Affinage

LPL

Lipoprotein lipase · UniProt P06858

Round 2 corrected
Length
475 aa
Mass
53.2 kDa
Annotated
2026-04-28
130 papers in source corpus 31 papers cited in narrative 31 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LPL is a secreted triglyceride hydrolase that cleaves the triacylglycerol core of chylomicrons and VLDL at the capillary lumen, delivering free fatty acids and monoacylglycerol to tissues; it also exerts non-catalytic functions including receptor-bridging for lipoprotein particle uptake and selective cholesteryl ester uptake independent of its catalytic activity (PMID:12483461, PMID:11751882). LPL is active as a homodimer, requires the ER chaperone LMF1 and the Sel1L-dependent ERAD pathway for proper folding and secretion, and is transported from subendothelial heparan sulfate proteoglycans to the endothelial surface by GPIHBP1, whose Ly6 domain is essential for LPL binding and which dramatically stabilizes LPL and is required for triglyceride-rich lipoprotein margination (PMID:24726386, PMID:25066055, PMID:27811232). LPL activity is tuned by a network of protein regulators—activated by ApoC-II, inhibited by ANGPTL4 (which targets the active-site lid domain), ANGPTL3/8, and ApoC-III, with ApoA5 selectively blocking ANGPTL3/8-mediated inhibition—and postprandial restoration of adipose LPL activity is achieved through plasmin-mediated cleavage of inhibitory ANGPTL complexes (PMID:30591589, PMID:33762177, PMID:36763533, PMID:32504883). Beyond lipolysis, LPL regulates insulin secretion in pancreatic islets and provides glycerol that supports cardiac ATP synthesis during ischemia via an AQP7/GPD2 metabolic axis (PMID:10488074, PMID:34807469).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1985 High

    Establishing that ApoC-III is a direct non-competitive inhibitor of LPL resolved how apolipoprotein composition of TRL particles modulates lipolysis rate.

    Evidence In vitro kinetic analysis of LPL-mediated VLDL hydrolysis with purified ApoC-III-2

    PMID:3973011

    Open questions at the time
    • Binding site of ApoC-III on LPL was not mapped
    • In vivo contribution of ApoC-III to LPL inhibition vs. receptor-mediated clearance was unresolved
  2. 1987 High

    Cloning and sequencing of LPL cDNA placed the enzyme within a lipase gene family and provided the molecular tools for all subsequent structure-function studies.

    Evidence cDNA cloning and sequencing from human adipose tissue library

    PMID:3823907

    Open questions at the time
    • No three-dimensional structure was available
    • Catalytic residues and domain boundaries were inferred by homology, not experimentally defined
  3. 1999 High

    Discovery that LPL expression in pancreatic islets negatively regulates insulin secretion revealed an unexpected extrahepatic, extra-adipose metabolic role for LPL.

    Evidence Gain- and loss-of-function experiments in INS-1 cells and LPL-deficient mouse islets with insulin secretion readouts

    PMID:10488074

    Open questions at the time
    • Molecular mechanism linking LPL activity to suppression of insulin secretion was not defined
    • Relative contribution of lipolytic products vs. bridging function in islets was unknown
  4. 2001 High

    Demonstrating that catalytically inactive LPL suffices for selective cholesteryl ester uptake separated LPL's non-catalytic bridging function from its hydrolytic activity, establishing dual functional modes.

    Evidence Transgenic mice expressing catalytically inactive LPL on LPL-null background with radiolabeled lipoprotein uptake assays

    PMID:11751882

    Open questions at the time
    • Identity of receptors engaged by LPL bridging was not established
    • Structural basis for bridging vs. catalytic function was unknown
  5. 2014 High

    Identification of GPIHBP1 as the obligate endothelial platform for LPL-mediated TRL margination resolved how LPL reaches the capillary lumen and why HSPG-bound LPL alone is insufficient for intravascular lipolysis.

    Evidence Fluorescence microscopy, IR-labeled lipoprotein margination assays, and EM tomography in wild-type and Gpihbp1−/− mice

    PMID:24726386

    Open questions at the time
    • Structural details of LPL–GPIHBP1 interaction were not resolved
    • How GPIHBP1 stabilizes LPL at the molecular level was unknown
  6. 2014 High

    Discovery that Sel1L physically interacts with LPL-LMF1 and is required for LPL ER exit defined the ER quality control pathway governing LPL biogenesis, explaining how misfolded LPL is triaged to autophagy.

    Evidence Adipocyte-specific Sel1L knockout mice, co-immunoprecipitation, ER fractionation, autophagy inhibition

    PMID:25066055

    Open questions at the time
    • Whether Sel1L acts directly on LPL folding or on LMF1-LPL complex stability was unclear
    • Contribution of proteasomal vs. autophagic degradation under physiological conditions was not quantified
  7. 2016 High

    Mapping GPIHBP1's Ly6 domain as the LPL-binding domain and showing that HSPG-bound LPL actively migrates to GPIHBP1 explained the directional transport of LPL from parenchymal cells to the capillary endothelium.

    Evidence GPIHBP1-coated agarose beads in Gpihbp1−/− adipose tissue; Ly6 domain W109S mutagenesis; monoclonal antibody domain mapping

    PMID:27811232 PMID:27875259

    Open questions at the time
    • Kinetics of LPL transfer from HSPGs to GPIHBP1 in vivo were not quantified
    • Role of GPIHBP1 acidic domain in LPL stabilization vs. transport was not fully resolved
  8. 2017 High

    Characterizing the LPL S447X gain-of-function variant showed it does not increase intrinsic enzymatic activity but instead enhances non-catalytic lipoprotein uptake, clarifying the mechanistic basis of a clinically important human variant.

    Evidence Purified recombinant LPLS447X vs. wild-type enzymatic, ANGPTL4 inhibition, and fluorescent lipoprotein uptake assays

    PMID:27984852

    Open questions at the time
    • Receptor(s) engaged by the exposed C-terminal region were not identified
    • In vivo significance of the enhanced uptake function was not directly tested
  9. 2018 High

    HDX-MS mapping of ANGPTL4 binding to LPL's active-site lid domain provided the first structural explanation for how ANGPTL4 inhibits LPL catalysis by occluding substrate access.

    Evidence Hydrogen-deuterium exchange mass spectrometry, chimeric LPL variants, LPL peptide mimetics, in vitro inhibition assays

    PMID:30591589

    Open questions at the time
    • Whether ANGPTL4 also destabilizes the LPL dimer through lid-domain binding was not resolved
    • ANGPTL3/8 binding site on LPL had not been comparably mapped
  10. 2021 High

    Demonstrating that ApoA5 lowers triglycerides by specifically blocking ANGPTL3/8-mediated LPL inhibition—rather than directly activating LPL—placed ApoA5 within the ANGPTL regulatory network as a selective counter-inhibitor.

    Evidence Immunoprecipitation-mass spectrometry of human serum, biolayer interferometry, functional LPL enzymatic assays

    PMID:33762177

    Open questions at the time
    • Structural basis of ApoA5–ANGPTL3/8 interaction was unknown at the time
    • In vivo tissue-specific contribution of ApoA5 to LPL derepression was not established
  11. 2022 High

    Mapping the shared LPL/ApoA5 binding epitope on the ANGPTL3/8 leucine-zipper interface revealed how two endogenous regulators compete for the same inhibitory complex and provided a therapeutic antibody target.

    Evidence HDX-MS on ANGPTL3/8; biolayer interferometry; anti-ANGPTL3/8 antibody lowered TG in vivo

    PMID:35307397

    Open questions at the time
    • Relative affinity of LPL vs. ApoA5 for ANGPTL3/8 in physiological conditions was not quantified
    • Whether this epitope is accessible on GPIHBP1-bound LPL in vivo was not addressed
  12. 2023 High

    Discovery that ANGPTL4/8 acts as a plasminogen activation scaffold—generating plasmin that cleaves inhibitory ANGPTL complexes to restore LPL activity—provided a feedforward mechanism for postprandial adipose lipolysis.

    Evidence Reconstituted in vitro tPA-plasminogen-ANGPTL4/8 system with catalytically inactive plasminogen and PAI-1 controls; LPL activity assays

    PMID:36763533 PMID:37666362

    Open questions at the time
    • In vivo validation that plasmin generation at adipose capillaries is the dominant mechanism for postprandial LPL reactivation is lacking
    • Whether plasmin also cleaves GPIHBP1-bound ANGPTL complexes in situ was not determined

Open questions

Synthesis pass · forward-looking unresolved questions
  • The full structural basis of LPL dimer-to-monomer transition during ANGPTL-mediated inactivation, the identity of receptors that mediate LPL's non-catalytic bridging uptake, and the in vivo significance of LPL regulation by ApoE isoforms remain unresolved.
  • High-resolution structure of ANGPTL4-bound or ANGPTL3/8-bound LPL has not been determined
  • Receptors mediating LPL bridging function are unidentified
  • In vivo role of ApoE isoform-specific LPL inhibition in human lipoprotein metabolism is not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 6 GO:0008289 lipid binding 2
Localization
GO:0005576 extracellular region 4 GO:0005886 plasma membrane 3 GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-1430728 Metabolism 8 R-HSA-162582 Signal Transduction 3 R-HSA-382551 Transport of small molecules 3
Partners
ANGPTL3ANGPTL4ANGPTL8APOA5APOC3GPIHBP1LMF1SEL1L
Complex memberships
LPL homodimerLPL-GPIHBP1 complexLPL-LMF1-Sel1L maturation complex

Evidence

Reading pass · 31 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1987 Human lipoprotein lipase (LPL) cDNA was cloned and sequenced, revealing a mature protein of 448 amino acids and identifying LPL as a member of a gene family that includes hepatic lipase and pancreatic lipase. Two distinct LPL mRNA species arising from alternative 3'-polyadenylation sites were detected in multiple tissues. cDNA cloning and sequencing Science High 3823907
1985 ApoC-III directly inhibits LPL activity in a non-competitive manner, as demonstrated by kinetic analyses of LPL-mediated hydrolysis of VLDL in the presence of purified ApoC-III-2, suggesting ApoC-III directly interacts with LPL. In vitro LPL activity assay with purified apolipoprotein, kinetic analysis The Journal of clinical investigation High 3973011
2002 LPL catalyzes hydrolysis of the triacylglycerol component of chylomicrons and VLDL, providing non-esterified fatty acids and 2-monoacylglycerol to tissues, and also possesses non-catalytic functions including bridging lipoproteins to cell-surface receptors and proteoglycans. Domain-function relationships established multiple LPL functional regions. Review synthesizing biochemical, mutagenesis, and transgenic animal studies Journal of molecular medicine High 12483461
2001 Catalytically inactive LPL alone (in the absence of active LPL) is sufficient to mediate selective cholesterol ester uptake from triglyceride-rich lipoproteins, but triglyceride hydrolysis and whole-particle lipoprotein uptake require active LPL. This demonstrates distinct catalytic and non-catalytic receptor-bridging functions of LPL. Transgenic mouse models breeding catalytically inactive LPL transgene onto LPL-deficient backgrounds; radiolabeled lipoprotein uptake assays The Journal of biological chemistry High 11751882
2014 GPIHBP1-bound LPL (not free LPL nor HSPG-bound LPL) is the principal determinant of triglyceride-rich lipoprotein (TRL) margination in heart capillaries. Fluorescence microscopy, infrared-dye-labeled lipoprotein assays, and EM tomography showed TRLs fail to marginate in Gpihbp1-/- mice even when LPL is expressed by endothelial cells and available on HSPGs. Fluorescence microscopy, quantitative lipoprotein margination assays, EM tomography in wild-type and Gpihbp1-/- mice Cell metabolism High 24726386
2014 Sel1L, an ER-associated degradation adaptor protein, physically interacts with and stabilizes the LPL maturation complex comprising LPL and LMF1. In the absence of Sel1L, LPL is retained in the ER, forms protein aggregates, and is degraded primarily by autophagy rather than being secreted. Adipocyte-specific Sel1L knockout mice; co-immunoprecipitation; ER fractionation; autophagy inhibition experiments Cell metabolism High 25066055
1999 LPL is expressed in pancreatic islets and directly regulates insulin secretion: islet LPL suppresses insulin release. INS-1 cells with increased LPL activity secreted less insulin, and cells with antisense LPL knockdown secreted more insulin, establishing LPL as a novel regulator of insulin secretion. LPL-deficient mouse islet isolation; in vitro insulin secretion assays; AAV-mediated LPL overexpression and antisense LPL knockdown in INS-1 cells The Journal of biological chemistry High 10488074
2016 HSPG-bound LPL in interstitial spaces is mobile and can detach from HSPGs to migrate to GPIHBP1 on capillary endothelial cells. This migration requires the Ly6 domain of GPIHBP1 (W109S mutation abolishes transfer) but not GPIHBP1's acidic domain. In vivo, GPIHBP1-coated agarose beads injected into GPIHBP1-deficient adipose tissue recruited LPL from adjacent adipocyte HSPGs. Cell culture mobility assays; GPIHBP1-coated agarose bead injection into adipose tissue of GPIHBP1-deficient mice; mutagenesis of GPIHBP1 domains Journal of lipid research High 27811232
2017 ApoC-III potently inhibits triglyceride hydrolysis by GPIHBP1-bound LPL to a greater extent than by free LPL. ApoC-III-enriched TRLs bound normally to GPIHBP1-bound LPL but were hydrolyzed more slowly. A natural ApoC-III variant (p.A23T) associated with low triglycerides showed reduced capacity to inhibit both free and GPIHBP1-bound LPL. Cell culture LPL-lipolysis assays with GPIHBP1-bound LPL on agarose beads; in vivo TRL binding assays in transgenic mouse hearts; recombinant apoC-III inhibition kinetics Journal of lipid research High 28694296
2018 ANGPTL4 binds LPL near the active-site lid domain and an adjacent alpha-helix, as mapped by hydrogen-deuterium exchange mass spectrometry and validated by chimeric LPL variants and LPL peptide mimetics. Binding of ANGPTL4 to the lid domain likely prevents substrate catalysis at the active site. Hydrogen-deuterium exchange mass spectrometry; chimeric LPL variants; LPL peptide mimetics; in vitro LPL inhibition assays The Journal of biological chemistry High 30591589
2021 ApoA5 lowers triglycerides by suppressing ANGPTL3/8-mediated LPL inhibition rather than by directly activating LPL. ApoA5 associates with ANGPTL3/8 in human serum (demonstrated by immunoprecipitation-MS) and blocks ANGPTL3/8 from inhibiting LPL, but has no effect on ANGPTL3, ANGPTL4, or ANGPTL4/8-mediated LPL inhibition. Immunoprecipitation-mass spectrometry; biolayer interferometry; functional LPL enzymatic assays; kinetic analyses Journal of lipid research High 33762177
2022 LPL and ApoA5 bind the same leucine zipper-like epitope on the ANGPTL3/8 complex, consisting of N-terminal regions of ANGPTL3 and ANGPTL8 unmasked upon complex formation. An anti-ANGPTL3/8 antibody targeting this epitope potently blocked ANGPTL3/8-mediated LPL inhibition in vitro and dramatically lowered triglycerides in vivo. Hydrogen-deuterium exchange mass spectrometry; molecular modeling; biolayer interferometry; in vitro LPL inhibition assays; in vivo mouse TG measurements Journal of lipid research High 35307397
2023 The ANGPTL4/8 complex binds both tissue plasminogen activator (tPA) and plasminogen, enhancing tPA activation of plasminogen to generate plasmin (mimicking fibrin). Plasmin then cleaves ANGPTL4/8, releasing LPL from partial inhibition and restoring full LPL activity. This mechanism explains how postprandial adipose tissue achieves maximal LPL activity. Pulldown assays; in vitro plasmin generation assays; LPL activity assays with catalytically inactive plasminogen mutant (S760A) and PAI-1 controls Proceedings of the National Academy of Sciences High 36763533
2023 ANGPTL4/8-mediated plasmin generation in adipose tissue selectively blocks inhibition of LPL by ANGPTL3/8 (via cleavage of ANGPTL3 within the ANGPTL3/8 complex), and also reduces inhibition by ANGPTL4, ANGPTL3, and ApoC3, while leaving ApoC2-mediated LPL stimulation unaffected. ANGPTL3/8 potently inhibits GPIHBP1-bound LPL activity. Recombinant protein LPL inhibition assays; functional assays with tPA + plasminogen system; GPIHBP1-LPL enzymatic activity assays Journal of lipid research High 37666362
2017 The LPL S447X gain-of-function truncation (removing 2 C-terminal amino acids) does not increase specific enzymatic activity on synthetic or natural substrates, nor does it alter ANGPTL4 inhibition kinetics. However, LPLS447X enhances lipoprotein particle uptake to a greater degree than wild-type LPL, likely by exposing C-terminal residues implicated in binding lipoprotein uptake receptors. Purified recombinant LPLS447X and LPL dimer comparison; in vitro enzymatic assays; fluorescent lipoprotein uptake assays; LPL structural modeling Biochemistry High 27984852
2010 Adiponectin increases LPL translocation to the cardiomyocyte cell surface via RhoA/ROCK-mediated actin cytoskeleton remodeling. Adiponectin stimulates RhoA activity, increases stress fiber formation, inhibits cofilin (reducing actin treadmilling), and this cytoskeletal remodeling is required for LPL translocation and subsequent heparin-releasable LPL activity. Primary adult rat cardiomyocytes; G-LISA RhoA activation assay; rhodamine-phalloidin immunofluorescence; immunofluorescence detection of surface LPL; heparin-releasable LPL activity assay; RhoA/ROCK inhibitor experiments Endocrinology Medium 21147877
2005 Beta-agonist isoproterenol increases cardiac LPL activity at the coronary lumen only during conditions of increased cardiac workload, and this effect is associated with AMPK activation and ACC280 inactivation. Simply switching from Langendorff to working heart conditions (increased afterload) induces AMPK/ACC280 phosphorylation and enhanced heparin-releasable LPL activity. In vivo isoproterenol treatment; Langendorff and isolated working heart preparations; AMPK and ACC280 phosphorylation assays; heparin-releasable LPL activity measurements American journal of physiology. Endocrinology and metabolism Medium 15687106
2004 Palmitoyl lysophosphatidylcholine (PLPC) maintains high coronary luminal LPL activity via PKC-epsilon activation in endothelial cells. PLPC is metabolized via phospholipase D to lysophosphatidic acid (LPA), which then mobilizes LPL from cardiomyocytes. PKC activation is essential for this LPL recruitment. Isolated heart perfusion; PKC inhibitor (calphostin) experiments; endothelial cell PKC activation assays; exogenous PLD experiments with myocytes; LPL activity measurements Journal of molecular and cellular cardiology Medium 15522270
2014 Endothelial cells respond to hyperglycemia by increasing GPIHBP1 expression, which enhances LPL shuttling across endothelial monolayers. Heparanase promotes GPIHBP1 expression by releasing PDGF from heparan sulfate proteoglycans, revealing a heparanase-PDGF-GPIHBP1 axis that regulates LPL-mediated fatty acid delivery to cardiomyocytes in the diabetic heart. Streptozotocin diabetic mouse model; in vitro endothelial cell glucose exposure; GPIHBP1 gene/protein expression; LPL transcytosis assay across endothelial monolayers; heparanase inhibition experiments American journal of physiology. Endocrinology and metabolism Medium 24735886
2016 Monoclonal antibodies against the Ly6 domain of GPIHBP1 (RE3, RG3) abolish LPL binding, while an antibody against the acidic domain (RF4) does not, demonstrating that GPIHBP1's Ly6 domain is specifically required for LPL binding. A Ly6 domain missense mutation (W109S) reduces antibody affinity and abolishes LPL binding. Monoclonal antibody generation; LPL binding assays with domain-specific antibodies; W109S GPIHBP1 mutant binding analysis Journal of lipid research Medium 27875259
2017 A conserved cysteine mutation in GPIHBP1 (p.C63Y) abolishes LPL binding and causes severe chylomicronemia in vivo. The mutant GPIHBP1 reaches the endothelial cell surface but at ~70% lower levels than wild-type, and the protein is predominantly monomeric, demonstrating that cysteine-mediated structure of GPIHBP1's Ly6 domain is essential for LPL capture. Knock-in mouse model (GPIHBP1 p.C63Y); immunohistochemistry; plasma TG measurements; Western blot analysis of GPIHBP1 oligomeric state Journal of lipid research Medium 28476858
2015 STAT3, constitutively activated in CLL cells, drives aberrant LPL expression by binding to the LPL promoter. Chromatin immunoprecipitation confirmed STAT3 occupancy at the LPL promoter; luciferase reporter assays demonstrated STAT3 activates the LPL promoter; STAT3-shRNA knockdown reduced LPL transcripts and protein. LPL-mediated triglyceride hydrolysis provides free fatty acids that CLL cells oxidize for energy. Luciferase reporter assays; chromatin immunoprecipitation; STAT3-shRNA knockdown; LPL-siRNA knockdown; fatty acid oxidation assays Molecular cancer research Medium 25733697
2018 LPL yield can be dramatically enhanced by co-expressing its maturation factor LMF1, and by introducing furin-resistance mutations (including an N-linked glycan addition at the furin cleavage site), without adversely altering LPL enzymatic activity, stability, or in vivo function. Recombinant protein expression in HEK cells; LPL enzymatic activity assays; stability measurements; in vivo lipid measurements Journal of lipid research Medium 30318473
2021 LPL expression in cardiomyocytes increases during myocardial infarction. Cardiomyocyte-specific LPL deficiency enhanced cardiac dysfunction and apoptosis after MI. LPL-derived glycerol is taken up via aquaporin 7 (AQP7) and converted by GPD2 to support ATP synthesis during ischemia, revealing an LPL/AQP7/GPD2 glycerol metabolic axis that protects the ischemic heart. Cardiomyocyte-specific LPL knockout mice; AQP7 and GPD2 knockout mice; MI model; cardiac function measurements; metabolic flux analyses FASEB journal Medium 34807469
2021 Apolipoprotein E (ApoE) content on VLDL inversely correlates with LPL-mediated TG hydrolysis rate. Exogenous APOE inhibits LPL lipolysis in a dose-dependent manner; APOE3 and especially APOE4 isoforms are effective LPL inhibitors, whereas APOE2 is not. This implicates VLDL-associated APOE as a physiological modulator of LPL activity. Novel in vitro LPL hydrolysis assay mimicking human plasma conditions; VLDL from 15 normolipidemic donors; mass spectrometry lipoprotein proteomics; exogenous APOE addition experiments Journal of lipid research Medium 34863862
2021 Fasting decreases LPL activity in human adipose tissue by ~60% without changing LPL mRNA or protein levels, concurrent with increased ANGPTL4 mRNA (+90%) and protein (+46%). Insulin downregulates ANGPTL4 in primary human adipocytes while cortisol and fatty acids upregulate it, establishing the mechanism by which fasting reduces adipose LPL activity via ANGPTL4 induction. Human adipose tissue biopsies (fasted vs. fed); LPL activity assays; ANGPTL4/LPL mRNA and protein measurements; primary human adipocyte cell culture with insulin and cortisol treatment Molecular metabolism Medium 32504883
2019 ApoC-III inhibition (via antisense oligonucleotide) lowers plasma TG in mice lacking apoE and functional syndecan-1 by increasing LPL activity in white adipose tissue (not by improving hepatic TRL clearance), demonstrating that apoE determines the dominant mechanism of apoC-III action: with apoE, apoC-III primarily inhibits receptor-mediated TRL clearance; without apoE, apoC-III instead inhibits tissue LPL activity. ApoC-III ASO treatment in Apoe-/-Ndst1f/fAlb-Cre+ mice; LPL activity measurements in white adipose tissue; VLDL production and TRL clearance assays Journal of lipid research Medium 31092690
2006 LPL-mediated lipolysis of VLDL in endothelial cells induces upregulation of AU-rich mRNAs (IL-8, ESM-1, VCAM-1, GM-CSF, TNF-alpha) and activates HuR (an AU-rich mRNA stabilizing protein) by increasing its polysomal localization. The free fatty acids and lipoprotein remnants generated by LPL activity mediate these downstream gene expression changes. cDNA subtraction; porcine aortic endothelial cell culture with LPL + VLDL; HuR polysomal localization assay; qPCR gene expression Atherosclerosis Low 16494882
2024 LPL regulation involves an extensive macromolecular interaction network: LPL oligomeric state (monomer/dimer) is central to its regulation, with dimeric LPL being the active form; multiple inhibitors (ANGPTL3/8, ANGPTL4, ApoC-III) and activators (ApoC-II, GPIHBP1) modulate activity through direct protein-protein interactions; and GPIHBP1 binding dramatically stabilizes LPL (Tm increases from ~35°C to ~58°C). Review synthesizing biophysical, structural, and biochemical studies including thermal stability measurements Sub-cellular biochemistry Medium 38963487
2019 ZHX2 inhibits lipid uptake in hepatocellular carcinoma cells through transcriptional repression of LPL. ZHX2 overexpression reduced LPL mRNA and protein; LPL overexpression reversed ZHX2-mediated inhibition of lipid accumulation and cell proliferation, establishing a ZHX2→LPL transcriptional regulatory axis in NAFLD-HCC progression. ZHX2 overexpression and KO in HCC cell lines; xenograft mouse models; luciferase reporter assays; ChIP; IHC in patient samples Cell death and differentiation Medium 31740790
2021 An expression system co-transfecting Drosophila Schneider 2 cells with human LPL, LMF1, and soluble GPIHBP1 yielded 4–28 mg/L of pure active LPL. Heparin-Sepharose purification disrupted the LPL-GPIHBP1 complex. Active-site mutant S132A, lipid-binding mutant W390A-W393A-W394A, and furin-resistant R297A were all successfully purified, enabling biochemical characterization of LPL's functional residues. Recombinant protein expression in Drosophila S2 cells; heparin affinity chromatography; LPL activity assays; site-directed mutagenesis Journal of lipid research Medium 34780727

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Biological, clinical and population relevance of 95 loci for blood lipids. Nature 2873 20686565
2013 Discovery and refinement of loci associated with lipid levels. Nature genetics 2409 24097068
2007 Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science (New York, N.Y.) 2225 17463246
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
1999 Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nature genetics 1381 10391209
2008 Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nature genetics 1310 18193043
2008 Identification of host proteins required for HIV infection through a functional genomic screen. Science (New York, N.Y.) 1165 18187620
2008 Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nature genetics 1130 18193044
2008 Common variants at 30 loci contribute to polygenic dyslipidemia. Nature genetics 1113 19060906
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2008 Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts. Nature genetics 695 19060911
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2002 Lipoprotein lipase: structure, function, regulation, and role in disease. Journal of molecular medicine (Berlin, Germany) 630 12483461
2008 Genome-wide association analysis of metabolic traits in a birth cohort from a founder population. Nature genetics 569 19060910
2008 Polymorphisms associated with cholesterol and risk of cardiovascular events. The New England journal of medicine 530 18354102
2019 Association of Triglyceride-Lowering LPL Variants and LDL-C-Lowering LDLR Variants With Risk of Coronary Heart Disease. JAMA 507 30694319
1994 Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. Gene 492 8125298
1987 Human lipoprotein lipase complementary DNA sequence. Science (New York, N.Y.) 482 3823907
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2012 Genome-wide association study identifies multiple loci influencing human serum metabolite levels. Nature genetics 436 22286219
2010 Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration. Proceedings of the National Academy of Sciences of the United States of America 433 20385819
2016 Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease. The New England journal of medicine 412 26934567
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2010 Genome-wide association study of hematological and biochemical traits in a Japanese population. Nature genetics 406 20139978
1985 Modulation of lipoprotein lipase activity by apolipoproteins. Effect of apolipoprotein C-III. The Journal of clinical investigation 399 3973011
1998 DNA sequence diversity in a 9.7-kb region of the human lipoprotein lipase gene. Nature genetics 378 9662394
2009 Mammalian BTBD12/SLX4 assembles a Holliday junction resolvase and is required for DNA repair. Cell 375 19596235
2008 Common genetic variation near MC4R is associated with waist circumference and insulin resistance. Nature genetics 365 18454146
2010 Common inherited variation in mitochondrial genes is not enriched for associations with type 2 diabetes or related glycemic traits. PLoS genetics 363 20714348
2010 Excess of rare variants in genes identified by genome-wide association study of hypertriglyceridemia. Nature genetics 354 20657596
2012 Mutations in LPL, APOC2, APOA5, GPIHBP1 and LMF1 in patients with severe hypertriglyceridaemia. Journal of internal medicine 201 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
2014 The GPIHBP1-LPL complex is responsible for the margination of triglyceride-rich lipoproteins in capillaries. Cell metabolism 130 24726386
2014 The ER-associated degradation adaptor protein Sel1L regulates LPL secretion and lipid metabolism. Cell metabolism 109 25066055
2011 Genetic variants in LPL, OASL and TOMM40/APOE-C1-C2-C4 genes are associated with multiple cardiovascular-related traits. BMC medical genetics 87 21943158
2005 Effects of dietary mulberry, Korean red ginseng, and banaba on glucose homeostasis in relation to PPAR-alpha, PPAR-gamma, and LPL mRNA expressions. Life sciences 79 15979095
2001 Inactive lipoprotein lipase (LPL) alone increases selective cholesterol ester uptake in vivo, whereas in the presence of active LPL it also increases triglyceride hydrolysis and whole particle lipoprotein uptake. The Journal of biological chemistry 79 11751882
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
2015 Aberrant LPL Expression, Driven by STAT3, Mediates Free Fatty Acid Metabolism in CLL Cells. Molecular cancer research : MCR 71 25733697
2021 ApoA5 lowers triglyceride levels via suppression of ANGPTL3/8-mediated LPL inhibition. Journal of lipid research 70 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 70 34803493
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 64 17600746
2015 Spectrum of mutations of the LPL gene identified in Italy in patients with severe hypertriglyceridemia. Atherosclerosis 62 25966443
2004 Long-term correction of murine lipoprotein lipase deficiency with AAV1-mediated gene transfer of the naturally occurring LPL(S447X) beneficial mutation. Human gene therapy 62 15353045
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 56 32504883
2019 Tumor suppressor ZHX2 inhibits NAFLD-HCC progression via blocking LPL-mediated lipid uptake. Cell death and differentiation 53 31740790
2016 Effect of Low-Power Laser (LPL) and Light-Emitting Diode (LED) on Inflammatory Response in Burn Wound Healing. Inflammation 53 27206919
2019 ApoC-III ASO promotes tissue LPL activity in the absence of apoE-mediated TRL clearance. Journal of lipid research 48 31092690
2017 Apolipoprotein C-III inhibits triglyceride hydrolysis by GPIHBP1-bound LPL. Journal of lipid research 47 28694296
2002 Effect of gender on phenotypic expression of the S447X mutation in LPL: the Copenhagen City Heart Study. Atherosclerosis 43 12208477
2022 An anti-ANGPTL3/8 antibody decreases circulating triglycerides by binding to a LPL-inhibitory leucine zipper-like motif. Journal of lipid research 42 35307397
2015 CETP/LPL/LIPC gene polymorphisms and susceptibility to age-related macular degeneration. Scientific reports 42 26503844
2015 Pathogenic classification of LPL gene variants reported to be associated with LPL deficiency. Journal of clinical lipidology 40 27055971
1998 Inhibition of LPL expression in human monocyte-derived macrophages is dependent on LDL oxidation state: a key role for lysophosphatidylcholine. Arteriosclerosis, thrombosis, and vascular biology 40 9672079
2016 Mobility of "HSPG-bound" LPL explains how LPL is able to reach GPIHBP1 on capillaries. Journal of lipid research 37 27811232
2008 The hepatic uptake of VLDL in lrp-ldlr-/-vldlr-/- mice is regulated by LPL activity and involves proteoglycans and SR-BI. Journal of lipid research 36 18367731
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 35 30591589
2018 MiR-27b Impairs Adipocyte Differentiation of Human Adipose Tissue-Derived Mesenchymal Stem Cells by Targeting LPL. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 34 29794473
2003 Lipoprotein lipase (LPL) gene variation and progression of carotid artery plaque. Stroke 34 12690214
2019 Role of LpL (Lipoprotein Lipase) in Macrophage Polarization In Vitro and In Vivo. Arteriosclerosis, thrombosis, and vascular biology 31 31434492
2010 Adiponectin increases LPL activity via RhoA/ROCK-mediated actin remodelling in adult rat cardiomyocytes. Endocrinology 31 21147877
2009 Genetic and epigenetic inactivation of LPL gene in human prostate cancer. International journal of cancer 31 19004026
2016 Identification and characterization of two novel mutations in the LPL gene causing type I hyperlipoproteinemia. Journal of clinical lipidology 30 27578112
2015 Insulin resistance caused by lipotoxicity is related to oxidative stress and endoplasmic reticulum stress in LPL gene knockout heterozygous mice. Atherosclerosis 30 25635326
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
2010 Effects of Glycyrrhizic Acid on Peroxisome Proliferator-Activated Receptor Gamma (PPARgamma), Lipoprotein Lipase (LPL), Serum Lipid and HOMA-IR in Rats. PPAR research 28 20011054
2007 Sex differences in abdominal, gluteal, and thigh LPL activity. American journal of physiology. Endocrinology and metabolism 28 17311894
2008 The association of common genetic variants in the APOA5, LPL and GCK genes with longitudinal changes in metabolic and cardiovascular traits. Diabetologia 27 19018513
2005 beta-Agonist stimulation produces changes in cardiac AMPK and coronary lumen LPL only during increased workload. American journal of physiology. Endocrinology and metabolism 27 15687106
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 26 37119902
2009 APOE, CETP and LPL genes show strong association with lipid levels in Greek children. Nutrition, metabolism, and cardiovascular diseases : NMCD 26 19403283
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
2022 The longitudinal triglyceride phenotype in heterozygotes with LPL pathogenic variants. Journal of clinical lipidology 24 36476373
2014 Molecular characterization of oxidative stress-inducible LipD of Mycobacterium tuberculosis H37Rv. Current microbiology 24 24232385
2003 Novel LPL mutation (L303F) found in a patient associated with coronary artery disease and severe systemic atherosclerosis. European journal of clinical investigation 24 12641539
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 23 36763533
2020 Artesunate inhibits atherosclerosis by upregulating vascular smooth muscle cells-derived LPL expression via the KLF2/NRF2/TCF7L2 pathway. European journal of pharmacology 23 32739175
2017 Biochemical Analysis of the Lipoprotein Lipase Truncation Variant, LPLS447X, Reveals Increased Lipoprotein Uptake. Biochemistry 23 27984852
2017 The complete genome sequence of Lactobacillus plantarum LPL-1, a novel antibacterial probiotic producing class IIa bacteriocin. Journal of biotechnology 23 29229543
2019 MicroRNA-224 impairs adipogenic differentiation of bovine preadipocytes by targeting LPL. Molecular and cellular probes 22 30703449
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
2017 MicroRNA-134 Promotes the Development of Atherosclerosis Via the ANGPTL4/LPL Pathway in Apolipoprotein E Knockout Mice. Journal of atherosclerosis and thrombosis 21 28867683
2016 Reduced LPL and subcutaneous lipid storage capacity are associated with metabolic syndrome in postmenopausal women with obesity. Obesity science & practice 21 28392937
2015 High adipose LPL activity and adipocyte hypertrophy reduce visceral fat and metabolic risk in obese, older women. Obesity (Silver Spring, Md.) 21 25612068
2015 Regional distribution of body fat in relation to DNA methylation within the LPL, ADIPOQ and PPARγ promoters in subcutaneous adipose tissue. Nutrition & diabetes 21 26148147
2014 A novel Lipoprotein lipase (LPL) agonist rescues the enzyme from inhibition by angiopoietin-like 4 (ANGPTL4). Bioorganic & medicinal chemistry letters 20 24703657
2010 Genetic variation in APOJ, LPL, and TNFRSF10B affects plasma fatty acid distribution in Alaskan Eskimos. The American journal of clinical nutrition 20 20410100
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 19 39392008
2022 CircRIC8B regulates the lipid metabolism of chronic lymphocytic leukemia through miR199b-5p/LPL axis. Experimental hematology & oncology 19 36064433
2021 Apolipoprotein E content of VLDL limits LPL-mediated triglyceride hydrolysis. Journal of lipid research 19 34863862
2018 Paeoniflorin regulates GALNT2-ANGPTL3-LPL pathway to attenuate dyslipidemia in mice. European journal of pharmacology 19 30096295
2017 Maternal Prenatal Folic Acid Supplementation Programs Offspring Lipid Metabolism by Aberrant DNA Methylation in Hepatic ATGL and Adipose LPL in Rats. Nutrients 19 28846595
2009 Genetic association study of selected candidate genes (ApoB, LPL, Leptin) and telomere length in obese and hypertensive individuals. BMC medical genetics 19 19772655
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
2019 A Novel Regulator of Preadipocyte Differentiation, Transcription Factor TCF21, Functions Partially Through Promoting LPL Expression. Frontiers in physiology 18 31065241
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
2022 Synergistic Inhibition of Plantaricin E/F and Lactic Acid Against Aeromonas hydrophila LPL-1 Reveals the Novel Potential of Class IIb Bacteriocin. Frontiers in microbiology 17 35242114
2016 Staphylococcus aureus Lpl Lipoproteins Delay G2/M Phase Transition in HeLa Cells. Frontiers in cellular and infection microbiology 17 28083519
2023 Decoding the role of angiopoietin-like protein 4/8 complex-mediated plasmin generation in the regulation of LPL activity. Journal of lipid research 16 37666362
2021 MicroRNA-432 inhibits milk fat synthesis by targeting SCD and LPL in ovine mammary epithelial cells. Food & function 16 34606535
2017 Mutating a conserved cysteine in GPIHBP1 reduces amounts of GPIHBP1 in capillaries and abolishes LPL binding. Journal of lipid research 16 28476858
2016 Monoclonal antibodies that bind to the Ly6 domain of GPIHBP1 abolish the binding of LPL. Journal of lipid research 16 27875259
2010 Variable effects of maternal and paternal-fetal contribution to the risk for preeclampsia combining GSTP1, eNOS, and LPL gene polymorphisms. The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians 16 20836743
2022 Landscape of immunoglobulin heavy chain gene repertoire and its clinical relevance to LPL/WM. Blood advances 15 35537114
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
2009 Variants of ESR1, APOE, LPL and IL-6 loci in young healthy subjects: association with lipid status and obesity. BMC research notes 15 19804633
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
2024 Macromolecular Interactions of Lipoprotein Lipase (LPL). Sub-cellular biochemistry 14 38963487
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 14 32256662
2019 Resistin up-regulates LPL expression through the PPARγ-dependent PI3K/AKT signaling pathway impacting lipid accumulation in RAW264.7 macrophages. Cytokine 14 30925325
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
2006 LPL-mediated lipolysis of VLDL induces an upregulation of AU-rich mRNAs and an activation of HuR in endothelial cells. Atherosclerosis 14 16494882
2004 Palmitoyl lysophosphatidylcholine mediated mobilization of LPL to the coronary luminal surface requires PKC activation. Journal of molecular and cellular cardiology 14 15522270
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
2018 Coexpression of novel furin-resistant LPL variants with lipase maturation factor 1 enhances LPL secretion and activity. Journal of lipid research 13 30318473
2017 ANGPTL3 is part of the machinery causing dyslipidemia majorily via LPL inhibition in mastitis mice. Experimental and molecular pathology 13 29104012
2012 1,3,5,8-tetrahydroxyxanthone regulates ANGPTL3-LPL pathway to lessen the ketosis in mice. European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences 13 22342712
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