Affinage

LPL

Lipoprotein lipase · UniProt P06858

Length
475 aa
Mass
53.2 kDa
Annotated
2026-06-10
100 papers in source corpus 29 papers cited in narrative 29 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LPL is the rate-limiting triglyceride hydrolase that processes triglyceride-rich lipoproteins (TRLs) at the capillary endothelium, and human genetic data establish its catalytic function as causal for cardiovascular protection—loss-of-function variants raise and gain-of-function variants lower coronary disease risk (PMID:26934567). Productive LPL requires posttranslational maturation in the ER: LMF1 is a posttranslational determinant of LPL activity (PMID:22345169, PMID:30318473), and the ER-associated adaptor Sel1L physically stabilizes the LPL–LMF1 maturation complex independently of Hrd1-mediated ERAD, without which LPL aggregates and is cleared by autophagy (PMID:25066055). Mature dimeric LPL—whose dimer stability and heparin binding depend on residues such as Tyr262 (PMID:8728326)—is mobilized from interstitial heparan sulfate proteoglycans, transferred to endothelial GPIHBP1 via its Ly6 domain (PMID:27811232), and shuttled across the endothelium to the capillary lumen, where GPIHBP1-bound (not HSPG-bound) LPL mediates TRL margination and lipolysis (PMID:24726386). LPL activity is tuned by a network of inhibitors and activators: ANGPTL4 binds the lid domain to occlude the active site (PMID:30591589), the ANGPTL3/8 complex binds near the lid and furin-cleavage region to inhibit LPL and promote furin-mediated cleavage (PMID:33656326), ApoC-III inhibits GPIHBP1-bound LPL more potently than free LPL (PMID:28694296), and APOE on VLDL inhibits hydrolysis in an isoform-dependent manner (PMID:34863862); ApoA5 derepresses LPL by competing with it for the same leucine-zipper-like epitope on ANGPTL3/8 (PMID:33762177, PMID:35307397). Postprandially, the ANGPTL4/8 complex recruits tPA and plasminogen to generate plasmin, which cleaves multiple LPL inhibitors while sparing ApoC-II activation, maximizing adipose LPL activity (PMID:36763533, PMID:37666362). LPL transcription is induced during adipogenesis through HNF-3/forkhead-binding promoter elements (PMID:1406652) and is driven by PPARs (PMID:8831913), GIP via a PI3K/PKB/AMPK/CREB/TORC2 axis (PMID:20693566), and STAT3 in CLL cells (PMID:25733697). Beyond lipolysis, LPL also acts non-catalytically to bridge lipoproteins for receptor uptake and arterial lipid deposition (PMID:17038632, PMID:27984852), supports glycerol-based cardiomyocyte ATP synthesis during ischemia (PMID:34807469), and in pancreatic islets suppresses insulin secretion (PMID:10488074). Frameshift and missense mutations causing loss of LPL mRNA or activity underlie primary LPL deficiency (PMID:8728326, PMID:1737848).

Mechanistic history

Synthesis pass · year-by-year structured walk · 28 steps
  1. 1992 High

    Established the transcriptional logic of adipocyte LPL induction by identifying the cis-elements and trans-factor class controlling differentiation-linked expression.

    Evidence CAT reporter deletion constructs, DNase I/exonuclease III footprinting and gel-shift assays in adipocytes

    PMID:1406652

    Open questions at the time
    • Identity of the specific HNF-3/forkhead factor binding LP-alpha/LP-beta not resolved
    • Does not link these elements to downstream metabolic regulators
  2. 1992 Medium

    Demonstrated a molecular cause of primary LPL deficiency, showing a frameshift mutation eliminates LPL mRNA and protein.

    Evidence Northern blot, immunocytochemistry and exon sequencing in a patient family

    PMID:1737848

    Open questions at the time
    • Single family; generalizability to other deficiency alleles untested
    • Mechanism of transcript loss inferred as NMD but not directly demonstrated
  3. 1996 Medium

    Defined structural determinants of LPL catalysis by showing Tyr262 is required for dimer stability and heparin binding.

    Evidence Site-directed mutagenesis, HEK-293 expression, heparin-Sepharose chromatography and activity assays

    PMID:8728326

    Open questions at the time
    • No high-resolution structure of the mutant
    • Effect on in vivo function not assessed
  4. 1996 Medium

    Placed LPL transcription downstream of pharmacologic PPAR activation, mechanistically explaining the hypotriglyceridemic effect of fibrates.

    Evidence Transcriptional reporter and PPAR activation assays in cell culture

    PMID:8831913

    Open questions at the time
    • PPAR isoform specificity at the LPL promoter not delineated
    • Review-style support limits experimental depth
  5. 1999 High

    Revealed a tissue-specific role beyond plasma lipolysis—islet LPL acts as a brake on insulin secretion.

    Evidence LPL heterozygous knockout mice, hyperinsulinemic clamp, and gain/loss-of-function in INS-1 cells

    PMID:10488074

    Open questions at the time
    • Molecular mediator linking islet LPL to secretory machinery unidentified
    • Whether the effect is catalytic or non-catalytic unresolved
  6. 2004 Medium

    Identified a phospholipid-driven signaling route for acute LPL mobilization to the coronary lumen.

    Evidence Perfused hearts and isolated cells with PKC inhibitor (calphostin), PLD and LPA treatments

    PMID:15522270

    Open questions at the time
    • Downstream effectors translocating LPL not defined
    • Physiological context of PLPC signaling unclear
  7. 2006 Medium

    Separated catalytic from non-catalytic functions of LPL, demonstrating a bridging-mediated proatherosclerotic activity.

    Evidence Adenoviral wild-type vs. catalytically inactive LPL gene transfer into arteries of LPL-/- and ApoE-/- mice

    PMID:17038632

    Open questions at the time
    • Receptor/ligand mediating non-catalytic lipid deposition not identified
    • Single delivery route
  8. 2010 High

    Resolved a GIP-driven transcriptional pathway converging on CREB/TORC2 at the LPL promoter.

    Evidence Promoter-reporter, RNAi knockdown, kinase inhibitors, ChIP and Co-IP in adipocyte/HEK systems

    PMID:20693566

    Open questions at the time
    • In vivo relevance of CRE-II regulation not established
    • Crosstalk with adipogenic HNF-3/PPAR inputs unaddressed
  9. 2010 Medium

    Linked adiponectin signaling to cytoskeletal control of LPL surface translocation in cardiomyocytes.

    Evidence RhoA/ROCK assays, cofilin phosphorylation, actin imaging and inhibitor controls in primary rat cardiomyocytes

    PMID:21147877

    Open questions at the time
    • Vesicular machinery transporting LPL not defined
    • Single species/cell type
  10. 2012 Medium

    Identified LMF1 as a posttranslational ER-maturation determinant of LPL activity in vivo.

    Evidence Tissue-specific LMF1 transgenic overexpression with LPL activity/mass measurements

    PMID:22345169

    Open questions at the time
    • Biochemical mechanism of LMF1-assisted folding not detailed
    • Single lab
  11. 2014 High

    Defined the obligate role of GPIHBP1-bound LPL—rather than HSPG-bound LPL—in TRL margination along capillaries.

    Evidence Imaging and infrared-dye lipoprotein assays in wild-type vs. Gpihbp1-/- mice with endothelial LPL re-expression

    PMID:24726386

    Open questions at the time
    • Quantitative kinetics of LPL handoff at the lumen not measured
    • Does not address LPL transport step itself
  12. 2014 High

    Established Sel1L as an ERAD-independent factor stabilizing the LPL–LMF1 complex required for secretion.

    Evidence Adipocyte-specific Sel1L KO mice, reciprocal Co-IP, localization, and autophagy-inhibitor rescue

    PMID:25066055

    Open questions at the time
    • Structural basis of Sel1L stabilization unknown
    • Whether Sel1L acts on monomeric or dimeric LPL not resolved
  13. 2014 Medium

    Showed disease-state regulation of LPL transport via hyperglycemia-driven GPIHBP1 upregulation through a heparanase-PDGF axis.

    Evidence Streptozotocin diabetic mice and in vitro glucose dose-response with EC transcytosis assays

    PMID:24735886

    Open questions at the time
    • Direct PDGF-to-GPIHBP1 transcriptional link not fully mapped
    • Single lab
  14. 2016 Medium

    Provided human-genetic causal anchoring for LPL function in cardiovascular disease.

    Evidence Large-scale sequencing/genotyping of CAD cases and controls with variant functional annotation

    PMID:26934567

    Open questions at the time
    • Association-based, not direct protein mechanism
    • Does not dissect catalytic vs. non-catalytic contribution to risk
  15. 2016 High

    Demonstrated that HSPG-bound LPL is mobile and transfers to GPIHBP1 via its Ly6 domain, defining the transport entry step.

    Evidence Cell-culture transfer assays, GPIHBP1-coated bead in vivo injection, and GPIHBP1 domain mutants

    PMID:27811232

    Open questions at the time
    • Driving force/affinity gradient for transfer not quantified
    • Whether transfer is uni- or bidirectional in vivo unclear
  16. 2017 High

    Localized ApoC-III inhibition preferentially to GPIHBP1-bound LPL, refining where the inhibitor acts.

    Evidence In vitro lipolysis with free vs. GPIHBP1-bead-bound LPL, TRL binding assays, and apoC-III variant validation

    PMID:28694296

    Open questions at the time
    • Structural basis of enhanced inhibition on GPIHBP1 not resolved
    • In vivo capillary-level confirmation limited
  17. 2017 High

    Characterized the S447* gain-of-function truncation, showing its benefit derives from enhanced lipoprotein uptake rather than higher specific activity.

    Evidence Purified recombinant LPL/LPLS447X with activity, ANGPTL4 Ki, uptake assays and structural modeling

    PMID:27984852

    Open questions at the time
    • Receptor mediating enhanced uptake not identified
    • Modeling not confirmed by experimental structure
  18. 2018 High

    Mapped the ANGPTL4 inhibitory mechanism to lid-domain binding occluding the catalytic site.

    Evidence HDX-MS with chimeric LPL variants and peptide-mimetic competition

    PMID:30591589

    Open questions at the time
    • No co-crystal structure of the LPL-ANGPTL4 complex
    • Irreversibility of unfolding inferred, not directly shown here
  19. 2018 Medium

    Showed LMF1 coexpression boosts LPL secretion and that furin cleavage limits recovery but not function.

    Evidence Mammalian coexpression with furin-resistant mutant activity/stability and in vivo function assays

    PMID:30318473

    Open questions at the time
    • Physiological role of furin cleavage in vivo unresolved
    • Single lab
  20. 2021 High

    Defined the ANGPTL3/8 inhibitory mechanism, combining active-site-proximal binding with furin-mediated LPL cleavage.

    Evidence HDX-MS epitope mapping plus furin inhibitor, furin siRNA, and ANGPTL3-antibody functional blocking

    PMID:33656326

    Open questions at the time
    • Sequence and consequence of the furin cleavage product not detailed
    • Relative contribution of occlusion vs. cleavage not quantified
  21. 2021 High

    Reframed ApoA5 as a derepressor that blocks ANGPTL3/8 inhibition rather than a direct LPL activator.

    Evidence IP-MS, BLI, and functional LPL kinetic assays with ApoA5 and various ANGPTL species

    PMID:33762177

    Open questions at the time
    • Stoichiometry of ApoA5–ANGPTL3/8 association in vivo unknown
    • Does not address ApoA5 effects on LPL maturation/transport
  22. 2021 Medium

    Demonstrated potent ANGPTL3/8 inhibition specifically of GPIHBP1-bound LPL.

    Evidence Recombinant GPIHBP1-LPL activity assays with ANGPTL3/8 vs. individual proteins

    PMID:39392008

    Open questions at the time
    • Limited experimental depth in source
    • Relationship to furin-cleavage mechanism not integrated
  23. 2021 Medium

    Identified VLDL APOE content as an isoform-dependent inhibitor of LPL hydrolysis, with ApoC-II non-predictive.

    Evidence Novel in vitro VLDL lipolysis assay across donors with proteomics and exogenous APOE isoform dose-response

    PMID:34863862

    Open questions at the time
    • Binding site/mechanism of APOE inhibition not mapped
    • In vivo relevance not established
  24. 2021 Medium

    Uncovered a non-lipolytic cardioprotective role in which LPL-derived glycerol fuels ATP synthesis during ischemia.

    Evidence Cardiomyocyte-specific LPL KO plus AQP7/GPD2 deficiency epistasis in a myocardial infarction model

    PMID:34807469

    Open questions at the time
    • Quantitative contribution of glycerol vs. fatty acid flux unclear
    • Single lab
  25. 2022 High

    Pinpointed a shared leucine-zipper-like epitope on ANGPTL3/8 bound by both LPL and ApoA5, defining a druggable competitive node.

    Evidence HDX-MS, molecular modeling, BLI, in vitro LPL assays and in vivo triglyceride lowering with an epitope-targeting antibody

    PMID:35307397

    Open questions at the time
    • High-resolution complex structure absent
    • Whether LPL binding to this epitope is productive or inhibitory not fully resolved
  26. 2023 High

    Revealed a postprandial proteolytic switch—ANGPTL4/8 recruits tPA/plasminogen to generate plasmin that cleaves ANGPTL4/8 to restore LPL activity.

    Evidence Pulldowns, reconstituted plasmin generation with catalytically dead plasminogen (S760A) and PAI-1 controls

    PMID:36763533

    Open questions at the time
    • In vivo demonstration of the plasmin switch limited
    • Spatial regulation in adipose capillaries not resolved
  27. 2023 High

    Extended the plasmin switch to broad inhibitor clearance, showing plasmin cleaves multiple LPL inhibitors while sparing ApoC-II activation.

    Evidence Reconstituted LPL activity assays systematically testing ANGPTL3/8, ANGPTL4, ANGPTL3, ApoC3 and ApoC2

    PMID:37666362

    Open questions at the time
    • Tissue specificity of inhibitor cleavage in vivo not mapped
    • Kinetics relative to meal timing not quantified
  28. 2023 High

    Showed ANGPTL4 acts on LPL in the interstitium before capillary transport, governing thermoneutral suppression of BAT lipolysis.

    Evidence Intracapillary LPL quantification in Angptl4-/- and Gpihbp1-/- mice with TRL margination assays

    PMID:36787365

    Open questions at the time
    • Molecular trigger linking temperature to ANGPTL4 expression unresolved
    • Reversibility of interstitial inhibition not assessed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the maturation/transport machinery (LMF1, Sel1L, GPIHBP1) and the inhibitor/activator network are coordinated in space and time at the capillary lumen, and the molecular identity of LPL's non-catalytic receptor-bridging partners, remain unresolved.
  • No integrated structural model of GPIHBP1-bound LPL with bound inhibitors
  • Receptor mediating non-catalytic lipoprotein uptake unidentified
  • In vivo coordination of postprandial plasmin switch with hormonal/temperature inputs not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 5 GO:0060090 molecular adaptor activity 2 GO:0016740 transferase activity 1
Localization
GO:0005886 plasma membrane 4 GO:0005576 extracellular region 3 GO:0005783 endoplasmic reticulum 3
Pathway
R-HSA-74160 Gene expression (Transcription) 4 R-HSA-9609507 Protein localization 4 R-HSA-1430728 Metabolism 3 R-HSA-392499 Metabolism of proteins 3
Partners
ANGPTL3ANGPTL4ANGPTL8APOA5APOC3GPIHBP1LMF1SEL1L
Complex memberships
LPL–LMF1 maturation complex

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 GPIHBP1-bound LPL is the main determinant of triglyceride-rich lipoprotein (TRL) margination along heart capillaries. TRLs fail to marginate in Gpihbp1-/- mice, and expression of LPL by endothelial cells in Gpihbp1-/- mice (where LPL binds only HSPGs) does not restore TRL margination, demonstrating that GPIHBP1-bound LPL—not HSPG-bound LPL—is required for this process. Fluorescence microscopy, quantitative infrared-dye-labeled lipoprotein assays, EM tomography in wild-type vs. Gpihbp1-/- mice; cell-culture studies Cell metabolism High 24726386
2016 HSPG-bound LPL is mobile: it can detach from heparan sulfate proteoglycans on cell surfaces and transfer to GPIHBP1, a process dependent on GPIHBP1's Ly6 domain (W109S mutation abolishes transfer) but not its acidic domain. This mobility was demonstrated both in cultured cells and in vivo by injecting GPIHBP1-coated beads into adipose tissue of Gpihbp1-/- mice. Cell-culture transfer assays (LPL movement to soluble GPIHBP1, GPIHBP1-coated beads, GPIHBP1-expressing cells); in vivo bead injection into Gpihbp1-/- mice; GPIHBP1 domain mutants Journal of lipid research High 27811232
2018 ANGPTL4 inhibits LPL by binding near the active site at the lid domain and an adjacent α-helix, as mapped by hydrogen-deuterium exchange MS and validated with chimeric LPL variants and an LPL peptide mimetic. Binding of ANGPTL4 to this lid region likely occludes substrate access to the catalytic site. Hydrogen-deuterium exchange MS; chimeric LPL variants; LPL peptide mimetic competition assays The Journal of biological chemistry High 30591589
2021 The ANGPTL3/8 complex inhibits LPL by binding near the lid domain, ApoC2 binding site, and furin cleavage region (mapped by HDX-MS), and promotes furin-mediated cleavage of LPL. ANGPTL3/8-mediated LPL cleavage is blocked by an ANGPTL3 antibody or a furin inhibitor, and siRNA knockdown of furin significantly reduces ANGPTL3/8-induced LPL cleavage. HDX-MS; LPL enzymatic activity assays; furin inhibitor treatment; furin siRNA knockdown; ANGPTL3 antibody blocking ACS chemical biology High 33656326
2021 ApoA5 lowers triglycerides by suppressing ANGPTL3/8-mediated LPL inhibition rather than by directly stimulating LPL. ApoA5 associates with ANGPTL3/8 in human serum (immunoprecipitation-MS, Western blot), blocks ANGPTL3/8-mediated LPL inhibition (functional LPL enzymatic assays), but has no direct effect on LPL activity and does not suppress inhibition by ANGPTL3, ANGPTL4, or ANGPTL4/8. Immunoprecipitation-MS; Western blotting; biolayer interferometry; functional LPL enzymatic assays; kinetic analyses Journal of lipid research High 33762177
2022 LPL and ApoA5 both bind the same leucine zipper-like epitope on the ANGPTL3/8 complex (N-terminal regions of ANGPTL3 and ANGPTL8 unmasked upon complex formation), mapped by HDX-MS and molecular modeling. An antibody targeting this same epitope potently blocks ANGPTL3/8-mediated LPL inhibition in vitro and markedly lowers triglycerides in vivo. Hydrogen-deuterium exchange MS; molecular modeling; biolayer interferometry; in vitro LPL enzymatic assays; in vivo triglyceride measurements Journal of lipid research High 35307397
2017 ApoC-III inhibits triglyceride hydrolysis by LPL and this inhibitory effect is exaggerated when LPL is bound to GPIHBP1 on agarose beads compared with free LPL. TRLs from APOC3-transgenic mice bind normally to GPIHBP1-bound LPL, but their triglycerides are hydrolyzed more slowly. A mutant apoC-III (p.A23T) associated with low plasma triglycerides displays reduced capacity to inhibit both free and GPIHBP1-bound LPL. In vitro lipolysis assays with free vs. GPIHBP1-bead-bound LPL; cell-culture TRL binding assays; in vivo heart capillary binding; recombinant apoC-III variants Journal of lipid research High 28694296
2023 ANGPTL4/8 complex recruits tissue plasminogen activator (tPA) and plasminogen, acting like fibrin to generate plasmin, which then cleaves ANGPTL4/8 and restores LPL activity. Addition of tPA + plasminogen to LPL-bound ANGPTL4/8 causes rapid, complete ANGPTL4/8 cleavage and increased LPL activity; catalytically inactive plasminogen (S760A) or PAI-1 blocks this restoration. Pulldown experiments; in vitro plasmin generation assays; LPL enzymatic activity assays; catalytically inactive plasminogen mutant (S760A); PAI-1 inhibitor controls Proceedings of the National Academy of Sciences of the United States of America High 36763533
2023 Plasmin generated by ANGPTL4/8 in adipose tissue postprandially blocks ANGPTL3/8-, ANGPTL4-, ANGPTL3-, and ApoC3-mediated LPL inhibition (by cleaving these inhibitors) while leaving ApoC2-mediated LPL activation intact, enabling maximal postprandial LPL activity in fat. In vitro LPL enzymatic activity assays with ANGPTL4/8 + tPA + plasminogen system; ANGPTL3 cleavage analysis; ApoC2 stimulation assays Journal of lipid research High 37666362
2014 Sel1L, an ER-associated degradation adaptor protein, is indispensable for LPL secretion independently of its role in Hrd1-mediated ERAD. Sel1L physically interacts with and stabilizes the LPL maturation complex (LPL + LMF1). Without Sel1L, LPL is retained in the ER, forms aggregates, and is degraded primarily by autophagy. Adipocyte-specific Sel1L knockout mice; co-immunoprecipitation (Sel1L with LPL and LMF1); immunofluorescence localization; autophagy inhibitor experiments; postheparin plasma LPL assays Cell metabolism High 25066055
2012 LMF1 (lipase maturation factor 1) overexpression in transgenic mice increases LPL specific activity in adipose and LPL protein level in heart, demonstrating that LMF1 is a posttranslational determinant of LPL activity via its role in ER maturation. Transgenic mouse overexpression (aP2-Lmf1, Mck-Lmf1); tissue LPL activity and mass measurements; human LMF1 variant association with postheparin LPL activity Arteriosclerosis, thrombosis, and vascular biology Medium 22345169
1999 LPL expressed in pancreatic islets suppresses insulin secretion. LPL+/- mice have twice the fasting insulin of wild-type despite lower glucose; isolated +/- islets secrete more insulin in vitro than +/+ islets. Overexpression of LPL in INS-1 cells (adeno-associated virus) decreases insulin secretion, while antisense LPL oligonucleotide increases it. LPL heterozygous knockout mice; hyperinsulinemic clamp; in vitro islet secretion assays; adeno-associated virus LPL overexpression and antisense knockdown in INS-1 cells The Journal of biological chemistry High 10488074
2010 Adiponectin increases LPL translocation to the cardiomyocyte cell surface via RhoA/ROCK-mediated actin cytoskeleton remodeling. Adiponectin stimulates RhoA activity, phosphorylates and inhibits cofilin (reducing actin treadmilling), promotes stress fiber formation, and increases heparin-releasable LPL activity. Inhibition of RhoA or ROCK prevents adiponectin-stimulated plasma membrane LPL content and activity. Primary adult rat cardiomyocytes; G-LISA RhoA activation assay; rhodamine-phalloidin immunofluorescence of actin; cofilin phosphorylation immunoblot; heparin-releasable LPL activity assay; RhoA/ROCK inhibitor treatment Endocrinology Medium 21147877
2021 LPL in cardiomyocytes promotes glycerol-based ATP synthesis during ischemia through the LPL/AQP7/GPD2 axis. Cardiomyocyte-specific LPL deficiency enhances cardiac dysfunction and apoptosis after myocardial infarction. LPL generates glycerol from triglycerides, which enters the glycolytic pathway via AQP7 and GPD2 under hypoxic conditions. Cardiomyocyte-specific LPL knockout mice; myocardial infarction model; GPD2 and AQP7 deficiency models; cardiac function measurements; apoptosis assays; PPARα agonist rescue experiments FASEB journal Medium 34807469
2004 Palmitoyl lysophosphatidylcholine (PLPC) mobilizes LPL to the coronary luminal surface via protein kinase C (PKC) activation in endothelial cells. Calphostin (PKC inhibitor) blocks PLPC-induced PKC activation and luminal LPL increase. PLPC is converted by phospholipase D to lysophosphatidic acid (LPA), which directly increases myocyte heparin-releasable LPL activity. Isolated perfused hearts; PKC activity assays; calphostin inhibitor; endothelial cell PKC assays; myocyte LPL activity with exogenous PLD and PLPC; LPA treatment Journal of molecular and cellular cardiology Medium 15522270
2006 LPL expressed in endothelial-intact arteries promotes lipid deposition and VCAM-1 upregulation via both catalytic and non-catalytic (bridging) mechanisms. In both LPL-deficient and ApoE-deficient mice, catalytically inactive LPL (hLPL194) increased arterial lipid deposition 5–6-fold, while active LPL increased it ~10-fold, demonstrating a non-enzymatic proatherosclerotic function of LPL. Adenoviral gene transfer of wild-type and catalytically inactive LPL into carotid arteries of LPL-/- and ApoE-/- mice; lipid deposition quantification; VCAM-1 immunostaining Arteriosclerosis, thrombosis, and vascular biology Medium 17038632
1992 Two cis-regulatory elements, LP-alpha (-702 to -666) and LP-beta (-468 to -430) in the LPL promoter, are required for differentiation-linked induction of LPL gene during adipogenesis. These elements bind factors resembling the HNF-3/fork head family of transcription factors, as shown by gel mobility shift and DNase I/exonuclease III protection assays. Both elements can confer differentiation-linked expression on heterologous promoters. Transient and stable transfection of CAT reporter constructs; DNase I hypersensitivity assays; gel mobility shift assays; DNase I and exonuclease III in vitro protection assays Molecular and cellular biology High 1406652
1996 Fibrates activate LPL gene transcription via peroxisome proliferator-activated receptors (PPARs), resulting in increased LPL production and a hypotriglyceridemic effect. PPARs also decrease ApoC-III transcription, providing a dual mechanism for triglyceride lowering. Reporter gene transcription assays; PPAR activation studies; fibrate treatment experiments in cell culture Atherosclerosis Medium 8831913
2010 GIP (glucose-dependent insulinotropic polypeptide), in the presence of insulin, increases LPL gene expression in human adipocytes via a PI3K/PKB/AMPK-dependent pathway that leads to CREB phosphorylation at Ser133 and nuclear localization of TORC2. CREB and TORC2 bind to a CRE-II site in the LPL promoter. RNAi knockdown of CREB and TORC2 reduces LPL expression. LPL promoter-reporter assays in HEK-293 cells; CREB/TORC2 RNAi knockdown; kinase inhibitor experiments; ChIP showing CREB/TORC2 binding to LPL promoter CRE-II site; co-immunoprecipitation of CREB/TORC2 interaction Journal of lipid research High 20693566
2015 STAT3 drives aberrant LPL expression in CLL cells by directly binding the LPL promoter. Luciferase reporter assays show STAT3 activates the LPL promoter; ChIP confirms STAT3 binding to the LPL promoter; STAT3-shRNA knockdown reduces LPL mRNA and protein. LPL in CLL cells catalyzes hydrolysis of triglycerides to free fatty acids, which are metabolized oxidatively—LPL siRNA reduces CLL cell fatty acid oxidation capacity and cell viability. Luciferase reporter assay; chromatin immunoprecipitation (ChIP); STAT3-shRNA knockdown; LPL-siRNA; fatty acid oxidation assays; cell viability assay Molecular cancer research : MCR High 25733697
1996 The Tyr262→His mutation in LPL abolishes enzymatic activity without affecting mRNA levels or in vitro LPL protein expression. Expression in HEK-293 cells showed LPL-262 has no enzymatic activity, and most of the protein is present as inactive monomer eluting at lower NaCl from heparin-Sepharose, indicating that Tyr262 is critical for LPL dimer stability and heparin binding. The Asp9→Asn mutation retains ~80% specific activity. In vitro expression in HEK-293 cells; enzymatic activity assay; heparin-Sepharose affinity chromatography; Northern blot; DNA sequencing Journal of lipid research Medium 8728326
1992 A single base deletion (G916) in exon 5 of the LPL gene causes a frameshift leading to premature termination; this results in complete absence of LPL mRNA (Northern blot of macrophages) and no detectable LPL protein, demonstrating that this nonsense-mediated mRNA decay mechanism underlies primary LPL deficiency in these patients. Northern blot analysis of macrophage poly(A)+RNA; immunocytochemistry; biosynthetic labeling; PCR-amplified exon sequencing; AluI restriction enzyme analysis of family members The Journal of clinical investigation Medium 1737848
2017 The LPLS447X gain-of-function truncation (removing 2 C-terminal amino acids) does not increase LPL specific activity on synthetic or natural substrates and does not alter ANGPTL4 inhibition Ki, but enhances lipoprotein particle uptake to a greater degree than wild-type LPL. Structural modeling suggests the truncation exposes residues involved in receptor binding. Purified recombinant LPL and LPLS447X dimers; specific activity assays on synthetic and natural substrates; ANGPTL4 inhibition Ki measurement; fluorescently labeled lipoprotein particle uptake assay; structural modeling Biochemistry High 27984852
2018 Coexpression of LPL with LMF1 dramatically enhances LPL secretion and activity. Furin-resistant LPL variants (including one with an N-linked glycan at the furin site) maintain normal enzymatic activity, stability, and in vivo function while yielding higher purification quantities, confirming that furin cleavage limits LPL recovery but not its function. Mammalian cell coexpression; LPL activity and secretion assays; Western blot; in vivo LPL function assays; furin cleavage-resistant mutant characterization Journal of lipid research Medium 30318473
2023 Intracapillary LPL levels in brown adipose tissue (BAT) decrease sharply at thermoneutral temperature (30°C) due to increased ANGPTL4 expression, which inhibits LPL before its transport into capillaries. Angptl4 deficiency normalizes both LPL levels and TRL margination in BAT at 30°C. In Gpihbp1-/- mice at 30°C, ANGPTL4-dependent decreases in LPL occur within interstitial spaces, confirming ANGPTL4 acts prior to LPL transport into capillaries. Antibody-based quantification of intracapillary LPL; Angptl4-/- and Gpihbp1-/- mouse models; TRL margination assay; immunofluorescence; qPCR of ANGPTL4 expression Proceedings of the National Academy of Sciences of the United States of America High 36787365
2014 In diabetes, GPIHBP1 expression in cardiac endothelial cells is upregulated by hyperglycemia to increase LPL shuttling from the interstitial space to the capillary lumen. High-glucose-induced GPIHBP1 increases LPL transcytosis across endothelial monolayers. Heparanase and PDGF act upstream: heparanase releases PDGF from heparan sulfates, which upregulates GPIHBP1 expression. Streptozotocin diabetic mouse model; GPIHBP1 gene/protein expression; in vitro glucose dose-response in endothelial cells; LPL shuttling assay across EC monolayers; heparanase treatment; PDGF pathway American journal of physiology. Endocrinology and metabolism Medium 24735886
2021 Apolipoprotein E (APOE) content on VLDL strongly inversely correlates with LPL-mediated triglyceride hydrolysis rate in a novel in vitro assay. Exogenous APOE inhibits LPL lipolysis in a dose-dependent manner; APOE3 and APOE4 isoforms are effective inhibitors while APOE2 is not. ApoC-II content does not predict hydrolysis rate. Novel in vitro LPL lipolysis assay with VLDL from 15 normolipidemic donors; proteomics/MS for VLDL protein composition; exogenous APOE isoform addition experiments Journal of lipid research Medium 34863862
2016 LPL loss-of-function variants (e.g., p.D36N) are associated with increased coronary artery disease risk and gain-of-function variants (p.S447*) are associated with protection, while ANGPTL4 loss-of-function mutations reduce triglyceride levels. These genetic data establish LPL function (triglyceride hydrolysis) as causal for cardiovascular protection. Large-scale DNA sequencing and genotyping (72,868 CAD cases, 120,770 controls); loss-of-function variant identification and phenotypic comparison The New England journal of medicine Medium 26934567
2021 ANGPTL3/8 potently inhibits LPL when bound to GPIHBP1, as demonstrated by recombinant protein assays measuring GPIHBP1-LPL activity in the presence of ANGPTL3/8 complex versus individual proteins. Recombinant protein activity assays with GPIHBP1-bound LPL; dedicated immunoassays for ANGPTL complexes Circulation Medium 39392008

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 Association of Triglyceride-Lowering LPL Variants and LDL-C-Lowering LDLR Variants With Risk of Coronary Heart Disease. JAMA 517 30694319
2016 Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease. The New England journal of medicine 415 26934567
2012 Mutations in LPL, APOC2, APOA5, GPIHBP1 and LMF1 in patients with severe hypertriglyceridaemia. Journal of internal medicine 204 22239554
2006 The lipogenic enzymes DGAT1, FAS, and LPL in adipose tissue: effects of obesity, insulin resistance, and TZD treatment. Journal of lipid research 135 16894240
1994 DNA variants at the LPL gene locus associate with angiographically defined severity of atherosclerosis and serum lipoprotein levels in a Welsh population. Arteriosclerosis and thrombosis : a journal of vascular biology 135 7912549
2014 The GPIHBP1-LPL complex is responsible for the margination of triglyceride-rich lipoproteins in capillaries. Cell metabolism 130 24726386
1996 Transcriptional control of triglyceride metabolism: fibrates and fatty acids change the expression of the LPL and apo C-III genes by activating the nuclear receptor PPAR. Atherosclerosis 121 8831913
2014 The ER-associated degradation adaptor protein Sel1L regulates LPL secretion and lipid metabolism. Cell metabolism 110 25066055
2010 GIP increases human adipocyte LPL expression through CREB and TORC2-mediated trans-activation of the LPL gene. Journal of lipid research 110 20693566
1992 Characterization of the human lipoprotein lipase (LPL) promoter: evidence of two cis-regulatory regions, LP-alpha and LP-beta, of importance for the differentiation-linked induction of the LPL gene during adipogenesis. Molecular and cellular biology 84 1406652
2020 Identification and functional characterization of mutations in LPL gene causing severe hypertriglyceridaemia and acute pancreatitis. Journal of cellular and molecular medicine 80 31901151
1995 The three genes lipB, lipC, and lipD involved in the extracellular secretion of the Serratia marcescens lipase which lacks an N-terminal signal peptide. Journal of bacteriology 79 7592412
1994 Analysis of DNA changes in the LPL gene in patients with familial combined hyperlipidemia. Arteriosclerosis and thrombosis : a journal of vascular biology 77 8049185
1994 The LPL gene in individuals with familial combined hyperlipidemia and decreased LPL activity. Arteriosclerosis and thrombosis : a journal of vascular biology 73 8199176
2021 ApoA5 lowers triglyceride levels via suppression of ANGPTL3/8-mediated LPL inhibition. Journal of lipid research 72 33762177
2021 Targeted Inhibition of LPL/FABP4/CPT1 fatty acid metabolic axis can effectively prevent the progression of nonalcoholic steatohepatitis to liver cancer. International journal of biological sciences 71 34803493
2015 Aberrant LPL Expression, Driven by STAT3, Mediates Free Fatty Acid Metabolism in CLL Cells. Molecular cancer research : MCR 71 25733697
1975 Lipd profiles of plasma lipoproteins of fasted and fed normal and choline-deficient rats. Lipids 68 167258
2009 Novel LPL mutations associated with lipoprotein lipase deficiency: two case reports and a literature review. Canadian journal of physiology and pharmacology 67 19295657
2007 Insulin regulation of lipoprotein lipase (LPL) activity and expression in gilthead sea bream (Sparus aurata). Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology 65 17600746
2002 The regulation of HSL and LPL expression by DHT and flutamide in human subcutaneous adipose tissue. Diabetes, obesity & metabolism 63 12047400
2015 Spectrum of mutations of the LPL gene identified in Italy in patients with severe hypertriglyceridemia. Atherosclerosis 62 25966443
2002 Effect of diet on adipose tissue and skeletal muscle VLDL receptor and LPL: implications for obesity and hyperlipidemia. Atherosclerosis 61 11882325
1999 Relative hypoglycemia and hyperinsulinemia in mice with heterozygous lipoprotein lipase (LPL) deficiency. Islet LPL regulates insulin secretion. The Journal of biological chemistry 60 10488074
2020 Fasting induces ANGPTL4 and reduces LPL activity in human adipose tissue. Molecular metabolism 58 32504883
2012 Association of LPL gene variant and LDL, HDL, VLDL cholesterol and triglyceride levels with ischemic stroke and its subtypes. Journal of the neurological sciences 57 22541364
1992 Molecular studies on primary lipoprotein lipase (LPL) deficiency. One base deletion (G916) in exon 5 of LPL gene causes no detectable LPL protein due to the absence of LPL mRNA transcript. The Journal of clinical investigation 52 1737848
2013 DNA methylation variations at CETP and LPL gene promoter loci: new molecular biomarkers associated with blood lipid profile variability. Atherosclerosis 49 23623643
2017 Apolipoprotein C-III inhibits triglyceride hydrolysis by GPIHBP1-bound LPL. Journal of lipid research 47 28694296
2017 Triglyceride Rich Lipoprotein -LPL-VLDL Receptor and Lp(a)-VLDL Receptor Pathways for Macrophage Foam Cell Formation. Journal of atherosclerosis and thrombosis 46 28428482
2022 An anti-ANGPTL3/8 antibody decreases circulating triglycerides by binding to a LPL-inhibitory leucine zipper-like motif. Journal of lipid research 44 35307397
2015 CETP/LPL/LIPC gene polymorphisms and susceptibility to age-related macular degeneration. Scientific reports 44 26503844
2012 MicroRNA-467b targets LPL gene in RAW 264.7 macrophages and attenuates lipid accumulation and proinflammatory cytokine secretion. Biochimie 44 22963823
2001 Lipoprotein lipase (LPL) deficiency: a new patient homozygote for the preponderant mutation Gly188Glu in the human LPL gene and review of reported mutations: 75 % are clustered in exons 5 and 6. Annales de genetique 43 11334614
2015 Pathogenic classification of LPL gene variants reported to be associated with LPL deficiency. Journal of clinical lipidology 40 27055971
2008 Lipoprotein lipase (LPL) is highly expressed and active in the ovary of European sea bass (Dicentrarchus labrax L.), during gonadal development. Comparative biochemistry and physiology. Part A, Molecular & integrative physiology 39 18511315
1997 Familial lipoprotein lipase (LPL) deficiency: a catalogue of LPL gene mutations identified in 20 patients from the UK, Sweden, and Italy. Human mutation 38 9401010
2016 Mobility of "HSPG-bound" LPL explains how LPL is able to reach GPIHBP1 on capillaries. Journal of lipid research 37 27811232
2018 Mapping the sites of the lipoprotein lipase (LPL)-angiopoietin-like protein 4 (ANGPTL4) interaction provides mechanistic insight into LPL inhibition. The Journal of biological chemistry 36 30591589
2003 Lipoprotein lipase (LPL) gene variation and progression of carotid artery plaque. Stroke 34 12690214
2021 The Angiopoietin-Like Protein 3 and 8 Complex Interacts with Lipoprotein Lipase and Induces LPL Cleavage. ACS chemical biology 33 33656326
2019 Role of LpL (Lipoprotein Lipase) in Macrophage Polarization In Vitro and In Vivo. Arteriosclerosis, thrombosis, and vascular biology 32 31434492
2009 Genetic and epigenetic inactivation of LPL gene in human prostate cancer. International journal of cancer 32 19004026
2016 Identification and characterization of two novel mutations in the LPL gene causing type I hyperlipoproteinemia. Journal of clinical lipidology 31 27578112
2010 Adiponectin increases LPL activity via RhoA/ROCK-mediated actin remodelling in adult rat cardiomyocytes. Endocrinology 31 21147877
2001 Evidence of LPL gene-exercise interaction for body fat and LPL activity: the HERITAGE Family Study. Journal of applied physiology (Bethesda, Md. : 1985) 31 11509533
1996 Homozygosity for two point mutations in the lipoprotein lipase (LPL) gene in a patient with familial LPL deficiency: LPL(Asp9-->Asn, Tyr262-->His). Journal of lipid research 31 8728326
2013 The effects of miR-467b on lipoprotein lipase (LPL) expression, pro-inflammatory cytokine, lipid levels and atherosclerotic lesions in apolipoprotein E knockout mice. Biochemical and biophysical research communications 30 24309104
2007 Allelic variation in ApoC3, ApoA5 and LPL genes and first and second generation antipsychotic effects on serum lipids in patients with schizophrenia. The pharmacogenomics journal 30 17726453
2021 GPIHBP1 and ANGPTL4 Utilize Protein Disorder to Orchestrate Order in Plasma Triglyceride Metabolism and Regulate Compartmentalization of LPL Activity. Frontiers in cell and developmental biology 29 34336854
2023 miR-128-3p regulates chicken granulosa cell function via 14-3-3β/FoxO and PPAR-γ/LPL signaling pathways. International journal of biological macromolecules 28 37119902
2007 Sex differences in abdominal, gluteal, and thigh LPL activity. American journal of physiology. Endocrinology and metabolism 28 17311894
2022 The longitudinal triglyceride phenotype in heterozygotes with LPL pathogenic variants. Journal of clinical lipidology 26 36476373
2019 Staphylococcus aureus Lpl protein triggers human host cell invasion via activation of Hsp90 receptor. Cellular microbiology 26 31515903
2009 APOE, CETP and LPL genes show strong association with lipid levels in Greek children. Nutrition, metabolism, and cardiovascular diseases : NMCD 26 19403283
2023 Angiopoietin-like protein 4/8 complex-mediated plasmin generation leads to cleavage of the complex and restoration of LPL activity. Proceedings of the National Academy of Sciences of the United States of America 25 36763533
2020 Artesunate inhibits atherosclerosis by upregulating vascular smooth muscle cells-derived LPL expression via the KLF2/NRF2/TCF7L2 pathway. European journal of pharmacology 25 32739175
2017 Adipose Tissue LPL Methylation is Associated with Triglyceride Concentrations in the Metabolic Syndrome. Clinical chemistry 25 29046332
2003 Association between lipoprotein lipase (LPL) gene and blood lipids: a common variant for a common trait? Genetic epidemiology 25 12687649
2014 Molecular characterization of oxidative stress-inducible LipD of Mycobacterium tuberculosis H37Rv. Current microbiology 24 24232385
2006 Expression of LPL in endothelial-intact artery results in lipid deposition and vascular cell adhesion molecule-1 upregulation in both LPL and ApoE-deficient mice. Arteriosclerosis, thrombosis, and vascular biology 24 17038632
2017 Biochemical Analysis of the Lipoprotein Lipase Truncation Variant, LPLS447X, Reveals Increased Lipoprotein Uptake. Biochemistry 23 27984852
2019 MicroRNA-224 impairs adipogenic differentiation of bovine preadipocytes by targeting LPL. Molecular and cellular probes 22 30703449
2013 Saturated fat-rich diet increases fetal lipids and modulates LPL and leptin receptor expression in rat placentas. The Journal of endocrinology 22 23482704
2012 Association of the HindIII and S447X polymorphisms in LPL gene with hypertension and type 2 diabetes in Mexican families. Disease markers 22 23089926
2024 Associations of Circulating ANGPTL3, C-Terminal Domain-Containing ANGPTL4, and ANGPTL3/8 and ANGPTL4/8 Complexes with LPL Activity, Diabetes, Inflammation, and Cardiovascular Mortality. Circulation 21 39392008
2021 LPL/AQP7/GPD2 promotes glycerol metabolism under hypoxia and prevents cardiac dysfunction during ischemia. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 21 34807469
2021 Apolipoprotein E content of VLDL limits LPL-mediated triglyceride hydrolysis. Journal of lipid research 21 34863862
2015 High adipose LPL activity and adipocyte hypertrophy reduce visceral fat and metabolic risk in obese, older women. Obesity (Silver Spring, Md.) 21 25612068
2020 Identification of a novel LPL nonsense variant and further insights into the complex etiology and expression of hypertriglyceridemia-induced acute pancreatitis. Lipids in health and disease 20 32264896
2022 CircRIC8B regulates the lipid metabolism of chronic lymphocytic leukemia through miR199b-5p/LPL axis. Experimental hematology & oncology 19 36064433
2018 Paeoniflorin regulates GALNT2-ANGPTL3-LPL pathway to attenuate dyslipidemia in mice. European journal of pharmacology 19 30096295
2023 Decoding the role of angiopoietin-like protein 4/8 complex-mediated plasmin generation in the regulation of LPL activity. Journal of lipid research 18 37666362
2022 A novel and controllable method for simultaneous preparation of human milk fat substitutes (OPL, OPO and LPL): two-step enzymatic ethanolysis-esterification strategy. Food research international (Ottawa, Ont.) 18 36596114
2018 Nobiletin reduces LPL-mediated lipid accumulation and pro-inflammatory cytokine secretion through upregulation of miR-590 expression. Biochemical and biophysical research communications 18 30471854
2015 Polymorphisms in the LPL and CETP Genes and Haplotype in the ESR1 Gene Are Associated with Metabolic Syndrome in Women from Southwestern Mexico. International journal of molecular sciences 18 26370976
2012 Transgenic expression and genetic variation of Lmf1 affect LPL activity in mice and humans. Arteriosclerosis, thrombosis, and vascular biology 18 22345169
2016 miR-29b Targets LPL and TDG Genes and Regulates Apoptosis and Triglyceride Production in MECs. DNA and cell biology 17 27854545
2016 Staphylococcus aureus Lpl Lipoproteins Delay G2/M Phase Transition in HeLa Cells. Frontiers in cellular and infection microbiology 17 28083519
2015 Feeding a High Concentrate Diet Down-Regulates Expression of ACACA, LPL and SCD and Modifies Milk Composition in Lactating Goats. PloS one 17 26086219
2022 Landscape of immunoglobulin heavy chain gene repertoire and its clinical relevance to LPL/WM. Blood advances 15 35537114
2020 Erchen Decoction Mitigates Lipid Metabolism Disorder by the Regulation of PPARγ and LPL Gene in a High-Fat Diet C57BL/6 Mice Model. Evidence-based complementary and alternative medicine : eCAM 15 32256662
2019 Resistin up-regulates LPL expression through the PPARγ-dependent PI3K/AKT signaling pathway impacting lipid accumulation in RAW264.7 macrophages. Cytokine 15 30925325
2016 Structure-activity and in vivo evaluation of a novel lipoprotein lipase (LPL) activator. Bioorganic & medicinal chemistry letters 15 27913180
2015 Contribution of mutations in low density lipoprotein receptor (LDLR) and lipoprotein lipase (LPL) genes to familial combined hyperlipidemia (FCHL): a reappraisal by using a resequencing approach. Atherosclerosis 15 26342331
2014 Endothelial cells respond to hyperglycemia by increasing the LPL transporter GPIHBP1. American journal of physiology. Endocrinology and metabolism 15 24735886
2007 Polymorphism of apolipoprotein E (APOE) and lipoprotein lipase (LPL) genes and ischaemic stroke in individuals of Yakut ethnicity. Journal of the neurological sciences 15 17328917
1996 Quantification of lipoprotein lipase (LPL) by dissociation-enhanced lanthanide fluorescence immunoassay. Comparison of immunoreactivity of LPL mass and enzyme activity of LPL. Journal of immunological methods 15 8699004
2024 Macromolecular Interactions of Lipoprotein Lipase (LPL). Sub-cellular biochemistry 14 38963487
2012 Genetic variation in MDR1, LPL and eNOS genes and the response to atorvastatin treatment in ischemic stroke. Human genetics 14 22810051
2008 Genetic screening of the LPL gene in hypertriglyceridaemic patients. Atherosclerosis 14 18068174
2004 Palmitoyl lysophosphatidylcholine mediated mobilization of LPL to the coronary luminal surface requires PKC activation. Journal of molecular and cellular cardiology 14 15522270
2000 Pseudodominance of lipoprotein lipase (LPL) deficiency due to a nonsense mutation (Tyr302>Term) in exon 6 of LPL gene in an Italian family from Sardinia (LPL(Olbia)). Clinical genetics 14 10735636
2023 Intracapillary LPL levels in brown adipose tissue, visualized with an antibody-based approach, are regulated by ANGPTL4 at thermoneutral temperatures. Proceedings of the National Academy of Sciences of the United States of America 13 36787365
2021 Association of NFκβ, TNFα, IL-6, IL-1β, and LPL Polymorphisms with Type 2 Diabetes Mellitus and Biochemical Parameters in a Mexican Population. Biochemical genetics 13 33599871
2019 Partial LPL deletions: rare copy-number variants contributing towards severe hypertriglyceridemia. Journal of lipid research 13 31519763
2018 Coexpression of novel furin-resistant LPL variants with lipase maturation factor 1 enhances LPL secretion and activity. Journal of lipid research 13 30318473
2001 Lipolytic and lipoprotein lipase (LPL)-inhibiting activities produced by a human lung cancer cell line responsible for cachexia induction. Anticancer research 13 11848498
2021 Expression and one-step purification of active LPL contemplated by biophysical considerations. Journal of lipid research 12 34780727
2019 Deciphering the role of V200A and N291S mutations leading to LPL deficiency. Atherosclerosis 12 30685441

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