Affinage

ANGPTL3

Angiopoietin-related protein 3 · UniProt Q9Y5C1

Length
460 aa
Mass
53.6 kDa
Annotated
2026-06-09
100 papers in source corpus 30 papers cited in narrative 30 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/9 claims corpus-supported (89%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ANGPTL3 is a liver-secreted regulator of plasma lipid metabolism that controls the partitioning of circulating triglycerides by inhibiting lipoprotein lipase (LPL) (PMID:12097324, PMID:11788823). It raises plasma triglycerides by reducing VLDL-triglyceride clearance rather than increasing hepatic VLDL-TG secretion, an activity that maps to its N-terminal coiled-coil domain (basic residues 61-66 required), whereas the C-terminal fibrinogen-like domain is dispensable for triglyceride raising (PMID:12097324, PMID:12909640). Cleavage in the linker region at Arg221 and Arg224 enhances this in vivo activity, and this proteolytic activation is governed endogenously by GALNT2-mediated O-glycosylation, which blocks proprotein convertase cleavage (PMID:12909640, PMID:32999434). Mechanistically, ANGPTL3 reduces LPL catalytic activity in a heparin-reversible manner, distinct from the irreversible inactivation produced by ANGPTL4 (PMID:19028676), and acts in a fed-state-specific manner complementary to ANGPTL4's fasting-state role (PMID:16081640). ANGPTL3 binds ANGPTL8 through its N-terminal domain to form a complex that is over 100-fold more potent at inhibiting GPIHBP1-bound LPL than ANGPTL3 alone, with ANGPTL3 being strictly required for ANGPTL8's triglyceride-raising activity; this complex is suppressed by ApoA5, which binds a leucine-zipper-like epitope on the complex shared with LPL (PMID:23150577, PMID:28413163, PMID:29031715, PMID:32487544, PMID:35307397). Through these activities ANGPTL3 directs postprandial dietary triglycerides into white adipose tissue, and its deficiency lowers triglycerides, accelerates remnant clearance, reduces hepatic VLDL-TG secretion, and promotes adipose beiging and increased energy expenditure (PMID:25954050, PMID:26305978, PMID:29358393). The ANGPTL3/8 complex also targets endothelial lipase, accounting for the HDL-cholesterol effects of ANGPTL3 inhibition (PMID:25964512, PMID:36372100). Independently of its lipase activity, the C-terminal fibrinogen-like domain binds integrin αvβ3 to drive endothelial adhesion, migration, and angiogenesis, and to potentiate TLR4/NF-κB-dependent M1 macrophage activation and atherosclerosis (PMID:11877390, PMID:38740260). ANGPTL3 transcription is negatively regulated by thyroid hormone receptor TRβ acting through HNF1α at its promoter (PMID:16505486).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 2002 High

    Established ANGPTL3 as a causative regulator of plasma lipid levels and defined its core action as inhibition of LPL, answering what gene underlies the hypolipidemic KK/San phenotype and how it raises triglycerides.

    Evidence Positional cloning in KK/San mice, recombinant protein rescue, in vitro LPL assay, and VLDL turnover/secretion studies in mice

    PMID:11788823 PMID:12097324

    Open questions at the time
    • Did not identify which protein domain mediates LPL inhibition
    • Did not define the biochemical mode of LPL inhibition
  2. 2002 High

    Identified a lipase-independent activity by showing the C-terminal fibrinogen-like domain binds integrin αvβ3 to drive endothelial adhesion, migration, and angiogenesis, establishing ANGPTL3 as a bifunctional protein.

    Evidence Co-IP, recombinant binding assays to αvβ3, endothelial migration/adhesion assays, signaling readouts, and rat corneal angiogenesis assay

    PMID:11877390

    Open questions at the time
    • In vivo physiological relevance of the angiogenic activity not established
    • Did not connect angiogenic function to lipid metabolism
  3. 2003 High

    Mapped the triglyceride-raising activity to the N-terminal coiled-coil domain and discovered linker cleavage at Arg221/Arg224 enhances activity, defining the structural and proteolytic basis of ANGPTL3 function.

    Evidence Deletion and site-directed mutagenesis, recombinant protein injection in mice, MS sequencing of plasma fragments, cleavage-resistant mutants

    PMID:12909640

    Open questions at the time
    • Did not identify the protease or its endogenous regulation
    • Did not resolve how cleavage mechanistically enhances LPL inhibition
  4. 2005 High

    Distinguished ANGPTL3 from ANGPTL4 by nutritional state, showing ANGPTL3 acts predominantly in the fed state with additive effects in double-knockouts, establishing non-redundant roles in LPL regulation.

    Evidence Single and double knockout mice with post-heparin LPL activity assays under fed/fasted conditions

    PMID:16081640 PMID:16508209

    Open questions at the time
    • Did not define molecular basis of nutritional-state specificity
    • Did not address tissue-specific LPL targeting
  5. 2006 High

    Identified transcriptional control of ANGPTL3 by TRβ acting through HNF1α, linking thyroid hormone signaling to lipid metabolism via ANGPTL3 expression.

    Evidence Hypothyroid rat and TR-deficient mouse studies, luciferase reporters, EMSA, and HNF1-site mutagenesis

    PMID:16505486

    Open questions at the time
    • Did not establish quantitative contribution of this axis to circulating ANGPTL3 in humans
  6. 2008 High

    Defined the biochemical mechanism of LPL inhibition as a reversible reduction of catalytic activity overcome by heparin, contrasting with ANGPTL4's irreversible inactivation.

    Evidence Enzyme kinetic analysis with purified recombinant proteins and heparin competition assays

    PMID:19028676

    Open questions at the time
    • Did not resolve the structural interface of ANGPTL3 with LPL
    • Did not address modulation by partner proteins
  7. 2012 High

    Discovered the ANGPTL3-ANGPTL8 partnership, showing ANGPTL8 binds the N-terminal domain of ANGPTL3 and requires ANGPTL3 for its triglyceride-raising activity.

    Evidence Co-IP and adenoviral expression with genetic epistasis in Angptl3-/- mice

    PMID:23150577

    Open questions at the time
    • Did not quantify the potency gain of the complex over ANGPTL3 alone
    • Did not map the binding interface
  8. 2015 High

    Resolved the in vivo basis of LDL and HDL lowering by ANGPTL3 blockade, showing reduced VLDL-TG secretion, non-canonical remnant clearance, and an endothelial-lipase-dependent HDL effect.

    Evidence Anti-ANGPTL3 antibody (REGN1500) in multiple receptor-knockout mouse lines, radiolabeled lipoprotein clearance, and EL-knockout epistasis

    PMID:25954050 PMID:25964512

    Open questions at the time
    • Identity of the non-canonical remnant clearance pathway not defined
    • Mechanism linking ANGPTL3 to VLDL-TG secretion intrahepatically not resolved
  9. 2015 High

    Established the physiological purpose of ANGPTL3 as directing fed-state dietary triglycerides into white adipose tissue, explaining the insulin-sensitive phenotype of its deficiency.

    Evidence Angptl3-/- mice with tissue-specific radiolabeled VLDL-TG, glucose uptake, and fatty acid tracer studies

    PMID:26305978

    Open questions at the time
    • Did not address ANGPTL8 contribution to tissue partitioning
    • Did not define signals driving fed-state adipose uptake
  10. 2017 High

    Demonstrated that the ANGPTL3/8 complex, not either protein alone, is the functional inhibitor of GPIHBP1-bound LPL, with ANGPTL3 activating an otherwise inactive ANGPTL8.

    Evidence Co-IP, NanoBiT split-luciferase, LPL activity assays including GPIHBP1-bound LPL, and in vivo epistasis in Angptl8-/- mice across two independent labs

    PMID:28413163 PMID:29031715

    Open questions at the time
    • Did not provide quantitative potency comparison resolved later
    • Structural epitope of inhibition not mapped
  11. 2018 High

    Extended the ANGPTL3/8 axis to whole-body energy balance, showing dual inactivation drives adipose beiging and hyperthermia via a β3-adrenergic pathway.

    Evidence A3A8 double-knockout mice, calorimetry, β3-AR pharmacology, thermoneutrality, and antibody neutralization

    PMID:29358393

    Open questions at the time
    • Mechanism linking LPL inhibition to β3-AR signaling not defined
  12. 2018 Medium

    Provided the first atomic-level view of the ANGPTL3 fibrinogen-like domain by crystallography, framing loss-of-function mutations structurally.

    Evidence X-ray crystallography of ANGPTL3 and ANGPTL4 fibrinogen-like domains

    PMID:29713054

    Open questions at the time
    • Limited functional validation reported
    • Structure of the LPL-inhibitory N-terminal domain not determined
  13. 2020 High

    Quantified the dramatic potency gain of the ANGPTL3/8 complex (>100-fold over ANGPTL3) and showed insulin regulates its secretion, defining the dominant physiological LPL inhibitor.

    Evidence Quantitative LPL inhibition assays with purified complexes, hepatocyte VLDL uptake, human serum ELISA, and insulin-treated secretion assays

    PMID:32487544

    Open questions at the time
    • Did not localize the inhibitory epitope on the complex
    • Tissue-specific targeting not fully resolved
  14. 2020 High

    Identified GALNT2-mediated O-glycosylation as the endogenous switch controlling ANGPTL3 proprotein-convertase cleavage and thus its activation state.

    Evidence GALNT2 gain- and loss-of-function in primary hepatocytes and mice with proprotein convertase inhibition and western blot of cleaved fragments

    PMID:32999434

    Open questions at the time
    • Did not identify the specific convertase in vivo
    • Glycosite mapping not reported
  15. 2021 High

    Identified ApoA5 as a direct negative regulator of the ANGPTL3/8 complex, specifically suppressing complex-mediated LPL inhibition via its C-terminus.

    Evidence IP-MS, biolayer interferometry, functional LPL assays, and C-terminal truncation mutants

    PMID:33762177

    Open questions at the time
    • Did not map the binding epitope, resolved subsequently
    • In vivo contribution quantified later
  16. 2022 High

    Mapped a shared leucine-zipper-like epitope on the ANGPTL3/8 complex bound by both LPL and ApoA5, unmasked upon complex formation, and validated it as a therapeutic target.

    Evidence HDX-MS, molecular modeling, biolayer interferometry, and in vitro/in vivo antibody blockade

    PMID:35307397

    Open questions at the time
    • High-resolution structure of the complex still lacking
    • Did not resolve EL-versus-LPL selectivity at the epitope
  17. 2022 Medium

    Established in humans that the ANGPTL3/8 complex targets both LPL and endothelial lipase whereas ANGPTL4 targets LPL alone, defining substrate specificity at population scale.

    Evidence Human genetic mimicry analysis using UK Biobank variants as instrumental variables

    PMID:36372100

    Open questions at the time
    • Indirect genetic inference rather than direct biochemical demonstration
    • Single analytical approach
  18. 2024 High

    Confirmed ApoA5's in vivo regulatory role and localized its activity to its C-terminus, showing it blocks ANGPTL3/8-mediated LPL detachment from the capillary surface.

    Evidence Recombinant LPL inhibition assays, C-terminal truncation mutants, and in vivo plasma TG and intravascular LPL quantification in Apoa5-/- mice

    PMID:38625948

    Open questions at the time
    • Did not resolve whether ApoA5 displaces or sequesters the complex
  19. 2024 Medium

    Defined an intrahepatic, LDLR-dependent function of ANGPTL3 in ApoB100 secretion and lipid handling, expanding its role beyond extracellular LPL inhibition.

    Evidence CRISPR ANGPTL3 and LDLR knockout in HepG2 cells with ApoB100 secretion, lipidomics, RNA-seq, and degradation-pathway inhibitor studies

    PMID:38219820

    Open questions at the time
    • Single cell-line model
    • Mechanism of LDLR-dependent intrahepatic action not resolved
  20. 2024 Medium

    Connected the integrin-binding fibrinogen-like domain to inflammatory atherogenesis, showing ANGPTL3 potentiates TLR4/NF-κB-driven M1 macrophage activation.

    Evidence AAV Angptl3 overexpression in atherosclerotic mice, phospho-proteomics, integrin β3 CRISPR knockout in THP-1 cells, and NF-κB reporter assays

    PMID:38740260

    Open questions at the time
    • Single lab
    • Relative contribution of this pathway versus lipid effects to atherosclerosis not quantified

Open questions

Synthesis pass · forward-looking unresolved questions
  • A high-resolution structure of the ANGPTL3/8 complex bound to LPL, the identity and regulation of the in vivo proprotein convertase, and the mechanistic basis of the non-canonical remnant clearance pathway remain unresolved.
  • No co-structure of complex with LPL or EL
  • Endogenous convertase not identified in vivo
  • Non-canonical remnant clearance receptor unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0140096 catalytic activity, acting on a protein 3 GO:0048018 receptor ligand activity 2
Localization
GO:0005576 extracellular region 4
Pathway
R-HSA-1430728 Metabolism 4 R-HSA-8963743 Digestion and absorption 2
Partners
ANGPTL8APOA5GALNT2ITGB3LIPGLPL
Complex memberships
ANGPTL3/8 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, and overexpression of Angptl3 in KK/San mice increases plasma triglyceride levels by reducing VLDL-triglyceride clearance rather than increasing hepatic VLDL-TG secretion rate. In vitro LPL activity assay with recombinant ANGPTL3 protein; radiolabeled VLDL turnover studies in mice; adenoviral overexpression; Triton WR1339 VLDL secretion assay The Journal of biological chemistry High 12097324
2002 ANGPTL3 binds integrin αvβ3 (but not Tie2 receptor) via its C-terminal fibrinogen-like domain, inducing integrin αvβ3-dependent haptotactic endothelial cell adhesion and migration, and activating Akt, MAPK, and focal adhesion kinase signaling; the fibrinogen-like domain alone is sufficient to induce angiogenesis in vivo. Co-immunoprecipitation (negative for Tie2); recombinant protein binding assays to αvβ3; endothelial cell adhesion/migration assays; phosphorylation assays; rat corneal angiogenesis assay The Journal of biological chemistry High 11877390
2002 Angptl3 positional cloning in KK/San hypolipidemic mice identified it as the causative gene; overexpression or injection of purified Angptl3 protein raised plasma lipid levels in these mice, establishing Angptl3 as a regulator of lipid metabolism. Positional cloning; adenoviral overexpression; intravenous injection of purified recombinant protein Nature genetics High 11788823
2003 The N-terminal coiled-coil domain (residues 17-207) of ANGPTL3, not the C-terminal fibrinogen-like domain, is responsible for increasing plasma triglyceride levels; basic amino acids in region 61-66 are required for LPL inhibition; ANGPTL3 is cleaved in vivo at Arg221↓Ala222 and Arg224↓Thr225 in the linker region, and this cleavage enhances its in vivo triglyceride-raising activity. Deletion mutagenesis; site-directed mutagenesis; recombinant protein injection in mice; mass spectrometry/sequencing of plasma ANGPTL3 fragments; cleavage-resistant mutant analysis The Journal of biological chemistry High 12909640
2005 Angptl3-deficient mice show hypotriglyceridemia with elevated post-heparin plasma LPL activity predominantly in the fed state, while Angptl4-deficient mice show greater effects in the fasted state; double-knockout mice show additive lipid lowering effects, establishing distinct nutritional-state-specific roles for each protein in LPL regulation. Targeted gene knockout mice; post-heparin plasma LPL activity assay; plasma triglyceride measurement under fed/fasted conditions; double-knockout generation Endocrinology High 16081640
2006 Thyroid hormone receptor TRβ negatively regulates ANGPTL3 gene transcription in a DNA-binding-independent manner through the HNF1 site in the proximal ANGPTL3 promoter; TRβ antagonizes HNF1α transcriptional activity without interfering with its DNA binding. Hypothyroid rat in vivo studies; TR-deficient mouse studies; transfection/luciferase reporter assays; site-directed mutagenesis of HNF1 site; electrophoretic mobility shift assay (EMSA); co-transfection The Journal of biological chemistry High 16505486
2006 Angptl3-null mice have markedly low plasma lipid levels due to accelerated triglyceride clearance; post-heparin plasma LPL and hepatic lipase activities are elevated ~1.57-fold and ~1.42-fold, respectively, relative to wild-type. Angptl3 knockout mice; triglyceride clearance study; post-heparin LPL and hepatic lipase activity assays Experimental animals High 16508209
2008 ANGPTL3 and ANGPTL4 inhibit LPL through distinct mechanisms: ANGPTL3 reduces LPL catalytic activity without altering its self-inactivation rate, and heparin overcomes ANGPTL3 inhibition; in contrast, ANGPTL4 irreversibly inactivates LPL and heparin cannot overcome this inhibition. Enzyme kinetic analysis with purified recombinant proteins; heparin competition assay; site-directed mutagenesis (Glu40 in ANGPTL4; cysteine residues) The Journal of biological chemistry High 19028676
2012 ANGPTL8 co-immunoprecipitates with the N-terminal domain of ANGPTL3 in mouse plasma; coexpression of ANGPTL8 with ANGPTL3 at physiological levels causes hypertriglyceridemia, while ANGPTL3 alone does not; ANGPTL8 expression in Angptl3-/- mice fails to promote hypertriglyceridemia, establishing ANGPTL3 as required for ANGPTL8's triglyceride-raising activity. Co-immunoprecipitation; adenoviral liver expression in mice; genetic epistasis (Angptl3-/- background); plasma triglyceride measurement Proceedings of the National Academy of Sciences of the United States of America High 23150577
2015 Anti-ANGPTL3 monoclonal antibody (REGN1500) reverses ANGPTL3-induced LPL inhibition in vitro; in vivo, REGN1500 increases LPL activity and reduces plasma TG; HDL-C reduction by REGN1500 acts through an endothelial lipase (EL)-dependent mechanism, as shown in EL-knockout mice. In vitro LPL activity assay; intravenous antibody administration in mice; EL-knockout mouse epistasis; plasma lipid measurement Journal of lipid research High 25964512
2015 Inactivation of ANGPTL3 reduces hepatic VLDL-TG secretion by ~61% without changing VLDL-ApoB100 particle number; LDL-cholesterol reduction is not due to altered clearance via ApoE, LDLR, LRP1, or Sdc1 but rather to accelerated clearance of lipolytic remnants via a non-canonical pathway, reducing LDL production. Anti-ANGPTL3 antibody (REGN1500) treatment in mice with genetic knockouts of Apoe, Ldlr, Lrp1, Sdc1 (singly and combined); radiolabeled VLDL/LDL clearance studies; hepatic lipid synthesis/oxidation assays Journal of lipid research High 25954050
2015 ANGPTL3 plays a major role in promoting VLDL-TG uptake into white adipose tissue (WAT) in the fed state; in Angptl3-/- mice, feeding-induced 8-fold increase in WAT VLDL-TG uptake is absent; compensation occurs via 10-fold increased glucose uptake and de novo lipogenesis in WAT, explaining increased insulin sensitivity in ANGPTL3 deficiency. Angptl3-/- mice; radiolabeled VLDL-TG uptake into tissues; glucose uptake tracer studies; isotopic fatty acid tracing; fat mass measurement Proceedings of the National Academy of Sciences of the United States of America High 26305978
2017 ANGPTL8 requires ANGPTL3 for LPL inhibitory activity: ANGPTL8 alone is inactive against LPL at physiological concentrations but forms a complex with ANGPTL3 that is far more efficacious than either alone; ANGPTL3 LPL-inhibitory activity is not required for it to activate ANGPTL8; an antibody to the C-terminus of ANGPTL8 blocks LPL inhibition without disrupting the ANGPTL3-ANGPTL8 complex. Co-immunoprecipitation; LPL activity assay; NanoBiT split-luciferase protein interaction assay; adenoviral overexpression in Angptl8-/- mice; western blotting Journal of lipid research High 28413163
2017 ANGPTL8 binds directly to ANGPTL3 and greatly enhances ANGPTL3's ability to bind and inhibit GPIHBP1-bound LPL; co-expression of ANGPTL3 and ANGPTL8 dramatically increases LPL inhibition compared to either alone; 2-fold ANGPTL3 overexpression increases plasma TG only in the presence of ANGPTL8. Co-immunoprecipitation; NanoBiT split-luciferase protein interaction assay; LPL activity assay (including GPIHBP1-bound LPL); adenoviral overexpression in Angptl8-/- mice Molecular metabolism High 29031715
2018 ANGPTL3 and ANGPTL8 are essential for efficient post-prandial storage of dietary TG in white adipose tissue; mice lacking both A3 and A8 have decreased fat mass and feeding-induced hyperthermia mediated by beiging of subcutaneous WAT via a β3-adrenergic receptor pathway; antibody-mediated dual inactivation of circulating A3 and A8 reproduces the hyperthermic phenotype. Double-knockout (A3A8) mice; calorimetry (O2 consumption); β3-AR agonist/antagonist pharmacology; thermoneutrality experiments; gene expression profiling of adipose depots; antibody neutralization in WT mice Proceedings of the National Academy of Sciences of the United States of America High 29358393
2018 Crystal structures of the fibrinogen-like domains of ANGPTL3 and ANGPTL4 were determined, providing structural insights into loss-of-function mutations and potential mechanisms of lipase inhibition. X-ray crystallography of fibrinogen-like domains of ANGPTL3 and ANGPTL4 Scientific reports Medium 29713054
2020 ANGPTL3/8 complex LPL-inhibitory activity is >100-fold more potent than ANGPTL3 alone; ANGPTL4/8 complex LPL-inhibitory activity is >100-fold less potent than ANGPTL4 alone; ANGPTL3/8 complex blocks LPL-facilitated hepatocyte VLDL uptake; insulin increases ANGPTL3/8 secretion from hepatocytes and ANGPTL4/8 secretion from adipocytes. Quantitative LPL inhibition assays with purified complexes; competition experiments; hepatocyte VLDL uptake assay; ELISA for complexes in human serum; cell-based secretion assays with insulin treatment Journal of lipid research High 32487544
2020 GALNT2 regulates ANGPTL3 cleavage: GALNT2 overexpression blocks proprotein convertase (PC)-mediated cleavage of Angptl3 in primary hepatocytes and in vivo in mice; suppression of Galnt2 dramatically increases Angptl3 cleavage in mice, establishing GALNT2-mediated O-glycosylation as a key endogenous regulator of ANGPTL3 activation. Primary hepatocyte culture with adenoviral GALNT2 overexpression; proprotein convertase inhibitor treatment; siRNA-mediated Galnt2 knockdown in mice; western blot detection of cleaved ANGPTL3 fragments Scientific reports High 32999434
2021 ApoA5 directly associates with the ANGPTL3/8 complex in human serum and suppresses ANGPTL3/8-mediated LPL inhibition; the C-terminal ~35-40 residues of ApoA5 are required for this suppression; ApoA5 does not directly affect LPL activity nor suppress ANGPTL3, ANGPTL4, or ANGPTL4/8 inhibition of LPL. Immunoprecipitation-mass spectrometry; western blotting; biolayer interferometry; functional LPL enzymatic assays; kinetic analysis; C-terminal truncation mutants in vitro and in vivo Journal of lipid research High 33762177
2022 LPL and ApoA5 both bind the same leucine zipper-like epitope on the ANGPTL3/8 complex formed by N-terminal regions of ANGPTL3 and ANGPTL8 that are 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; bio-layer interferometry; in vitro LPL inhibition assay; in vivo TG measurement with antibody treatment Journal of lipid research High 35307397
2022 Genetic mimicry analysis in humans establishes that the ANGPTL3-ANGPTL8 complex targets both LPL and endothelial lipase (EL/LIPG) in vivo, while ANGPTL4 exclusively targets LPL; the ANGPTL8 R59W variant more strongly affects EL inhibition than LPL inhibition. Human genetic mimicry analysis using UK Biobank data (>110,000 individuals) with variants in LPL, LIPG, LIPC, ANGPTL3, ANGPTL4, ANGPTL8 as instrumental variables; validation in 13,000+ European individuals Journal of lipid research Medium 36372100
2024 ANGPTL3 deficiency in HepG2 cells reduces ApoB100 secretion ~50% via increased early presecretory lysosomal degradation and decreased triglyceride secretion; ANGPTL3-/- cells show increased fatty acid oxidation and altered expression of PPARα targets; when LDLR is also absent, ANGPTL3 deficiency rescues LDL clearance without secretion defects, revealing LDLR-dependent intrahepatic ANGPTL3 function. CRISPR/Cas9 ANGPTL3 and LDLR knockout in HepG2 cells; ApoB100 secretion assay; lipid synthesis/oxidation measurements; targeted lipidomics; RNA sequencing; lysosomal/proteasomal inhibitor studies Journal of lipid research Medium 38219820
2024 ANGPTL3 downregulation by siRNA in primary human hepatocyte spheroids and HepG2 cells increases intracellular neutral lipids/triglycerides by reducing beta-oxidation; the mechanism involves decreased intracellular deiodinase type 1 (DIO1) protein levels, resembling primary intracellular hepatocyte hypothyroidism. siRNA knockdown of ANGPTL3 in 3D primary human hepatocyte spheroids, HepG2/LX-2 spheroids, and 2D cultures; neutral lipid staining; beta-oxidation assays; DIO1 protein measurement by western blot Arteriosclerosis, thrombosis, and vascular biology Medium 38385290
2024 The C-terminal fibrinogen-like domain of ANGPTL3 binds macrophage integrin αvβ3, activates Akt phosphorylation, upregulates TLR4 expression, and potentiates NF-κB activity in response to LPS, thereby promoting M1 macrophage activation and accelerating atherosclerosis; integrin β3 knockout in THP-1 cells attenuates ANGPTL3-induced Akt phosphorylation. AAV-mediated Angptl3 overexpression in Ldlr-/- and ApoE-/- mice; FLAG-tagged Angptl3 tracing with immunostaining; phospho-proteomic profiling; CRISPR/Cas9 integrin β3 knockout in THP-1 cells; MILLIPLEX cytokine assay; western blot; NF-κB luciferase reporter Journal of advanced research Medium 38740260
2014 Angptl3 is expressed in neurons of the mediobasal hypothalamus; hypothalamic Angptl3 suppression increases food intake and reduces energy expenditure, while intracerebroventricular (ICV) Angptl3 administration stimulates hypothalamic LPL activity and increases long-chain fatty acid/LCFA-CoA levels; co-administration of the LPL inhibitor apoC-III blocks Angptl3's central metabolic effects, establishing LPL activation as the mechanism of Angptl3 action in the hypothalamic lipid-sensing pathway. Hypothalamic Angptl3 siRNA suppression; ICV Angptl3 injection; LPL activity assay; LCFA/LCFA-CoA measurement; ApoC-III co-administration; lipid-sensing pathway inhibitors Diabetes Medium 25338813
2019 miR-181d directly binds the 3'-UTR of ANGPTL3 mRNA and represses ANGPTL3 protein expression, as confirmed by 3'-UTR luciferase assay and overexpression studies in hepatocyte cell cultures. 3'-UTR luciferase reporter assay; miR-181d overexpression in hepatocytes; RT-PCR; ELISA for ANGPTL3 protein Scientific reports Medium 31413305
2015 ANGPTL3 knockdown in oral squamous cell carcinoma (OSCC) cells inactivates ERK phosphorylation and causes G1 cell-cycle arrest with upregulation of p21Cip1 and p27Kip1, reducing cellular growth in vitro and in xenografts. ANGPTL3 shRNA knockdown in OSCC cell lines; MTT proliferation assay; western blot for phospho-ERK; flow cytometry for cell cycle; xenograft tumor growth Cancer medicine Low 25644496
2019 ANGPTL3 binds vasodilator-stimulated phosphoprotein (VASP) and inhibits VASP phosphorylation at amino acid 157 in renal cell carcinoma (RCC) cells; ANGPTL3 overexpression inhibits RCC cell metastatic ability. Co-immunoprecipitation (ANGPTL3-VASP interaction); western blot for VASP phosphorylation; overexpression in RCC cell lines; migration/invasion assays Biochemical and biophysical research communications Low 31270029
2022 The C-terminal fibrinogen-like domain of ANGPTL3 (ANGPTL3-Fld) facilitates lipolysis in 3T3-L1 adipocytes by activating ERK via the PDGFRβ-PLCγ-AMPK axis when combined with β-adrenergic stimulation; ANGPTL3-Fld alone inhibits hormone-sensitive lipase (HSL) but in combination with isoproterenol results in net HSL activation and enhanced free fatty acid release. 3T3-L1 adipocyte treatment with recombinant ANGPTL3-Fld ± isoproterenol; free fatty acid release assay; western blot for phospho-HSL, phospho-ERK; BRAF-ERK pathway inhibitors Biomolecules Low 35454174
2024 C-terminal sequences (last ~35-40 amino acids) of APOA5 are required for suppression of ANGPTL3/8-mediated LPL inhibition in vitro and for regulating intracapillary LPL levels and plasma TG in vivo; WT APOA5 blocks ANGPTL3/8-mediated LPL detachment from cultured cells, while C-terminal truncation mutants (APOA5Δ35, APOA5Δ40) lose this activity. Recombinant protein LPL inhibition assays; C-terminal truncation mutants of mouse and human APOA5; in vivo plasma TG measurement in Apoa5-/- mice; intravascular LPL quantification; antibody blocking of APOA5 C-terminus Proceedings of the National Academy of Sciences of the United States of America High 38625948

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 695 28538136
2010 Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. The New England journal of medicine 594 20942659
2017 Cardiovascular and Metabolic Effects of ANGPTL3 Antisense Oligonucleotides. The New England journal of medicine 494 28538111
2017 ANGPTL3 Deficiency and Protection Against Coronary Artery Disease. Journal of the American College of Cardiology 388 28385496
2012 Atypical angiopoietin-like protein that regulates ANGPTL3. Proceedings of the National Academy of Sciences of the United States of America 387 23150577
2005 Transgenic angiopoietin-like (angptl)4 overexpression and targeted disruption of angptl4 and angptl3: regulation of triglyceride metabolism. Endocrinology 363 16081640
2002 Angptl3 regulates lipid metabolism in mice. Nature genetics 354 11788823
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 322 33649229
2002 ANGPTL3 decreases very low density lipoprotein triglyceride clearance by inhibition of lipoprotein lipase. The Journal of biological chemistry 320 12097324
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 228 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 223 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 184 25964512
2017 ANGPTL8 requires ANGPTL3 to inhibit lipoprotein lipase and plasma triglyceride clearance. Journal of lipid research 179 28413163
2016 The ANGPTL3-4-8 model, a molecular mechanism for triglyceride trafficking. Open biology 178 27053679
2024 Zodasiran, an RNAi Therapeutic Targeting ANGPTL3, for Mixed Hyperlipidemia. The New England journal of medicine 176 38809174
2015 Inactivation of ANGPTL3 reduces hepatic VLDL-triglyceride secretion. Journal of lipid research 162 25954050
2017 ANGPTL8 promotes the ability of ANGPTL3 to bind and inhibit lipoprotein lipase. Molecular metabolism 160 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 134 32487544
2015 Hepatic ANGPTL3 regulates adipose tissue energy homeostasis. Proceedings of the National Academy of Sciences of the United States of America 124 26305978
2008 The angiopoietin-like proteins ANGPTL3 and ANGPTL4 inhibit lipoprotein lipase activity through distinct mechanisms. The Journal of biological chemistry 118 19028676
2017 Role of angiopoietin-like 3 (ANGPTL3) in regulating plasma level of low-density lipoprotein cholesterol. Atherosclerosis 95 29183623
2016 The role of ANGPTL3 in controlling lipoprotein metabolism. Endocrine 92 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 85 37626170
2021 Local delivery of USC-derived exosomes harboring ANGPTL3 enhances spinal cord functional recovery after injury by promoting angiogenesis. Stem cell research & therapy 77 33413639
2021 ApoA5 lowers triglyceride levels via suppression of ANGPTL3/8-mediated LPL inhibition. Journal of lipid research 72 33762177
2021 An updated ANGPTL3-4-8 model as a mechanism of triglyceride partitioning between fat and oxidative tissues. Progress in lipid research 70 34793860
2021 ANGPTL3 as therapeutic target. Current opinion in lipidology 68 34581310
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
2022 Broadening the Scope of Dyslipidemia Therapy by Targeting APOC3 (Apolipoprotein C3) and ANGPTL3 (Angiopoietin-Like Protein 3). Arteriosclerosis, thrombosis, and vascular biology 66 36579649
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
2004 ANGPTL3 is increased in both insulin-deficient and -resistant diabetic states. Biochemical and biophysical research communications 65 15094378
2015 ANGPTL3 is a novel biomarker as it activates ERK/MAPK pathway in oral cancer. Cancer medicine 63 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 61 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 55 30011918
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) 50 40179932
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
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 44 29358393
2018 Structures of Angptl3 and Angptl4, modulators of triglyceride levels and coronary artery disease. Scientific reports 43 29713054
2023 ANGPTL3 inhibition, dyslipidemia, and cardiovascular diseases. Trends in cardiovascular medicine 42 36746257
2021 Vaccine targeting ANGPTL3 ameliorates dyslipidemia and associated diseases in mouse models of obese dyslipidemia and familial hypercholesterolemia. Cell reports. Medicine 40 34841293
2025 Phase 1 Trial of CRISPR-Cas9 Gene Editing Targeting ANGPTL3. The New England journal of medicine 39 41211945
2022 ANGPTL3 as a Drug Target in Hyperlipidemia and Atherosclerosis. Current atherosclerosis reports 39 36367663
2020 A randomized study investigating the safety, tolerability, and pharmacokinetics of evinacumab, an ANGPTL3 inhibitor, in healthy Japanese and Caucasian subjects. Atherosclerosis 39 33130482
2019 ANGPTL3: a novel biomarker and promising therapeutic target. Journal of drug targeting 39 30615486
2021 Monoclonal Antibodies in the Management of Familial Hypercholesterolemia: Focus on PCSK9 and ANGPTL3 Inhibitors. Current atherosclerosis reports 37 34698927
2016 The Arg59Trp variant in ANGPTL8 (betatrophin) is associated with total and HDL-cholesterol in American Indians and Mexican Americans and differentially affects cleavage of ANGPTL3. Molecular genetics and metabolism 36 27117576
2023 Advances in Dyslipidaemia Treatments: Focusing on ApoC3 and ANGPTL3 Inhibitors. Journal of lipid and atherosclerosis 33 38299167
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 32 38895109
2015 A vital role for Angptl3 in the PAN-induced podocyte loss by affecting detachment and apoptosis in vitro. BMC nephrology 31 25884163
2011 Effects of ANGPTL3 antisense oligodeoxynucleotides transfection on the cell growths and invasion of human hepatocellular carcinoma cells. Hepato-gastroenterology 31 21940333
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
2022 Angiopoietin-Like Protein 3 (ANGPTL3) Inhibitors in the Management of Refractory Hypercholesterolemia. Clinical pharmacology : advances and applications 28 35873366
2023 Liver-specific in vivo base editing of Angptl3 via AAV delivery efficiently lowers blood lipid levels in mice. Cell & bioscience 25 37322547
2024 ANGPTL3 accelerates atherosclerotic progression via direct regulation of M1 macrophage activation in plaque. Journal of advanced research 24 38740260
2022 Angiopoietin-like 3 (ANGPTL3) drives cell proliferation, migration and angiogenesis in cervical cancer via binding to integrin alpha v beta 3. Bioengineered 24 35038961
2018 Fenofibrate Exerts Protective Effects in Diabetic Retinopathy via Inhibition of the ANGPTL3 Pathway. Investigative ophthalmology & visual science 24 30128492
2016 Different relationship between ANGPTL3 and HDL components in female non-diabetic subjects and type-2 diabetic patients. Cardiovascular diabetology 24 27620179
2019 Reduced miR-181d level in obesity and its role in lipid metabolism via regulation of ANGPTL3. Scientific reports 23 31413305
2023 ANGPTL3 Deficiency and Risk of Hepatic Steatosis. Circulation 22 37712257
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
2022 Podocyte protection by Angptl3 knockout via inhibiting ROS/GRP78 pathway in LPS-induced acute kidney injury. International immunopharmacology 21 35086056
2022 Genetic Mimicry Analysis Reveals the Specific Lipases Targeted by the ANGPTL3-ANGPTL8 Complex and ANGPTL4. Journal of lipid research 21 36372100
2018 ANGPTL3 possibly promotes cardiac angiogenesis through improving proangiogenic ability of endothelial progenitor cells after myocardial infarction. Lipids in health and disease 21 30086775
2020 GALNT2 regulates ANGPTL3 cleavage in cells and in vivo of mice. Scientific reports 20 32999434
2025 Effect of ANGPTL3 Inhibition With Solbinsiran in Preclinical and Early Human Studies. Journal of the American College of Cardiology 19 40158211
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 19 38484368
2019 ANGPTL3 inhibits renal cell carcinoma metastasis by inhibiting VASP phosphorylation. Biochemical and biophysical research communications 19 31270029
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
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
2014 Regulation of energy balance by the hypothalamic lipoprotein lipase regulator Angptl3. Diabetes 16 25338813
2024 ANGPTL3 and ApoC-III inhibitors for treating hypertriglyceridemia in context: horses for courses? Current opinion in lipidology 15 38372218
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 15 38625948
2024 Inhibition of the ANGPTL3/8 Complex for the Prevention and Treatment of Atherosclerotic Cardiovascular Disease. Current atherosclerosis reports 15 39565562
2020 Statin therapy reduces plasma angiopoietin-like 3 (ANGPTL3) concentrations in hypercholesterolemic patients via reduced liver X receptor (LXR) activation. Atherosclerosis 15 33242792
2006 Cloning, chromosome mapping and expression characteristics of porcine ANGPTL3 and -4. Cytogenetic and genome research 15 16717449
2024 ANGPTL3 deficiency impairs lipoprotein production and produces adaptive changes in hepatic lipid metabolism. Journal of lipid research 14 38219820
2024 ANGPTL3 Downregulation Increases Intracellular Lipids by Reducing Energy Utilization. Arteriosclerosis, thrombosis, and vascular biology 14 38385290
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 14 36618267
2021 A haplotype of the ANGPTL3 gene is associated with CVD risk, diabetes mellitus, hypertension, obesity, metabolic syndrome, and dyslipidemia. Gene 14 33636293
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
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
2022 ANGPTL3 impacts proteinuria and hyperlipidemia in primary nephrotic syndrome. Lipids in health and disease 13 35399079
2022 New Therapeutic Approaches to the Treatment of Dyslipidemia 1: ApoC-III and ANGPTL3. Journal of lipid and atherosclerosis 13 36761060
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 The Fibrinogen-like Domain of ANGPTL3 Facilitates Lipolysis in 3T3-L1 Cells by Activating the Intracellular Erk Pathway. Biomolecules 12 35454174

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