":"2020","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/32029511","citation_count":16,"is_preprint":false},{"pmid":"27578137","id":"PMC_27578137","title":"Type 1 hyperlipoproteinemia in a child with large homozygous deletion encompassing GPIHBP1.","date":"2016","source":"Journal of clinical lipidology","url":"https://pubmed.ncbi.nlm.nih.gov/27578137","citation_count":16,"is_preprint":false},{"pmid":"23186339","id":"PMC_23186339","title":"Localization of lipoprotein lipase and GPIHBP1 in mouse pancreas: effects of diet and leptin deficiency.","date":"2012","source":"BMC physiology","url":"https://pubmed.ncbi.nlm.nih.gov/23186339","citation_count":15,"is_preprint":false},{"pmid":"24735886","id":"PMC_24735886","title":"Endothelial cells respond to hyperglycemia by increasing the LPL transporter GPIHBP1.","date":"2014","source":"American journal of physiology. Endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/24735886","citation_count":15,"is_preprint":false},{"pmid":"31169500","id":"PMC_31169500","title":"GPIHBP1 expression in gliomas promotes utilization of lipoprotein-derived nutrients.","date":"2019","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/31169500","citation_count":15,"is_preprint":false},{"pmid":"25873395","id":"PMC_25873395","title":"Evidence for Two Distinct Binding Sites for Lipoprotein Lipase on Glycosylphosphatidylinositol-anchored High Density Lipoprotein-binding Protein 1 (GPIHBP1).","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25873395","citation_count":15,"is_preprint":false},{"pmid":"24589565","id":"PMC_24589565","title":"Type 1 hyperlipoproteinemia due to a novel deletion of exons 3 and 4 in the GPIHBP1 gene.","date":"2014","source":"Atherosclerosis","url":"https://pubmed.ncbi.nlm.nih.gov/24589565","citation_count":14,"is_preprint":false},{"pmid":"36064883","id":"PMC_36064883","title":"GPIHBP1 autoantibody is an independent risk factor for the recurrence of hypertriglyceridemia-induced acute pancreatitis.","date":"2022","source":"Journal of clinical lipidology","url":"https://pubmed.ncbi.nlm.nih.gov/36064883","citation_count":14,"is_preprint":false},{"pmid":"30721842","id":"PMC_30721842","title":"Gpihbp1 deficiency accelerates atherosclerosis and plaque instability in diabetic Ldlr-/- mice.","date":"2019","source":"Atherosclerosis","url":"https://pubmed.ncbi.nlm.nih.gov/30721842","citation_count":13,"is_preprint":false},{"pmid":"29449313","id":"PMC_29449313","title":"Impaired thermogenesis and sharp increases in plasma triglyceride levels in GPIHBP1-deficient mice during cold exposure.","date":"2018","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/29449313","citation_count":12,"is_preprint":false},{"pmid":"29046479","id":"PMC_29046479","title":"Lipoprotein lipase reaches the capillary lumen in chickens despite an apparent absence of GPIHBP1.","date":"2017","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/29046479","citation_count":12,"is_preprint":false},{"pmid":"32375710","id":"PMC_32375710","title":"Management of a pregnant patient with chylomicronemia from a novel mutation in GPIHBP1: a case report.","date":"2020","source":"BMC pregnancy and childbirth","url":"https://pubmed.ncbi.nlm.nih.gov/32375710","citation_count":12,"is_preprint":false},{"pmid":"24704550","id":"PMC_24704550","title":"Equivalent binding of wild-type lipoprotein lipase (LPL) and S447X-LPL to GPIHBP1, the endothelial cell LPL transporter.","date":"2014","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/24704550","citation_count":11,"is_preprint":false},{"pmid":"27494936","id":"PMC_27494936","title":"An LPL-specific monoclonal antibody, 88B8, that abolishes the binding of LPL to GPIHBP1.","date":"2016","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/27494936","citation_count":11,"is_preprint":false},{"pmid":"37974401","id":"PMC_37974401","title":"AAV-mediated hepatic LPL expression ameliorates severe hypertriglyceridemia and acute pancreatitis in Gpihbp1 deficient mice and rats.","date":"2023","source":"Molecular therapy : the journal of the American Society of Gene Therapy","url":"https://pubmed.ncbi.nlm.nih.gov/37974401","citation_count":11,"is_preprint":false},{"pmid":"30287259","id":"PMC_30287259","title":"An ELISA for quantifying GPIHBP1 autoantibodies and making a diagnosis of the GPIHBP1 autoantibody syndrome.","date":"2018","source":"Clinica chimica acta; international journal of clinical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30287259","citation_count":10,"is_preprint":false},{"pmid":"28443263","id":"PMC_28443263","title":"A 1-month-old infant with chylomicronemia due to GPIHBP1 gene mutation treated by plasmapheresis.","date":"2017","source":"Annals of pediatric endocrinology & metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/28443263","citation_count":10,"is_preprint":false},{"pmid":"29452893","id":"PMC_29452893","title":"A novel mutation in GPIHBP1 causes familial chylomicronemia syndrome.","date":"2018","source":"Journal of clinical lipidology","url":"https://pubmed.ncbi.nlm.nih.gov/29452893","citation_count":10,"is_preprint":false},{"pmid":"28819221","id":"PMC_28819221","title":"Functional validation of GPIHBP1 and identification of a functional mutation in GPIHBP1 for milk fat traits in dairy cattle.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28819221","citation_count":10,"is_preprint":false},{"pmid":"30947712","id":"PMC_30947712","title":"Association between skeletal muscle mass and serum concentrations of lipoprotein lipase, GPIHBP1, and hepatic triglyceride lipase in young Japanese men.","date":"2019","source":"Lipids in health and disease","url":"https://pubmed.ncbi.nlm.nih.gov/30947712","citation_count":9,"is_preprint":false},{"pmid":"31669931","id":"PMC_31669931","title":"Genetic variants in the LPL and GPIHBP1 genes, in patients with severe hypertriglyceridaemia, detected with high resolution melting analysis.","date":"2019","source":"Clinica chimica acta; international journal of clinical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31669931","citation_count":9,"is_preprint":false},{"pmid":"29739862","id":"PMC_29739862","title":"Novel GPIHBP1-independent pathway for clearance of plasma TGs in Angptl4-/-Gpihbp1-/- mice.","date":"2018","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/29739862","citation_count":7,"is_preprint":false},{"pmid":"30598475","id":"PMC_30598475","title":"An upstream enhancer regulates Gpihbp1 expression in a tissue-specific manner.","date":"2018","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/30598475","citation_count":7,"is_preprint":false},{"pmid":"19458350","id":"PMC_19458350","title":"Some things just have to be done in vivo: GPIHBP1, caloric delivery, and the generation of remnant lipoproteins.","date":"2009","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/19458350","citation_count":7,"is_preprint":false},{"pmid":"29056530","id":"PMC_29056530","title":"The effect of combined diet and exercise intervention on body weight and the serum GPIHBP1 concentration in overweight/obese middle-aged women.","date":"2017","source":"Clinica chimica acta; international journal of clinical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29056530","citation_count":6,"is_preprint":false},{"pmid":"37951027","id":"PMC_37951027","title":"The GPIHBP1-LPL complex and its role in plasma triglyceride metabolism: Insights into chylomicronemia.","date":"2023","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/37951027","citation_count":5,"is_preprint":false},{"pmid":"36402671","id":"PMC_36402671","title":"A case of hyperchylomicronemia associated with GPIHBP1 autoantibodies and fluctuating thyroid autoimmune disease.","date":"2022","source":"Journal of clinical lipidology","url":"https://pubmed.ncbi.nlm.nih.gov/36402671","citation_count":5,"is_preprint":false},{"pmid":"30408040","id":"PMC_30408040","title":"Decreased GPIHBP1 protein levels in visceral adipose tissue partly underlie the hypertriglyceridemic phenotype in insulin resistance.","date":"2018","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/30408040","citation_count":5,"is_preprint":false},{"pmid":"37981531","id":"PMC_37981531","title":"Molecular genetic testing and measurement of levels of GPIHBP1 autoantibodies in patients with severe hypertriglyceridemia: The importance of identifying the underlying cause of hypertriglyceridemia.","date":"2023","source":"Journal of clinical lipidology","url":"https://pubmed.ncbi.nlm.nih.gov/37981531","citation_count":5,"is_preprint":false},{"pmid":"32771483","id":"PMC_32771483","title":"The antagonic behavior of GPIHBP1 between EAT and circulation does not reflect lipolytic enzymes levels in the tissue and serum from coronary patients.","date":"2020","source":"Clinica chimica acta; international journal of clinical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32771483","citation_count":4,"is_preprint":false},{"pmid":"35101360","id":"PMC_35101360","title":"Circulating GPIHBP1 levels and microvascular complications in patients with type 2 diabetes: A cross-sectional study.","date":"2022","source":"Journal of clinical lipidology","url":"https://pubmed.ncbi.nlm.nih.gov/35101360","citation_count":4,"is_preprint":false},{"pmid":"36051701","id":"PMC_36051701","title":"A homozygous variant in the GPIHBP1 gene in a child with severe hypertriglyceridemia and a systematic literature review.","date":"2022","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36051701","citation_count":4,"is_preprint":false},{"pmid":"36613909","id":"PMC_36613909","title":"Biochemical, Clinical, and Genetic Characteristics of Mexican Patients with Primary Hypertriglyceridemia, Including the First Case of Hyperchylomicronemia Syndrome Due to GPIHBP1 Deficiency.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36613909","citation_count":4,"is_preprint":false},{"pmid":"40450000","id":"PMC_40450000","title":"KLF13 promotes esophageal cancer progression and regulates triacylglyceride and free fatty acid metabolism through GPIHBP1.","date":"2025","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/40450000","citation_count":3,"is_preprint":false},{"pmid":"35185060","id":"PMC_35185060","title":"Anti-GPIHBP1 Antibody-Positive Autoimmune Hyperchylomicronemia and Immune Thrombocytopenia.","date":"2022","source":"Journal of atherosclerosis and thrombosis","url":"https://pubmed.ncbi.nlm.nih.gov/35185060","citation_count":3,"is_preprint":false},{"pmid":"37172802","id":"PMC_37172802","title":"Severe hypertriglyceridemia caused by Gpihbp1 deficiency facilitates vascular remodeling through increasing endothelial activation and oxidative stress.","date":"2023","source":"Biochimica et biophysica acta. Molecular and cell biology of lipids","url":"https://pubmed.ncbi.nlm.nih.gov/37172802","citation_count":3,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":55503,"output_tokens":8541,"usd":0.147312},"stage2":{"model":"claude-opus-4-6","input_tokens":12350,"output_tokens":3987,"usd":0.242138},"total_usd":0.38945,"stage1_batch_id":"msgbatch_01DzrsgVgYngY1hvM3DU1yF2","stage2_batch_id":"msgbatch_01KA9b7iRzKFdhoBUT7vCvSe","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"Expression cloning with fluorescent-labeled HDL; phosphatidylinositol-specific phospholipase C treatment; selective lipid uptake assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — original reconstitution/expression cloning with multiple functional assays in a single foundational paper\",\n      \"pmids\": [\"12496272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Gpihbp1 knockout mouse model; transfected CHO cell binding assays; immunofluorescence microscopy for localization\",\n      \"journal\": \"Current opinion in lipidology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined phenotype plus direct localization and functional binding assays, replicated across multiple papers\",\n      \"pmids\": [\"17620854\", \"18854402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"CHO cell-based binding assays; peptide competition; site-directed mutagenesis; antibody blocking\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis plus multiple orthogonal competition assays in one study\",\n      \"pmids\": [\"18713736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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      \"method\": \"N-glycosidase/endoglycosidase digestion; site-directed mutagenesis; immunofluorescence microscopy; cell-based binding assays\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis with subcellular localization and functional binding readout\",\n      \"pmids\": [\"18340083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Luciferase reporter assay; PPARγ agonist treatment; endothelial PPARγ conditional knockout mice; RT-PCR\",\n      \"journal\": \"Molecular endocrinology (Baltimore, Md.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reporter assay plus in vivo conditional KO with defined transcriptional readout\",\n      \"pmids\": [\"18787041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Intravenous heparin injection in Gpihbp1-/- vs wild-type mice; plasma LPL kinetics; Intralipid challenge\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined in vivo kinetic phenotype, consistent with multiple lines of evidence\",\n      \"pmids\": [\"18845532\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Site-directed mutagenesis; CHO cell surface binding assays; cell-free LPL-binding bead assay; phospholipase C release assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — systematic mutagenesis with multiple orthogonal binding assays\",\n      \"pmids\": [\"19726683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Patient genetic screening; CHO cell-based binding assays; cell-surface expression studies\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — human mutation functionally validated in cell-based assays with orthogonal controls\",\n      \"pmids\": [\"19304573\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro LPL activity assays; double-knockout mouse models; neutralizing antibody treatment\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro assay plus genetic epistasis in double-KO mice, replicated with antibody treatment\",\n      \"pmids\": [\"19542565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Family genetic sequencing; CHO cell-based and cell-free LPL binding assays; adipose tissue biopsy LPL analysis\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — human mutations functionally validated in orthogonal cell-based and cell-free binding assays\",\n      \"pmids\": [\"20026666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Surface plasmon resonance; peptide competition binding assays with isolated acidic peptide and Ly6 domain; salt and heparin dissociation experiments\",\n      \"journal\": \"The Journal of biological chemistry (inferred; published 2015 per PMID 25873395)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — biophysical reconstitution with multiple orthogonal methods demonstrating two distinct binding sites\",\n      \"pmids\": [\"25873395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Positron emission tomography with radiolabeled GPIHBP1-specific antibodies; immunofluorescence microscopy; Gpihbp1-/- and Lpl-/- mouse models\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct in vivo imaging with genetic controls and immunofluorescence validation\",\n      \"pmids\": [\"20889497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Cell-based and cell-free binding assays with lipase family members and apoAV-phospholipid disks; mutant GPIHBP1 constructs\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — systematic panel of binding assays with domain mutants\",\n      \"pmids\": [\"20966398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Systematic alanine scanning mutagenesis of the Ly6 domain; immunofluorescence microscopy binding assay; Western blot binding assay; endothelial transcytosis assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — comprehensive mutagenesis with transport functional readout\",\n      \"pmids\": [\"21478160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Cell-based and cell-free LPL-GPIHBP1 binding assays; LPL catalytic activity assays; endothelial transcytosis assays; monoclonal antibody epitope mapping\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mutagenesis with multiple orthogonal assays defining binding domain\",\n      \"pmids\": [\"21518912\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Bidirectional transcytosis assays in cultured endothelial cells and live mice; dynasore/genistein inhibition; caveolin-1 KO cells; transmission EM and dual-axis EM tomography\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including EM structural evidence and pharmacological inhibition in vitro and in vivo\",\n      \"pmids\": [\"23008484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"LPL domain deletion and mutagenesis; cell-based and cell-free GPIHBP1 binding assays; refolding experiment after denaturing conditions\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — domain reconstitution with mutagenesis validation\",\n      \"pmids\": [\"22493000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Fluorescence microscopy; quantitative assay with infrared-dye-labeled lipoproteins; EM tomography; in vivo and cell-culture studies in Gpihbp1-/- mice\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple imaging modalities in vivo with genetic controls\",\n      \"pmids\": [\"24726386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — systematic mutagenesis in multiple expression systems with functional binding readout\",\n      \"pmids\": [\"25387803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Cell-based binding and activity assays with LPL-GPIHBP1 complexes on endothelial cells; temperature-dependent experiments; N-terminal fragment vs full-length ANGPTL4 comparison\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-based assays with mechanistic dissection of binding vs inactivation steps\",\n      \"pmids\": [\"25809481\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Hydrogen-deuterium exchange/mass spectrometry; surface plasmon resonance; zero-length cross-linking; LPL activity assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple biophysical methods reconstituting interaction with structural and functional validation\",\n      \"pmids\": [\"26725083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Hydrogen-deuterium exchange/mass spectrometry; LPL unfolding assays; ANGPTL4 variant functional assays; GPIHBP1 domain mutants\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mechanistic reconstitution with structural and mutagenesis validation\",\n      \"pmids\": [\"27929370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Cell-culture LPL transfer assays; GPIHBP1-coated bead injection in Gpihbp1-/- mice; domain mutant GPIHBP1 constructs\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo experiments with domain-specific mutants\",\n      \"pmids\": [\"27811232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Immunoassays; Western blot; immunocytochemistry; LPL-GPIHBP1 blocking assays with patient plasma\",\n      \"journal\": \"The New England journal of medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic blocking assays with clinical validation in six patients, independent of monogenic causes\",\n      \"pmids\": [\"28402248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro reconstituted system plus in vivo validation\",\n      \"pmids\": [\"28694296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Monoclonal antibody panel; LPL binding assays; immunohistochemistry of human tissues\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — antibody-based functional blocking assays with tissue localization\",\n      \"pmids\": [\"27875259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Mass spectrometry identification of O-sulfation; surface plasmon resonance; ANGPTL4 unfolding protection assays; biophysical binding kinetics\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — PTM identified by MS plus multiple orthogonal biophysical assays\",\n      \"pmids\": [\"29899144\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"X-ray crystallography of LPL-GPIHBP1 complex (2.5–3.0 Å); biochemical characterization; co-expression with LMF1 chaperone\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure at high resolution with biochemical validation, independently reported in two studies\",\n      \"pmids\": [\"30559189\", \"31072929\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"EC high-glucose exposure; heparanase treatment; VEGF neutralization; Notch signaling inhibition; coculture with cardiomyocytes; in vivo diabetic heart perfusion\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple in vitro and in vivo experiments but from single lab\",\n      \"pmids\": [\"26586663\", \"24735886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"CRISPR/Cas9 enhancer deletion; RT-PCR; immunohistochemistry for LPL localization\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR KO with defined transcriptional and localization phenotype, single lab\",\n      \"pmids\": [\"30598475\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Immunohistochemistry; NanoSIMS isotope imaging of TRL-derived lipid uptake; in vivo glioma model\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization with functional NanoSIMS imaging of lipid delivery\",\n      \"pmids\": [\"31169500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"NanoBiT split-luciferase real-time binding assay on endothelial cells; pharmacological inhibitor testing; ANGPTL protein addition\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — novel real-time assay with multiple orthogonal agents tested\",\n      \"pmids\": [\"32029511\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Biophysical studies; domain-specific mutant GPIHBP1; transcytosis assays; HSPG interaction studies\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal mechanistic assays defining three distinct functions of the AD\",\n      \"pmids\": [\"36037340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"LPL-specific monoclonal antibody (88B8) that cannot detect GPIHBP1-bound LPL; confocal microscopy; immunogold electron microscopy; NanoSIMS imaging\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple imaging modalities demonstrating glycocalyx localization and functional lipid delivery\",\n      \"pmids\": [\"37871217\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GPIHBP1 is a GPI-anchored protein of capillary endothelial cells that binds LPL in subendothelial spaces via two structural domains — an intrinsically disordered acidic N-terminal domain (which accelerates LPL capture by electrostatic steering, stabilizes LPL's catalytic domain against unfolding, and shields LPL's basic patch from HSPG interactions to enable transcytosis) and a three-fingered LU/Ly6 domain (which mediates high-affinity, hydrophobic binding to LPL's C-terminal lipid-binding domain) — and 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; GPIHBP1-bound LPL is also protected from inactivation by ANGPTL4, and autoantibodies against GPIHBP1 block all these functions, causing acquired chylomicronemia.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"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].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"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.\",\n      \"evidence\": \"Expression cloning with fluorescent HDL; phospholipase C release and selective lipid uptake assays in transfected cells\",\n      \"pmids\": [\"12496272\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"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.\",\n      \"evidence\": \"Gpihbp1−/− mice with severe chylomicronemia (TG ~5000 mg/dL); CHO cell binding assays for LPL and chylomicrons; immunofluorescence localization on luminal capillary endothelium\",\n      \"pmids\": [\"17620854\", \"18854402\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of LPL binding unknown\", \"Transcytosis mechanism not yet demonstrated\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"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.\",\n      \"evidence\": \"Alanine substitution of acidic domain residues 38–48; peptide competition; cysteine mutagenesis; N-glycosylation site mutagenesis with immunofluorescence and binding assays\",\n      \"pmids\": [\"18713736\", \"18340083\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of each domain to binding kinetics not quantified\", \"Whether the two domains bind the same or different regions of LPL was unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrating that PPARγ directly regulates GPIHBP1 transcription in endothelial cells established a metabolic signaling axis controlling LPL platform expression.\",\n      \"evidence\": \"PPARγ agonist treatment; functional PPAR binding site in Gpihbp1 promoter by luciferase assay; endothelial-specific PPARγ conditional knockout reducing Gpihbp1 mRNA\",\n      \"pmids\": [\"18787041\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Other transcription factors contributing to tissue-specific expression not identified\", \"Post-transcriptional regulation not explored\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"19304573\", \"20026666\", \"19542565\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of ANGPTL4 protection by GPIHBP1 not yet resolved\", \"Quantitative contribution of ANGPTL4 regulation to the chylomicronemia phenotype not separated from transport defects\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"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.\",\n      \"evidence\": \"Systematic alanine scanning mutagenesis; LPL C418Y/E421K mutations abolishing GPIHBP1 binding but not catalytic activity; endothelial transcytosis assays\",\n      \"pmids\": [\"21478160\", \"21518912\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution structure of the interface not available\", \"Whether LPL monomer or dimer binds GPIHBP1 was debated\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"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.\",\n      \"evidence\": \"Bidirectional transcytosis assays; dynasore/genistein inhibition; caveolin-1 KO cells; EM tomography showing GPIHBP1/LPL in vesicles; LPL domain deletion constructs\",\n      \"pmids\": [\"23008484\", \"22493000\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific vesicular machinery mediating GPIHBP1 transcytosis not identified\", \"Sorting signals for basolateral-to-apical directionality unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"24726386\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which luminal LPL–GPIHBP1 complex captures TRLs not structurally resolved\", \"Role of apoC-II in this context not dissected\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"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.\",\n      \"evidence\": \"Hydrogen-deuterium exchange mass spectrometry; surface plasmon resonance; zero-length cross-linking; ANGPTL4 unfolding protection assays with domain-specific mutants\",\n      \"pmids\": [\"26725083\", \"27929370\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether acidic domain protection is stoichiometric or catalytic was unclear\", \"Structural model of acidic domain–basic patch interaction at atomic level not available\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"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.\",\n      \"evidence\": \"Immunoassays and LPL–GPIHBP1 blocking assays with plasma from six patients; clinical characterization\",\n      \"pmids\": [\"28402248\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Epitope specificity of autoantibodies beyond Ly6 vs acidic domain not mapped\", \"Prevalence in the broader chylomicronemia population unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"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.\",\n      \"evidence\": \"X-ray crystallography; mass spectrometry identification of O-sulfation; SPR kinetics\",\n      \"pmids\": [\"30559189\", \"31072929\", \"29899144\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"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.\",\n      \"evidence\": \"Domain-specific mutant GPIHBP1 constructs; transcytosis assays; HSPG interaction studies; biophysical binding measurements\",\n      \"pmids\": [\"36037340\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"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.\",\n      \"evidence\": \"Conformation-specific monoclonal antibody (88B8) detecting free but not GPIHBP1-bound LPL; confocal and immunogold EM; NanoSIMS imaging of lipid delivery\",\n      \"pmids\": [\"37871217\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 1, 2, 10, 27]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 15, 17, 32, 33]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [15, 32, 33]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [8, 20, 21, 26]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 11, 25, 33]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 5, 17, 24, 33]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [15, 22, 32]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [15, 32]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"LPL\",\n      \"ANGPTL4\",\n      \"ANGPTL3\",\n      \"APOA5\",\n      \"APOC3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}