Affinage

ANGPTL3

Angiopoietin-related protein 3 · UniProt Q9Y5C1

Length
460 aa
Mass
53.6 kDa
Annotated
2026-04-28
100 papers in source corpus 30 papers cited in narrative 30 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ANGPTL3 is a liver-secreted glycoprotein that functions as a central regulator of plasma lipoprotein metabolism by inhibiting lipoprotein lipase (LPL) and endothelial lipase, directing VLDL-triglyceride flux to white adipose tissue in the fed state. Its N-terminal coiled-coil domain is necessary and sufficient for LPL inhibition, while in vivo cleavage at Arg221/Arg224 by proprotein convertases — regulated by GALNT2-mediated O-glycosylation — is required for full activity; formation of a circulating complex with ANGPTL8 enhances LPL-inhibitory potency more than 100-fold, and this complex is physiologically antagonized by ApoA5, which competes for the same leucine zipper-like LPL-binding epitope (PMID:12097324, PMID:12909640, PMID:32487544, PMID:35307397, PMID:32999434). The C-terminal fibrinogen-like domain binds integrin αvβ3 on endothelial cells and macrophages to promote angiogenesis and pro-inflammatory macrophage activation via Akt and NF-κB signaling (PMID:11877390, PMID:38740260). Intracellularly, ANGPTL3 deficiency in hepatocytes reduces ApoB100 secretion by routing nascent ApoB to presecretory lysosomal degradation, revealing a cell-autonomous role in lipoprotein assembly independent of its extracellular lipase-inhibitory function (PMID:38219820).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2002 High

    Positional cloning of the KK/San hypolipidemic mouse and recombinant protein experiments established that ANGPTL3 is a secreted factor whose gain or loss directly controls circulating lipid levels, and that it acts by inhibiting LPL enzymatic activity in vitro and in vivo.

    Evidence Positional cloning, purified protein injection, adenoviral overexpression, in vitro LPL activity assay, radiolabeled VLDL turnover in mice

    PMID:11788823 PMID:12097324

    Open questions at the time
    • Mechanism of LPL inhibition at the molecular level not resolved
    • Relative contribution of LPL vs. other lipases unknown
    • Physiological context (fed vs. fasted) not addressed
  2. 2002 High

    Independent of lipase regulation, ANGPTL3's C-terminal fibrinogen-like domain was shown to bind integrin αvβ3 (not Tie2), activating endothelial adhesion, migration, and angiogenesis via FAK/Akt/MAPK signaling, establishing a second functional axis for the protein.

    Evidence Recombinant protein binding to αvβ3, haptotaxis migration assay, rat corneal angiogenesis, phosphorylation blots

    PMID:11877390

    Open questions at the time
    • Physiological relevance of integrin signaling in vivo under normal conditions unclear
    • Whether integrin binding contributes to lipid phenotype not tested
  3. 2003 High

    Domain dissection established that the N-terminal coiled-coil domain (residues 17–165) is necessary and sufficient for triglyceride elevation and LPL inhibition, and that in vivo proteolytic cleavage at Arg221/Arg224 is required for full systemic activity but not for in vitro LPL inhibition.

    Evidence Deletion mutagenesis, cleavage-resistant mutants, mass spectrometry of plasma fragments in mice

    PMID:12909640

    Open questions at the time
    • Identity of the in vivo protease not confirmed
    • How cleavage activates the N-terminal fragment mechanistically not known
  4. 2005 High

    Genetic epistasis with Angptl4 knockout mice revealed that ANGPTL3 functions predominantly in the fed state to suppress LPL, while ANGPTL4 operates in fasting, establishing nutritional-state-dependent partitioning of lipase regulation.

    Evidence Single and double KO mice, post-heparin LPL activity, plasma lipid measurements

    PMID:16081640 PMID:16508209

    Open questions at the time
    • Molecular basis for fed-state specificity of ANGPTL3 not identified
    • Role of hepatic lipase inhibition in the phenotype not fully delineated
  5. 2008 High

    Kinetic analysis clarified that ANGPTL3 and ANGPTL4 inhibit LPL through distinct biochemical mechanisms: ANGPTL3 reduces catalytic activity reversibly and is overcome by heparin, whereas ANGPTL4 induces irreversible inactivation resistant to heparin.

    Evidence Purified recombinant protein enzyme kinetics, heparin competition assay, site-directed mutagenesis

    PMID:19028676

    Open questions at the time
    • Structural basis for ANGPTL3's reversible inhibition not resolved
    • Whether these mechanisms apply to GPIHBP1-bound LPL not tested at this time
  6. 2012 High

    Discovery that ANGPTL8 physically associates with ANGPTL3 and is required for ANGPTL3-mediated hypertriglyceridemia at physiological expression levels established the ANGPTL3/8 complex as the functional unit of postprandial LPL suppression.

    Evidence Co-immunoprecipitation from plasma, AAV liver expression, epistasis in Angptl3−/− mice, hepatocyte culture

    PMID:23150577

    Open questions at the time
    • Stoichiometry and structure of the complex unknown
    • How ANGPTL8 activates ANGPTL3 mechanistically not determined
  7. 2015 High

    Antibody-mediated ANGPTL3 inactivation and tracer studies showed that ANGPTL3 controls VLDL-TG routing to white adipose tissue in the fed state and that its loss reduces hepatic VLDL-TG secretion and lowers HDL-C through an endothelial lipase-dependent mechanism, expanding ANGPTL3's role beyond LPL inhibition.

    Evidence Anti-ANGPTL3 antibody (REGN1500) in multiple KO backgrounds, radiolabeled VLDL-TG tissue uptake, EL-KO epistasis

    PMID:25954050 PMID:25964512 PMID:26305978

    Open questions at the time
    • Mechanism by which ANGPTL3 regulates hepatic VLDL-TG secretion not identified
    • Non-canonical LDL clearance pathways not molecularly defined
  8. 2017 High

    Mutagenesis of ANGPTL3's LPL-inhibitory residues showed that ANGPTL3 serves as a structural scaffold to activate ANGPTL8, which provides the dominant inhibitory activity in the complex, and that the complex potently inhibits GPIHBP1-bound LPL.

    Evidence Activity-null ANGPTL3 mutant, NanoBiT interaction assay, co-IP, LPL assays with GPIHBP1, Angptl8−/− mouse epistasis

    PMID:28413163 PMID:29031715

    Open questions at the time
    • Structural basis for scaffold function not resolved
    • Whether ANGPTL3 has any residual LPL inhibitory role in the complex in vivo unclear
  9. 2020 High

    Quantitative biochemistry demonstrated >100-fold potentiation of LPL inhibition by ANGPTL3/8 complex vs. ANGPTL3 alone and revealed that insulin drives hepatic ANGPTL3/8 secretion, linking the complex to postprandial physiology; separately, GALNT2-mediated O-glycosylation was shown to block proprotein convertase cleavage of ANGPTL3, providing a post-translational regulatory switch.

    Evidence Quantitative LPL inhibition assays, hepatocyte insulin stimulation, human serum immunoassay, GALNT2 gain/loss-of-function in primary hepatocytes and mice

    PMID:32487544 PMID:32999434

    Open questions at the time
    • Identity of the specific proprotein convertase(s) responsible for in vivo cleavage not confirmed
    • How insulin signaling converges on ANGPTL8 co-secretion with ANGPTL3 not resolved
  10. 2021 High

    ApoA5 was identified as a selective physiological antagonist of the ANGPTL3/8 complex — it binds the complex (but not ANGPTL3, ANGPTL4, or ANGPTL4/8 alone) and suppresses its LPL-inhibitory activity, providing a counterregulatory mechanism for postprandial triglyceride clearance.

    Evidence IP-MS from human serum, biolayer interferometry, kinetic LPL inhibition assays with specificity controls

    PMID:33762177

    Open questions at the time
    • Binding affinity and stoichiometry of ApoA5 for the complex not precisely determined
    • In vivo contribution of ApoA5 antagonism to fed-state TG handling not quantified
  11. 2022 High

    HDX-MS epitope mapping revealed that LPL and ApoA5 compete for the same leucine zipper-like epitope on the ANGPTL3/8 complex, formed by N-terminal regions of both subunits and unmasked only upon complex formation, providing a structural explanation for ApoA5-mediated antagonism.

    Evidence Hydrogen-deuterium exchange MS, molecular modeling, biolayer interferometry, antibody targeting of the epitope in vitro and in vivo

    PMID:35307397

    Open questions at the time
    • Full atomic-resolution structure of the ANGPTL3/8 complex not available
    • Whether additional co-factors modulate epitope accessibility in vivo not known
  12. 2024 High

    Multiple 2024 studies expanded ANGPTL3's mechanism in three directions: (1) the C-terminal FLD activates macrophage integrin αvβ3–Akt–TLR4–NF-κB signaling to promote M1 polarization in atherosclerotic plaques; (2) intracellular ANGPTL3 deficiency in hepatocytes reduces ApoB100 secretion by diverting nascent ApoB to presecretory lysosomal degradation; (3) ApoA5's C-terminal ~35–40 residues are essential for suppressing ANGPTL3/8-mediated LPL inhibition and LPL detachment from endothelium.

    Evidence CRISPR KO of integrin β3 in THP-1 and ANGPTL3 in HepG2, AAV overexpression in Ldlr−/− mice, ApoA5 truncation mutagenesis in Apoa5−/− mice, GPIHBP1-LPL activity assay in large human cohorts

    PMID:38219820 PMID:38625948 PMID:38740260 PMID:39392008

    Open questions at the time
    • Whether intracellular ANGPTL3 function involves a specific binding partner for ApoB routing is unknown
    • Relative contribution of integrin αvβ3 macrophage signaling vs. lipase inhibition to atherosclerosis not separated in vivo
    • Full structural model of ApoA5–ANGPTL3/8 ternary complex not available

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include the atomic-resolution structure of the ANGPTL3/8 complex and its ternary interactions with LPL and ApoA5, the identity of the proprotein convertase responsible for in vivo cleavage, the molecular mechanism by which intracellular ANGPTL3 regulates ApoB100 presecretory degradation, and whether central nervous system ANGPTL3 has physiologically meaningful metabolic roles independent of hepatic secretion.
  • No high-resolution structure of the ANGPTL3/8 complex
  • Proprotein convertase identity for Arg221/224 cleavage unresolved
  • Intracellular binding partners mediating ApoB routing unknown
  • Central ANGPTL3 function reported by single lab only

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 8 GO:0008289 lipid binding 1
Localization
GO:0005576 extracellular region 6 GO:0005829 cytosol 1
Pathway
R-HSA-1430728 Metabolism 8 R-HSA-162582 Signal Transduction 2 R-HSA-392499 Metabolism of proteins 2
Partners
ANGPTL8APOA5GALNT2HNF1AITGB3LIPGLPL
Complex memberships
ANGPTL3/ANGPTL8 complex

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 ANGPTL3 directly inhibits lipoprotein lipase (LPL) activity in vitro, reducing VLDL-triglyceride clearance. Overexpression in KK/San mutant mice raised plasma triglycerides and VLDL, while turnover studies confirmed enhanced VLDL-TG clearance in mutant mice lacking Angptl3. In vitro LPL activity assay with recombinant ANGPTL3 protein; in vivo VLDL turnover with radiolabeled VLDL; adenoviral overexpression in mice The Journal of biological chemistry High 12097324
2002 Angptl3 regulates circulating lipid levels in mice; overexpression or injection of purified Angptl3 protein increases plasma lipid levels, and loss-of-function mutation causes hypolipidemia. The protein was positionally cloned from the KK/San hypolipidemic mouse. Positional cloning; adenoviral overexpression; intravenous injection of purified protein in KK/San and C57BL/6J mice Nature genetics High 11788823
2002 ANGPTL3 binds integrin αvβ3 (not Tie2 receptor) via its C-terminal fibrinogen-like domain, inducing integrin αvβ3-dependent endothelial cell adhesion, migration, and angiogenesis in vivo, and activating Akt, MAPK, and FAK signaling. Co-immunoprecipitation (failed for Tie2); recombinant protein binding assay to αvβ3; haptotaxis migration assay; rat corneal angiogenesis assay; phosphorylation assays The Journal of biological chemistry High 11877390
2003 The N-terminal coiled-coil domain (residues 17-165) of ANGPTL3 is necessary and sufficient for raising plasma triglycerides and inhibiting LPL. ANGPTL3 is cleaved in vivo at Arg221-Ala222 and Arg224-Thr225 (between the coiled-coil and fibrinogen-like domains), and this cleavage is required for full in vivo activity in raising plasma triglycerides but not for in vitro LPL inhibition. Deletion mutagenesis in mice; recombinant protein analysis; mass spectrometry of plasma cleavage fragments; cleavage-resistant mutant comparison The Journal of biological chemistry High 12909640
2005 Angptl3-deficient mice display hypotriglyceridemia with elevated post-heparin LPL activity predominantly in the fed state, while Angptl4-deficient mice show a greater effect in the fasted state, demonstrating that Angptl3 and Angptl4 regulate LPL during different nutritional states. Double knockout mice show additive effects. Targeted gene disruption in mice; plasma lipid measurements; post-heparin LPL activity assay; in vitro LPL inhibition with purified recombinant Angptl4 Endocrinology High 16081640
2006 Angptl3-null mice show elevated post-heparin LPL and hepatic lipase activities (1.57-fold and 1.42-fold, respectively) with accelerated triglyceride clearance, confirming that ANGPTL3 inhibits both LPL and hepatic lipase in vivo. Angptl3 knockout mouse model; post-heparin lipase activity assay; triglyceride clearance study Experimental animals High 16508209
2006 Thyroid hormone negatively regulates ANGPTL3 transcription via TRβ in a DNA-binding-independent manner, requiring the HNF1 site in the proximal ANGPTL3 promoter. TRβ antagonizes HNF1α transcriptional activity without interfering with its DNA binding. In vivo hypothyroid rat model; TRβ-deficient mice; transfection/luciferase reporter assays; site-directed mutagenesis; electrophoretic mobility shift assay The Journal of biological chemistry High 16505486
2008 ANGPTL3 and ANGPTL4 inhibit LPL through distinct mechanisms: ANGPTL3 reduces LPL catalytic activity without altering its self-inactivation rate and its effect is overcome by heparin, whereas ANGPTL4 accelerates irreversible LPL inactivation in a heparin-resistant manner. Glu40 in ANGPTL4 is critical by mutagenesis. Enzyme kinetic analysis with purified recombinant proteins; heparin competition assay; site-directed mutagenesis of ANGPTL4 The Journal of biological chemistry High 19028676
2012 ANGPTL8 co-immunoprecipitates with the N-terminal domain of ANGPTL3 in plasma. Co-expression of ANGPTL8 with physiological levels of ANGPTL3 in mouse liver causes hypertriglyceridemia (whereas ANGPTL3 alone does not), and ANGPTL8 increases the appearance of N-terminal ANGPTL3 in hepatocyte culture medium. In Angptl3-/- mice, ANGPTL8 expression fails to cause hypertriglyceridemia, placing ANGPTL8 upstream of or dependent on ANGPTL3. Co-immunoprecipitation from plasma; adeno-associated virus liver expression; epistasis in Angptl3-/- mice; hepatocyte culture Proceedings of the National Academy of Sciences of the United States of America High 23150577
2015 Inactivation of ANGPTL3 with a monoclonal antibody (REGN1500) reduces hepatic VLDL-TG secretion by 61% without altering ApoB-100 particle number, and does not affect canonical clearance pathways (ApoE, LDLR, LRP1, Sdc1). The low LDL-C is attributed to altered VLDL particle composition leading to faster clearance via non-canonical pathways. Anti-ANGPTL3 antibody treatment in mice with single or compound knockouts of lipoprotein clearance receptors; radiolabeled VLDL and LDL clearance studies; hepatic lipid synthesis measurements Journal of lipid research High 25954050
2015 REGN1500 anti-ANGPTL3 antibody reverses ANGPTL3-induced LPL inhibition in vitro, increases LPL activity and lowers plasma TG in mice, and reduces HDL-C through an endothelial lipase (EL)-dependent mechanism (shown using EL knockout mice). In vitro LPL activity rescue assay; EL knockout mouse model; antibody administration to normolipidemic and dyslipidemic mice and monkeys Journal of lipid research High 25964512
2015 ANGPTL3 is required for postprandial routing of VLDL-TG to white adipose tissue (WAT). Angptl3-/- mice fail to increase VLDL-TG uptake into WAT upon feeding; compensatory de novo lipogenesis from glucose occurs in WAT, explaining increased insulin sensitivity with ANGPTL3 loss. Angptl3-/- mouse model; radiolabeled VLDL-TG uptake studies across tissues; glucose tracer studies; lipogenesis assays Proceedings of the National Academy of Sciences of the United States of America High 26305978
2017 ANGPTL8 requires ANGPTL3 expression to inhibit LPL and raise plasma TG. Using a mutant ANGPTL3 lacking LPL-inhibitory activity, ANGPTL3 structural scaffolding (not its LPL inhibitory function) is sufficient to activate ANGPTL8. The major inhibitory activity of the complex derives from ANGPTL8, and an antibody to the C-terminus of ANGPTL8 reversed LPL inhibition without disrupting the complex. Adenoviral expression; ANGPTL3 activity-null mutant; antibody epitope mapping; LPL activity assay; in vivo TG measurement Journal of lipid research High 28413163
2017 ANGPTL8 physically interacts with ANGPTL3 (co-immunoprecipitation, NanoBiT split-luciferase), and the ANGPTL3-ANGPTL8 complex has dramatically increased ability to inhibit LPL (especially GPIHBP1-bound LPL) compared to either protein alone. ANGPTL8 increases ANGPTL3's binding to LPL; adenovirus overexpression of ANGPTL3 raises plasma TG only in the presence of endogenous ANGPTL8. Co-immunoprecipitation; NanoBiT split-luciferase protein interaction assay; LPL activity assay; adenoviral overexpression in Angptl8-/- mice Molecular metabolism High 29031715
2018 Mice lacking both ANGPTL3 and ANGPTL8 (A3A8 mice) have decreased fat mass and feeding-induced hyperthermia (+1°C) with beiging of subcutaneous WAT, due to increased β3-adrenergic receptor-dependent thermogenesis. Antibody-mediated inactivation of both circulating A3 and A8 also induced hyperthermia in wild-type mice. Double knockout mouse model; temperature measurement; O2 consumption; gene expression; β3-AR antagonist/agonist pharmacology; antibody blockade Proceedings of the National Academy of Sciences of the United States of America High 29358393
2018 Crystal structures of the fibrinogen-like domain of ANGPTL3 (and ANGPTL4) were solved, providing structural insights into loss-of-function mutations and the mechanism of action. X-ray crystallography Scientific reports Medium 29713054
2020 ANGPTL3/8 complex (postprandially increased) inhibits LPL with >100-fold greater potency than ANGPTL3 alone, while ANGPTL4/8 complex is >100-fold less potent than ANGPTL4 alone. The ANGPTL3/8 complex also blocks LPL-facilitated hepatocyte VLDL-C uptake. Insulin increases ANGPTL3/8 secretion from hepatocytes and ANGPTL4/8 from adipocytes. Quantitative LPL inhibition assay; complex immunoassay in human serum; cell-based LPL-facilitated uptake assay; competition assays; hepatocyte and adipocyte culture with insulin Journal of lipid research High 32487544
2020 GALNT2-mediated O-glycosylation near the ANGPTL3 cleavage site inhibits proprotein convertase (PC)-mediated cleavage of ANGPTL3 in primary hepatocytes and in vivo in mice. GALNT2 overexpression blocks cleavage; GALNT2 knockdown increases cleavage dramatically. Primary hepatocyte culture; adeno-associated virus-mediated GALNT2 overexpression and knockdown in mice; PC inhibitor treatment; western blot for cleavage fragments Scientific reports High 32999434
2021 ApoA5 associates with the ANGPTL3/8 complex in human serum and lowers TG by suppressing ANGPTL3/8-mediated LPL inhibition. ApoA5 has no direct effect on LPL and does not suppress ANGPTL3, ANGPTL4, or ANGPTL4/8 alone. Immunoprecipitation-MS; biolayer interferometry; LPL activity assay; kinetic analysis of LPL inhibition Journal of lipid research High 33762177
2022 LPL and ApoA5 both bind the same ANGPTL3/8 epitope consisting of N-terminal regions of ANGPTL3 and ANGPTL8 (a leucine zipper-like motif unmasked upon complex formation). An anti-ANGPTL3/8 antibody targeting this epitope potently blocks ANGPTL3/8-mediated LPL inhibition in vitro and dramatically lowers TG in vivo. Hydrogen-deuterium exchange mass spectrometry; molecular modeling; biolayer interferometry; LPL activity assay; in vivo mouse TG measurement Journal of lipid research High 35307397
2022 Human genetic mimicry analysis shows that the ANGPTL3-ANGPTL8 complex targets both LPL and endothelial lipase (EL/LIPG) in humans, while ANGPTL4 impacts plasma metabolic parameters exclusively via LPL. Genetic mimicry analysis using UK Biobank data (n>110,000) with validated European cohorts; Mendelian randomization-type approach comparing LPL/EL/HL genetic variants with ANGPTL variants Journal of lipid research Medium 36372100
2019 ANGPTL3 binds vasodilator-stimulated phosphoprotein (VASP) and inhibits VASP phosphorylation at amino acid 157 in renal cell carcinoma cells, suppressing metastatic ability. Pulldown/binding assay; western blot for phospho-VASP; ANGPTL3 overexpression with invasion/migration assays Biochemical and biophysical research communications Low 31270029
2019 miR-181d directly binds to and represses the ANGPTL3 transcript (3'-UTR-luciferase assay), providing a post-transcriptional regulatory mechanism for ANGPTL3 expression. 3'-UTR luciferase reporter assay; miR-181d overexpression in hepatocyte cell culture; RT-PCR and ELISA Scientific reports Medium 31413305
2020 Statin treatment reduces plasma ANGPTL3 concentrations via decreased oxysterol-mediated liver X receptor (LXR) activation. Simvastatin reduces intracellular oxysterol levels, diminishing LXR-driven ANGPTL3 transcription and secretion in human hepatoma cells. Clinical comparison of statin-treated vs. naïve FH patients; statin discontinuation study; Huh7 cell culture with LXR agonist/antagonist; oxysterol measurement; ANGPTL3 mRNA and protein quantification Atherosclerosis Medium 33242792
2024 ANGPTL3's C-terminal fibrinogen-like domain acts as a ligand for macrophage integrin αvβ3 in atherosclerotic plaques, inducing Akt phosphorylation and upregulating TLR4 expression, which amplifies NF-κB activity and M1 macrophage activation (IL-1β, TNF-α). Integrin β3-deficient THP-1 cells show attenuated Akt phosphorylation in response to ANGPTL3. AAV-mediated Angptl3 overexpression in Ldlr-/- and ApoE-/- mice; FLAG-tagged protein tracing; phospho-proteomics; CRISPR-Cas9 integrin β3 knockout in THP-1; Western blot; MILLIPLEX cytokine assay; NF-κB reporter assay Journal of advanced research Medium 38740260
2024 ANGPTL3 deficiency in hepatocytes (CRISPR KO) reduces ApoB100 secretion (~50%) by increasing early presecretory lysosomal degradation of ApoB100, accompanied by decreased triglyceride secretion and increased fatty acid oxidation. When LDLR is also absent, ANGPTL3 deficiency instead promotes late presecretory proteasomal regulation of ApoB100 without impaired secretion, and rescues LDL clearance. CRISPR/Cas9 ANGPTL3 KO in HepG2 cells; double ANGPTL3/LDLR KO; ApoB100 secretion assays; lysosomal/proteasomal inhibitor treatments; targeted lipidomics; RNA sequencing Journal of lipid research High 38219820
2024 C-terminal sequences in APOA5 (last ~35-40 residues) are essential for suppressing ANGPTL3/8's ability to inhibit LPL catalytic activity and to detach LPL from endothelial binding sites. Truncated APOA5 mutants (APOA5Δ35 and APOA5Δ40) fail to suppress ANGPTL3/8, and an antibody against the C-terminal peptide of APOA5 raised plasma TG in mice. Recombinant protein LPL activity assay; in vivo mouse TG measurements in Apoa5-/- mice; endothelial LPL detachment assay; antibody blocking experiment Proceedings of the National Academy of Sciences of the United States of America High 38625948
2024 ANGPTL3/8 potently inhibits GPIHBP1-bound LPL enzymatic activity (confirmed by recombinant protein assay), and circulating ANGPTL3/8 complex levels positively associate with LDL-C and triglycerides in two large human cohorts. Recombinant protein GPIHBP1-LPL activity assay; dedicated immunoassays for ANGPTL3/8 complex in 2394 and 6188 human participants Circulation High 39392008
2014 Angptl3 is expressed in neurons of the mediobasal hypothalamus and acts centrally to regulate energy balance. Intracerebroventricular (ICV) Angptl3 stimulates hypothalamic LPL activity and increases long-chain fatty acid levels in the hypothalamus. Suppression of hypothalamic Angptl3 increases food intake and reduces energy expenditure; co-administration of ApoC3 (LPL inhibitor) antagonizes Angptl3's central metabolic effects. Hypothalamic Angptl3 suppression (viral delivery); ICV protein injection; LPL activity assay; lipid-sensing pathway inhibitors; hypothalamic LCFA-CoA measurement Diabetes Medium 25338813
2024 ANGPTL3 downregulation in hepatocytes (siRNA) increases intracellular neutral lipid content by reducing deiodinase type 1 (DIO1) protein levels, thereby decreasing β-oxidation and causing triglyceride accumulation in lipid droplets. siRNA knockdown of ANGPTL3 in 3D hepatocyte spheroids and 2D cell lines; DIO1 protein measurement; β-oxidation assay; neutral lipid staining Arteriosclerosis, thrombosis, and vascular biology Medium 38385290

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease. The New England journal of medicine 684 28538136
2010 Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. The New England journal of medicine 589 20942659
2017 Cardiovascular and Metabolic Effects of ANGPTL3 Antisense Oligonucleotides. The New England journal of medicine 492 28538111
2012 Atypical angiopoietin-like protein that regulates ANGPTL3. Proceedings of the National Academy of Sciences of the United States of America 384 23150577
2017 ANGPTL3 Deficiency and Protection Against Coronary Artery Disease. Journal of the American College of Cardiology 383 28385496
2005 Transgenic angiopoietin-like (angptl)4 overexpression and targeted disruption of angptl4 and angptl3: regulation of triglyceride metabolism. Endocrinology 362 16081640
2002 Angptl3 regulates lipid metabolism in mice. Nature genetics 354 11788823
2002 ANGPTL3 decreases very low density lipoprotein triglyceride clearance by inhibition of lipoprotein lipase. The Journal of biological chemistry 320 12097324
2021 Lipid nanoparticle-mediated codelivery of Cas9 mRNA and single-guide RNA achieves liver-specific in vivo genome editing of Angptl3. Proceedings of the National Academy of Sciences of the United States of America 314 33649229
2020 Vupanorsen, an N-acetyl galactosamine-conjugated antisense drug to ANGPTL3 mRNA, lowers triglycerides and atherogenic lipoproteins in patients with diabetes, hepatic steatosis, and hypertriglyceridaemia. European heart journal 223 32860031
2002 ANGPTL3 stimulates endothelial cell adhesion and migration via integrin alpha vbeta 3 and induces blood vessel formation in vivo. The Journal of biological chemistry 222 11877390
2003 Protein region important for regulation of lipid metabolism in angiopoietin-like 3 (ANGPTL3): ANGPTL3 is cleaved and activated in vivo. The Journal of biological chemistry 187 12909640
2015 ANGPTL3 blockade with a human monoclonal antibody reduces plasma lipids in dyslipidemic mice and monkeys. Journal of lipid research 181 25964512
2017 ANGPTL8 requires ANGPTL3 to inhibit lipoprotein lipase and plasma triglyceride clearance. Journal of lipid research 177 28413163
2016 The ANGPTL3-4-8 model, a molecular mechanism for triglyceride trafficking. Open biology 176 27053679
2024 Zodasiran, an RNAi Therapeutic Targeting ANGPTL3, for Mixed Hyperlipidemia. The New England journal of medicine 161 38809174
2015 Inactivation of ANGPTL3 reduces hepatic VLDL-triglyceride secretion. Journal of lipid research 161 25954050
2017 ANGPTL8 promotes the ability of ANGPTL3 to bind and inhibit lipoprotein lipase. Molecular metabolism 157 29031715
2013 Angptl3 deficiency is associated with increased insulin sensitivity, lipoprotein lipase activity, and decreased serum free fatty acids. Arteriosclerosis, thrombosis, and vascular biology 140 23661675
2012 Mutations in the ANGPTL3 gene and familial combined hypolipidemia: a clinical and biochemical characterization. The Journal of clinical endocrinology and metabolism 136 22659251
2020 Angiopoietin-like protein 8 differentially regulates ANGPTL3 and ANGPTL4 during postprandial partitioning of fatty acids. Journal of lipid research 132 32487544
2015 Hepatic ANGPTL3 regulates adipose tissue energy homeostasis. Proceedings of the National Academy of Sciences of the United States of America 123 26305978
2008 The angiopoietin-like proteins ANGPTL3 and ANGPTL4 inhibit lipoprotein lipase activity through distinct mechanisms. The Journal of biological chemistry 118 19028676
2011 Characterization of three kindreds with familial combined hypolipidemia caused by loss-of-function mutations of ANGPTL3. Circulation. Cardiovascular genetics 110 22062970
2017 Role of angiopoietin-like 3 (ANGPTL3) in regulating plasma level of low-density lipoprotein cholesterol. Atherosclerosis 94 29183623
2016 The role of ANGPTL3 in controlling lipoprotein metabolism. Endocrine 90 26754661
2006 Angptl3-null mice show low plasma lipid concentrations by enhanced lipoprotein lipase activity. Experimental animals 86 16508209
2023 RNA interference targeting ANGPTL3 for triglyceride and cholesterol lowering: phase 1 basket trial cohorts. Nature medicine 83 37626170
2021 ANGPTL3 Inhibition With Evinacumab Results in Faster Clearance of IDL and LDL apoB in Patients With Homozygous Familial Hypercholesterolemia-Brief Report. Arteriosclerosis, thrombosis, and vascular biology 82 33691480
2021 Local delivery of USC-derived exosomes harboring ANGPTL3 enhances spinal cord functional recovery after injury by promoting angiogenesis. Stem cell research & therapy 76 33413639
2021 ApoA5 lowers triglyceride levels via suppression of ANGPTL3/8-mediated LPL inhibition. Journal of lipid research 70 33762177
2021 An updated ANGPTL3-4-8 model as a mechanism of triglyceride partitioning between fat and oxidative tissues. Progress in lipid research 68 34793860
2020 Pharmacological aspects of ANGPTL3 and ANGPTL4 inhibitors: New therapeutic approaches for the treatment of atherogenic dyslipidemia. Pharmacological research 68 31931117
2012 Prevalence of ANGPTL3 and APOB gene mutations in subjects with combined hypolipidemia. Arteriosclerosis, thrombosis, and vascular biology 68 22247256
2016 Circulating angiopoietin-like protein 8 (ANGPTL8) and ANGPTL3 concentrations in relation to anthropometric and metabolic profiles in Korean children: a prospective cohort study. Cardiovascular diabetology 66 26739706
2022 Broadening the Scope of Dyslipidemia Therapy by Targeting APOC3 (Apolipoprotein C3) and ANGPTL3 (Angiopoietin-Like Protein 3). Arteriosclerosis, thrombosis, and vascular biology 65 36579649
2004 ANGPTL3 is increased in both insulin-deficient and -resistant diabetic states. Biochemical and biophysical research communications 65 15094378
2021 ANGPTL3 as therapeutic target. Current opinion in lipidology 64 34581310
2015 ANGPTL3 is a novel biomarker as it activates ERK/MAPK pathway in oral cancer. Cancer medicine 62 25644496
2006 The lipoprotein lipase inhibitor ANGPTL3 is negatively regulated by thyroid hormone. The Journal of biological chemistry 62 16505486
2021 Angiopoietin-Like Protein 3 (ANGPTL3) Modulates Lipoprotein Metabolism and Dyslipidemia. International journal of molecular sciences 59 34298929
2011 Identification of a novel mutation in the ANGPTL3 gene in two families diagnosed of familial hypobetalipoproteinemia without APOB mutation. Clinica chimica acta; international journal of clinical chemistry 58 22155345
2021 ANGPTL3 and Apolipoprotein C-III as Novel Lipid-Lowering Targets. Current atherosclerosis reports 55 33694000
2018 Angiopoietin-Like 3 (ANGPTL3) and Atherosclerosis: Lipid and Non-Lipid Related Effects. Journal of cardiovascular development and disease 53 30011918
2018 Increased thermogenesis by a noncanonical pathway in ANGPTL3/8-deficient mice. Proceedings of the National Academy of Sciences of the United States of America 43 29358393
2018 Structures of Angptl3 and Angptl4, modulators of triglyceride levels and coronary artery disease. Scientific reports 43 29713054
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
2025 Durability and efficacy of solbinsiran, a GalNAc-conjugated siRNA targeting ANGPTL3, in adults with mixed dyslipidaemia (PROLONG-ANG3): a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet (London, England) 39 40179932
2023 ANGPTL3 inhibition, dyslipidemia, and cardiovascular diseases. Trends in cardiovascular medicine 39 36746257
2022 ANGPTL3 as a Drug Target in Hyperlipidemia and Atherosclerosis. Current atherosclerosis reports 39 36367663
2019 ANGPTL3: a novel biomarker and promising therapeutic target. Journal of drug targeting 39 30615486
2021 Vaccine targeting ANGPTL3 ameliorates dyslipidemia and associated diseases in mouse models of obese dyslipidemia and familial hypercholesterolemia. Cell reports. Medicine 38 34841293
2020 A randomized study investigating the safety, tolerability, and pharmacokinetics of evinacumab, an ANGPTL3 inhibitor, in healthy Japanese and Caucasian subjects. Atherosclerosis 38 33130482
2021 Monoclonal Antibodies in the Management of Familial Hypercholesterolemia: Focus on PCSK9 and ANGPTL3 Inhibitors. Current atherosclerosis reports 35 34698927
2012 Triacylglycerol-rich lipoproteins protect lipoprotein lipase from inactivation by ANGPTL3 and ANGPTL4. Biochimica et biophysica acta 33 22732211
2024 Drug-target Mendelian randomization analysis supports lowering plasma ANGPTL3, ANGPTL4, and APOC3 levels as strategies for reducing cardiovascular disease risk. European heart journal open 31 38895109
2015 A vital role for Angptl3 in the PAN-induced podocyte loss by affecting detachment and apoptosis in vitro. BMC nephrology 31 25884163
2023 Advances in Dyslipidaemia Treatments: Focusing on ApoC3 and ANGPTL3 Inhibitors. Journal of lipid and atherosclerosis 30 38299167
2019 Angiopoietin-like protein 3 (ANGPTL3) deficiency and familial combined hypolipidemia. Journal of biomedical research 30 29752428
2018 New medications targeting triglyceride-rich lipoproteins: Can inhibition of ANGPTL3 or apoC-III reduce the residual cardiovascular risk? Atherosclerosis 30 29544086
2011 Effects of ANGPTL3 antisense oligodeoxynucleotides transfection on the cell growths and invasion of human hepatocellular carcinoma cells. Hepato-gastroenterology 30 21940333
2025 Phase 1 Trial of CRISPR-Cas9 Gene Editing Targeting ANGPTL3. The New England journal of medicine 28 41211945
2022 Angiopoietin-Like Protein 3 (ANGPTL3) Inhibitors in the Management of Refractory Hypercholesterolemia. Clinical pharmacology : advances and applications 28 35873366
2021 Selective targeting of angiopoietin-like 3 (ANGPTL3) with vupanorsen for the treatment of patients with familial partial lipodystrophy (FPLD): results of a proof-of-concept study. Lipids in health and disease 26 34865644
2023 Liver-specific in vivo base editing of Angptl3 via AAV delivery efficiently lowers blood lipid levels in mice. Cell & bioscience 24 37322547
2016 Different relationship between ANGPTL3 and HDL components in female non-diabetic subjects and type-2 diabetic patients. Cardiovascular diabetology 24 27620179
2022 Angiopoietin-like 3 (ANGPTL3) drives cell proliferation, migration and angiogenesis in cervical cancer via binding to integrin alpha v beta 3. Bioengineered 23 35038961
2019 Reduced miR-181d level in obesity and its role in lipid metabolism via regulation of ANGPTL3. Scientific reports 23 31413305
2018 Fenofibrate Exerts Protective Effects in Diabetic Retinopathy via Inhibition of the ANGPTL3 Pathway. Investigative ophthalmology & visual science 23 30128492
2023 ANGPTL3 Deficiency and Risk of Hepatic Steatosis. Circulation 21 37712257
2022 Genetic Mimicry Analysis Reveals the Specific Lipases Targeted by the ANGPTL3-ANGPTL8 Complex and ANGPTL4. Journal of lipid research 21 36372100
2022 Podocyte protection by Angptl3 knockout via inhibiting ROS/GRP78 pathway in LPS-induced acute kidney injury. International immunopharmacology 20 35086056
2020 GALNT2 regulates ANGPTL3 cleavage in cells and in vivo of mice. Scientific reports 20 32999434
2024 ANGPTL3 accelerates atherosclerotic progression via direct regulation of M1 macrophage activation in plaque. Journal of advanced research 19 38740260
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
2018 Paeoniflorin regulates GALNT2-ANGPTL3-LPL pathway to attenuate dyslipidemia in mice. European journal of pharmacology 19 30096295
2015 Post-GWAS methodologies for localisation of functional non-coding variants: ANGPTL3. Atherosclerosis 19 26800306
2021 Association between ANGPTL3, 4, and 8 and lipid and glucose metabolism markers in patients with diabetes. PloS one 18 34293055
2021 Transcriptomic therapy for dyslipidemias utilizing nucleic acids targeted at ANGPTL3. Future cardiology 18 34651521
2019 ANGPTL3 inhibits renal cell carcinoma metastasis by inhibiting VASP phosphorylation. Biochemical and biophysical research communications 18 31270029
2020 Structure and Function of Angiopoietin-like Protein 3 (ANGPTL3) in Atherosclerosis. Current medicinal chemistry 17 31223079
2009 Plasma angiopoietin-like protein 3 (ANGPTL3) concentration is associated with uremic dyslipidemia. Atherosclerosis 17 19540497
2025 Effect of ANGPTL3 Inhibition With Solbinsiran in Preclinical and Early Human Studies. Journal of the American College of Cardiology 15 40158211
2024 ANGPTL3 and ApoC-III inhibitors for treating hypertriglyceridemia in context: horses for courses? Current opinion in lipidology 15 38372218
2024 Reductions in remnant cholesterol and VLDL cholesterol through inhibition of ANGPTL3 protein synthesis: an analysis from the TRANSLATE-TIMI 70 trial. European journal of preventive cardiology 15 38484368
2014 Regulation of energy balance by the hypothalamic lipoprotein lipase regulator Angptl3. Diabetes 15 25338813
2006 Cloning, chromosome mapping and expression characteristics of porcine ANGPTL3 and -4. Cytogenetic and genome research 15 16717449
2024 Inhibition of the ANGPTL3/8 Complex for the Prevention and Treatment of Atherosclerotic Cardiovascular Disease. Current atherosclerosis reports 14 39565562
2020 ANGPTL3 deficiency alters the lipid profile and metabolism of cultured hepatocytes and human lipoproteins. Biochimica et biophysica acta. Molecular and cell biology of lipids 14 32151767
2020 Statin therapy reduces plasma angiopoietin-like 3 (ANGPTL3) concentrations in hypercholesterolemic patients via reduced liver X receptor (LXR) activation. Atherosclerosis 14 33242792
2019 Molecular analysis of APOB, SAR1B, ANGPTL3, and MTTP in patients with primary hypocholesterolemia in a clinical laboratory setting: Evidence supporting polygenicity in mutation-negative patients. Atherosclerosis 14 30782561
2015 Functional variants of lipid level modifier MLXIPL, GCKR, GALNT2, CILP2, ANGPTL3 and TRIB1 genes in healthy Roma and Hungarian populations. Pathology oncology research : POR 14 25573592
2024 ANGPTL3 deficiency impairs lipoprotein production and produces adaptive changes in hepatic lipid metabolism. Journal of lipid research 13 38219820
2024 ANGPTL3 Downregulation Increases Intracellular Lipids by Reducing Energy Utilization. Arteriosclerosis, thrombosis, and vascular biology 13 38385290
2024 Carboxyl-terminal sequences in APOA5 are important for suppressing ANGPTL3/8 activity. Proceedings of the National Academy of Sciences of the United States of America 13 38625948
2022 ANGPTL3 impacts proteinuria and hyperlipidemia in primary nephrotic syndrome. Lipids in health and disease 13 35399079
2021 A haplotype of the ANGPTL3 gene is associated with CVD risk, diabetes mellitus, hypertension, obesity, metabolic syndrome, and dyslipidemia. Gene 13 33636293
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
2022 Targeting ANGPTL3 by GalNAc-conjugated siRNA ANGsiR10 lowers blood lipids with long-lasting and potent efficacy in mice and monkeys. Molecular therapy. Nucleic acids 12 36618267