Affinage

ANGPTL4

Angiopoietin-related protein 4 · UniProt Q9BY76

Length
406 aa
Mass
45.2 kDa
Annotated
2026-04-28
100 papers in source corpus 36 papers cited in narrative 35 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ANGPTL4 is a secreted glycoprotein that serves as a central regulator of lipid metabolism by inhibiting lipoprotein lipase (LPL), endothelial lipase, and hepatic lipase in a tissue-specific manner, while also modulating intracellular lipolysis, inflammatory signaling, and cellular redox responses. The protein forms oligomers that are proteolytically cleaved by proprotein convertases; oligomerization of the N-terminal domain is essential for LPL inhibition, which occurs through binding at a site overlapping the APOC2 interface and promoting irreversible unfolding of LPL's catalytic domain (PMID:19270337, PMID:37094117). ANGPTL8 antagonizes ANGPTL4 by forming ANGPTL4/8 complexes with >100-fold reduced LPL-inhibitory potency, providing a fed-state mechanism to redirect fatty acids toward adipose storage (PMID:32487544). Transcriptionally regulated by PPARα/γ/δ, glucocorticoid receptor, HIF-1α/TAZ, NFAT, and SMAD3, ANGPTL4 integrates metabolic and inflammatory cues: in adipose tissue it mediates fasting-induced LPL suppression and glucocorticoid-driven lipolysis that raises hepatic ceramide synthesis to impair insulin signaling; in macrophages it regulates foam cell formation and monocyte differentiation; and human loss-of-function variants confer lower triglycerides and protection from coronary artery disease (PMID:22267746, PMID:28743803, PMID:27460411, PMID:26933753).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2000 High

    Establishing ANGPTL4 as a fasting-induced, PPARα-regulated secreted factor resolved how nutritional state could hormonally control plasma lipid partitioning.

    Evidence Subtractive hybridization in PPARα-null mice with plasma protein detection across fed/fasted states

    PMID:10862772

    Open questions at the time
    • Molecular target of ANGPTL4 in lipid metabolism unknown
    • Protein structure and processing not characterized
  2. 2005 High

    Demonstrating that ANGPTL4 directly inhibits LPL in vitro and that its genetic gain/loss of function raises/lowers plasma triglycerides identified LPL as the primary enzymatic target.

    Evidence Purified recombinant protein LPL inhibition assay; transgenic overexpression and targeted gene disruption in mice

    PMID:16081640

    Open questions at the time
    • Mechanism of LPL inactivation unknown
    • Structural basis of interaction not resolved
    • Tissue-specific contributions not dissected
  3. 2009 High

    Revealing that ANGPTL4 oligomerization (but not proteolytic cleavage) is required for LPL inhibition, and that the E40K variant disrupts oligomer stability, connected protein quaternary structure to function and explained a human lipid-lowering variant.

    Evidence Mutagenesis of oligomerization and cleavage sites in HEK-293A cells; LPL activity assays; in vivo mouse validation

    PMID:19270337

    Open questions at the time
    • Structural details of oligomer–LPL interaction not resolved
    • Whether E40K affects other ANGPTL4 functions unknown
  4. 2012 High

    Showing that ANGPTL4 stimulates intracellular lipolysis via cAMP signaling downstream of glucocorticoid receptor activation established a second metabolic function beyond extracellular LPL inhibition.

    Evidence Purified human ANGPTL4 added to primary Angptl4−/− adipocytes; cAMP measurement; pharmacological dissection; Angptl4 knockout mice

    PMID:22267746

    Open questions at the time
    • Receptor mediating ANGPTL4-induced cAMP signaling not identified
    • Relationship between intracellular lipolysis and LPL inhibition unclear
  5. 2012 High

    Identification of tissue-specific cis-regulatory modules in ANGPTL4 intron 3 and their suppression by microbiota demonstrated how host–microbe interactions regulate lipid metabolism through transcriptional control of ANGPTL4.

    Evidence Transgenic reporter assays in gnotobiotic zebrafish with mutagenesis of regulatory elements

    PMID:22479192

    Open questions at the time
    • Microbial signal and host receptor mediating suppression not identified
    • Relevance to mammalian intestinal regulation not directly tested
  6. 2014 High

    Demonstrating that free fatty acids induce ANGPTL4 via PPARδ in non-exercising muscle while AMPK suppresses ANGPTL4 in exercising muscle revealed a metabolic switch directing triglyceride fuel toward active tissue.

    Evidence Human biopsies, animal exercise models, in vitro PPARδ and AMPK manipulation

    PMID:24591600

    Open questions at the time
    • Precise AMPK-mediated transcriptional mechanism not delineated
    • Whether ANGPTL4 directly activates AMPK or acts indirectly was uncertain
  7. 2016 High

    Large-scale human exome sequencing established that ANGPTL4 loss-of-function variants (including E40K) lower triglycerides by ~35% and protect against coronary artery disease, validating ANGPTL4 as a therapeutic target.

    Evidence Exome sequencing of 42,930 participants; anti-ANGPTL4 monoclonal antibody in mice and non-human primates

    PMID:26933753 PMID:26934567

    Open questions at the time
    • Safety concerns of full ANGPTL4 inhibition (mesenteric lymphadenitis observed in KO mice) not resolved
    • Contribution of non-LPL functions to cardiovascular protection unknown
  8. 2017 High

    Elucidating the ANGPTL4→lipolysis→ceramide→PP2A/PKCζ pathway explained how glucocorticoid-induced insulin resistance is mechanistically linked to ANGPTL4-driven adipose lipolysis.

    Evidence Angptl4 knockout mice; metabolomics; PP2A/PKCζ activity assays; ceramide synthesis inhibitors

    PMID:28743803

    Open questions at the time
    • Whether this pathway operates in human glucocorticoid resistance not directly tested
    • Whether ANGPTL4-driven ceramide signaling contributes to other insulin-resistant states unknown
  9. 2018 High

    Tissue-specific knockouts of ANGPTL4 in white and brown adipose tissue independently showed enhanced LPL activity, improved glucose tolerance, and metabolic benefits, dissecting the adipose-autonomous contributions of ANGPTL4.

    Evidence Adipose-specific and BAT-specific Angptl4 knockout mice with LPL activity, insulin signaling, and thermogenesis readouts

    PMID:29563332 PMID:29627378

    Open questions at the time
    • How adipose ANGPTL4 coordinates with hepatic and macrophage ANGPTL4 in vivo not fully resolved
    • Long-term consequences of tissue-specific deletion not studied
  10. 2020 High

    Quantitative reconstitution showed that ANGPTL4/8 complex formation reduces LPL-inhibitory activity >100-fold, providing the molecular basis for insulin-mediated redirection of fatty acids toward adipose storage in the fed state.

    Evidence Recombinant protein LPL inhibition assays; immunoassays in human serum; hepatocyte/adipocyte insulin treatment

    PMID:32487544

    Open questions at the time
    • Structure of the ANGPTL4/8 complex not determined
    • Stoichiometry and kinetics of complex formation in vivo not quantified
  11. 2020 High

    Human fasting studies confirmed that ANGPTL4 protein rises in subcutaneous adipose tissue coincident with LPL activity decline without changes in LPL protein, validating ANGPTL4 as the post-translational LPL regulator during fasting in humans.

    Evidence Prospective human adipose biopsies before/after 26-h fast; cortisol/FFA/insulin treatment of primary human adipocytes

    PMID:32504883

    Open questions at the time
    • Whether visceral adipose behaves identically not assessed
    • Quantitative relationship between ANGPTL4 protein level and LPL inactivation rate in humans not established
  12. 2020 High

    Hematopoietic ANGPTL4 deficiency was shown to promote myeloid expansion, foam cell formation, and atherosclerosis via increased CD36 and reduced ABCA1, establishing a macrophage-intrinsic anti-atherogenic role distinct from systemic lipid lowering.

    Evidence Bone marrow transplantation in atherosclerosis-prone mice; flow cytometry; CD36/ABCA1 localization assays

    PMID:27460411

    Open questions at the time
    • Direct mechanism linking ANGPTL4 to ABCA1 surface localization not defined
    • Whether macrophage ANGPTL4 acts through LPL or a separate pathway not fully resolved
  13. 2021 High

    Hepatocyte-specific ANGPTL4 deletion revealed a liver-autonomous function: inhibition of hepatic lipase (not LPL), controlling remnant lipoprotein catabolism and hepatic fatty acid oxidation.

    Evidence Hepatocyte-specific Angptl4 knockout mice; hepatic lipase activity assays; antisense inhibition; AMPK activation assays

    PMID:34255741

    Open questions at the time
    • Structural basis of ANGPTL4–hepatic lipase interaction unknown
    • Whether hepatic ANGPTL4 also inhibits LPL in liver endothelium not excluded
  14. 2022 High

    Large-scale human genetic mimicry analysis confirmed that ANGPTL4's effect on plasma lipids in humans operates exclusively through LPL, not hepatic lipase or endothelial lipase, despite in vitro evidence of EL/HL inhibition.

    Evidence Genetic mimicry analysis across >110,000 UK Biobank participants validated in 11 European populations

    PMID:36372100

    Open questions at the time
    • Whether tissue-specific HL/EL inhibition has local effects not captured by plasma lipid measurements remains possible
    • Rare variant effects on non-LPL lipases not powered
  15. 2023 High

    HDX-MS mapping resolved how ANGPTL4 inhibits LPL: it binds overlapping the APOC2 site and destabilizes lid-anchoring structures, promoting irreversible unfolding of the α/β-hydrolase domain — a fundamentally different mechanism from competitive inhibition.

    Evidence Hydrogen-deuterium exchange mass spectrometry; thermal stability assays comparing ANGPTL4 and APOC2 effects on LPL

    PMID:37094117

    Open questions at the time
    • Full atomic-resolution structure of the ANGPTL4–LPL complex not yet available
    • How oligomeric state of ANGPTL4 modulates unfolding kinetics not determined
  16. 2023 Medium

    Identification of FMNL2-dependent actin polymerization at ANGPTL4-containing vesicles (Rab8a+/myosin Vb+) downstream of TGFβ/PKC revealed a regulated secretory trafficking pathway controlling ANGPTL4 release and cancer cell invasion.

    Evidence Super-resolution microscopy; FMNL2 knockdown/phosphorylation mutants; PKC inhibition; invasion assays

    PMID:36691769

    Open questions at the time
    • Whether this trafficking pathway operates in non-cancer contexts unknown
    • Generalizability beyond TGFβ-driven secretion not tested
    • Single-lab finding
  17. 2024 Medium

    Discovery that podocyte/tubule-secreted ANGPTL4 binds Integrin β1 and modulates DPP4–Integrin β1 association to drive STING-mediated fibrogenic signaling expanded ANGPTL4's roles beyond lipid metabolism to kidney fibrosis.

    Evidence Podocyte- and tubule-specific Angptl4 mutant mice; co-IP between ANGPTL4, Integrin β1, DPP4; STING pathway assays; kidney-targeted antisense inhibition

    PMID:39630889

    Open questions at the time
    • Structural basis of ANGPTL4–Integrin β1 interaction not determined
    • Whether this pathway operates in non-diabetic kidney disease unknown
    • Single-lab finding

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of the receptor mediating ANGPTL4's cAMP-dependent intracellular lipolytic signaling, the full atomic structure of the ANGPTL4 oligomer–LPL complex, and how ANGPTL4's metabolic and non-metabolic (inflammatory, ferroptotic, fibrogenic) functions are coordinated in vivo.
  • No receptor identified for ANGPTL4-induced cAMP/lipolysis signaling
  • No high-resolution structure of full-length ANGPTL4 oligomer bound to LPL
  • Integration of metabolic and non-metabolic functions in tissue-specific contexts not systematically addressed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 6
Localization
GO:0005576 extracellular region 4 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-1430728 Metabolism 9 R-HSA-162582 Signal Transduction 5 R-HSA-74160 Gene expression (Transcription) 5 R-HSA-168256 Immune System 3
Partners
ANGPTL8APOC2DPP4FMNL2IQGAP1ITGB1LPL
Complex memberships
ANGPTL4/8 complex

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 ANGPTL4 (FIAF) is a PPARα target gene identified by subtractive hybridization; it is predominantly expressed in adipose tissue, secreted into blood plasma, and plasma levels increase with fasting and decrease with chronic high-fat feeding, establishing its role as a fasting-regulated endocrine factor. Subtractive hybridization (SABRE), mRNA quantification, plasma protein detection across wild-type and PPARα-null mice The Journal of biological chemistry High 10862772
2005 Recombinant ANGPTL4 protein directly inhibits LPL activity in vitro; transgenic overexpression of human ANGPTL4 in liver elevates plasma triglycerides and reduces post-heparin LPL activity, while ANGPTL4-deficient mice show hypotriglyceridemia and increased LPL activity, with greater effect in the fasted state. In vitro LPL inhibition assay with purified recombinant protein; transgenic overexpression; targeted gene disruption in mice; post-heparin plasma LPL activity measurement Endocrinology High 16081640
2009 ANGPTL4 forms dimers and tetramers intracellularly before secretion; it is cleaved by a proprotein convertase at RRKR(164), releasing an oligomeric N-terminal domain and monomeric C-terminal fibrinogen-like domain. Oligomerization, but not cleavage, is required for LPL inhibition. The E40K variant is synthesized and processed normally but N-terminal oligomers fail to accumulate extracellularly, abolishing LPL inhibition. Expression in HEK-293A cells; mutagenesis of oligomerization and cleavage sites; LPL activity assays; in vivo validation in mice The Journal of biological chemistry High 19270337
2012 ANGPTL4 mediates fasting-induced intracellular lipolysis in white adipose tissue downstream of glucocorticoid receptor activation; ANGPTL4 stimulates cAMP signaling upstream of adenylate cyclase and downstream of receptor activation in adipocytes, and purified human ANGPTL4 alone is sufficient to increase cAMP and induce lipolysis in primary Angptl4−/− adipocytes. Angptl4 knockout mice; glucocorticoid receptor blockade; primary adipocyte treatment with purified human ANGPTL4; cAMP measurement; phosphorylation of lipolytic enzymes; pharmacological dissection of signaling The Journal of biological chemistry High 22267746
2012 Tissue-specific cis-regulatory modules within angptl4 intron 3 drive expression in liver, pancreatic islet β-cells, and intestinal enterocytes in zebrafish; the microbiota suppresses the transcriptional activity of the intestine-specific regulatory module, thereby reducing intestinal Angptl4 expression. Transgenic reporter assays in zebrafish; gnotobiotic colonization; site-directed mutagenesis of regulatory sequences; comparative sequence analysis across 12 teleost species PLoS genetics High 22479192
2013 Butyrate induces intestinal ANGPTL4 expression via a PPARγ-independent, butyrate-responsive element ~0.5 kb upstream of the transcription start site, while PPARγ ligands act on a downstream PPAR-responsive element; these two pathways are additive. RT-PCR; promoter dissection; PPARγ inhibitor and siRNA experiments; germ-free mouse colonization with Clostridium tyrobutyricum; butyrate gavage American journal of physiology. Gastrointestinal and liver physiology High 23518684
2014 In non-exercising muscle during acute exercise, ANGPTL4 is induced by elevated plasma free fatty acids via PPARδ activation; in exercising muscle, ANGPTL4 induction is counteracted by AMPK-mediated downregulation, promoting local triglyceride uptake as fuel. Human biopsy studies; animal exercise models; in vitro PPARδ and AMPK manipulation; combination of human, animal, and cell data Proceedings of the National Academy of Sciences of the United States of America High 24591600
2015 Adipose-derived Angptl4 links glucagon receptor antagonist-induced adipose triglyceride metabolism to α-cell proliferation; Angptl4 is upregulated via PPARγ activation in white adipose tissue following glucagon receptor antagonist treatment, and Angptl4 supplementation specifically promotes α-cell proliferation, while Angptl4 knockout mice treated with glucagon receptor antagonist do not show increased glucagon or α-cell proliferation. Angptl4 knockout mice; glucagon receptor antagonist treatment; Angptl4 protein supplementation; pancreatic α-cell quantification Proceedings of the National Academy of Sciences of the United States of America High 26621734
2016 ANGPTL4 loss-of-function mutations in humans (including E40K) are associated with 35% lower triglyceride levels and protection from coronary artery disease; monoclonal antibody inhibition of Angptl4 in mice and monkeys reduces triglyceride levels, confirming LPL inhibition as the functional mechanism. Exome sequencing of 42,930 participants; genetic association study; anti-ANGPTL4 monoclonal antibody in mice and non-human primates; lipid measurements The New England journal of medicine High 26933753 26934567
2017 Glucocorticoid-induced insulin resistance is mediated by Angptl4: Angptl4 stimulates lipolysis in white adipose tissue, raising fatty acid flux to the liver and increasing hepatic ceramide synthesis via ceramide synthetic enzymes. Ceramide then activates PP2A and PKCζ to impair insulin signaling. Pharmacological inhibition of ceramide synthesis or PKCζ rescued glucose intolerance in wild-type but not Angptl4-null mice. Angptl4 knockout mice; metabolomic profiling; PP2A and PKCζ activity assays; ceramide synthesis inhibitors; genetic epistasis Science signaling High 28743803
2018 Crystal structures of the fibrinogen-like domains of ANGPTL4 (and ANGPTL3) were solved, providing structural insights into loss-of-function mutation sites and potential mechanisms of LPL interaction. X-ray crystallography of fibrinogen-like domain Scientific reports Medium 29713054
2018 Adipose tissue-specific deletion of ANGPTL4 results in enhanced LPL activity, rapid clearance of circulating TAGs, increased adipose lipolysis and fatty acid oxidation, decreased hepatic ectopic lipid deposition, reduced nPKC membrane translocation, improved insulin signaling, improved glucose tolerance, and attenuated atherosclerosis in high-fat diet-fed mice. Adipose-specific Angptl4 knockout mice; LPL activity assays; metabolic turnover studies; insulin signaling assays; atherosclerosis quantification JCI insight High 29563332
2018 Brown adipose tissue-specific deletion of ANGPTL4 results in enhanced LPL activity, increased circulating TAG clearance, increased fatty acid oxidation, reduced fatty acid synthesis, improved glucose tolerance, and enhanced thermogenesis during cold exposure. BAT-specific Angptl4 knockout mice; LPL activity assays; fatty acid oxidation and synthesis measurements; cold exposure thermogenesis assay Molecular metabolism High 29627378
2018 In exercising skeletal muscle, Angptl4 treatment activates AMPK signaling (phosphorylation of AMPK and ACC) and increases mitochondrial maximum respiratory capacity; Angptl4-knockout mice show attenuated exercise-induced AMPK phosphorylation and reduced exercise endurance. C2C12 myotube treatment with recombinant Angptl4; Angptl4 knockout mice; treadmill and swimming endurance tests; AMPK/ACC phosphorylation assays Journal of applied physiology Medium 29952246
2019 TAZ directly regulates ANGPTL4 as a target gene; ANGPTL4 sensitizes ovarian cancer cells to ferroptosis by activating NOX2; TAZ removal confers ferroptosis resistance whereas constitutively active TAZ enhances susceptibility via the ANGPTL4-NOX2 axis. TAZ knockdown and overexpression; ANGPTL4 depletion; NOX2 activity assays; ferroptosis assays in ovarian cancer cell lines; integrative genomic analysis Molecular cancer research : MCR Medium 31641008
2019 ANGPTL4 from MSCs is induced by RORα in response to inflammatory mediators (IL-1β); RORα binds the ANGPTL4 promoter; ANGPTL4 secreted by MSCs suppresses macrophage polarization toward the pro-inflammatory phenotype, and ANGPTL4-deficient MSCs fail to inhibit inflammatory macrophage polarization. MSC-macrophage co-culture; ANGPTL4-deficient MSC generation; ChIP demonstrating RORα binding to ANGPTL4 promoter; peritonitis and myocardial infarction animal models JCI insight Medium 31434807
2020 ANGPTL8 forms complexes with ANGPTL4, and the ANGPTL4/8 complex has >100-fold reduced LPL-inhibitory activity compared to ANGPTL4 alone; conversely ANGPTL3/8 has >100-fold increased LPL-inhibitory activity vs ANGPTL3 alone. Insulin increases ANGPTL4/8 secretion from adipocytes, which during feeding blocks ANGPTL4-mediated LPL inhibition in adipose tissue, directing fatty acids toward fat storage. Quantitative LPL inhibition assays with recombinant proteins and complexes; immunoassay quantification of complexes in human serum; competition experiments; hepatocyte and adipocyte insulin treatment Journal of lipid research High 32487544
2020 Oleic acid induces ANGPTL4 expression in colorectal cancer cells; ANGPTL4 is required for c-Jun-mediated transactivation of NOX4, leading to increased ROS and upregulation of MMP-1 and MMP-9, promoting cancer cell metastasis. ANGPTL4 depletion abrogates oleic acid-induced NOX4 induction and metastatic seeding. ANGPTL4 knockdown; NOX4 transcription assays; ROS measurement; MMP expression; in vitro invasion assays; in vivo tumor extravasation model Theranostics Medium 32641980
2021 ANGPTL4 promotes the unfolding of LPL leading to LPL cleavage and subsequent degradation in adipocytes; ANGPTL8 opposes this by keeping LPL active after feeding. In macrophages and cardiomyocytes, ANGPTL4 acts as a lipid-inducible feedback regulator of LPL-mediated lipid uptake. In hepatocytes, ANGPTL4 functions as a local inhibitor of hepatic lipase. Review integrating mechanistic studies from multiple labs (genetic models, biochemical assays, unfolding experiments) Journal of lipid research High 34801488
2021 Hepatocyte-specific Angptl4 deficiency increases hepatic lipase (HL) activity, facilitating catabolism of TAG-rich lipoprotein remnants in the liver, reducing circulating TAG and cholesterol; it also promotes fatty acid uptake leading to increased fatty acid oxidation, ROS production, and AMPK activation in hepatocytes. Hepatocyte-specific Angptl4 mutant mice; metabolic turnover studies; hepatic lipase activity assays; fatty acid oxidation measurement; AMPK activation assays; liver-targeted antisense inhibition The Journal of clinical investigation High 34255741
2021 ANGPTL4 is a more potent inhibitor of endothelial lipase (EL) than ANGPTL3; formation of the ANGPTL4/8 complex markedly reduces ANGPTL4's EL-inhibitory activity, while ANGPTL3/8 complex formation increases EL inhibition compared to ANGPTL3 alone. In vitro recombinant protein EL inhibition assays; comparison of ANGPTL3, ANGPTL4, ANGPTL3/8, and ANGPTL4/8 complex activities Heliyon High 34504977
2022 Genetic mimicry analysis in >110,000 individuals demonstrates that ANGPTL4 suppression is highly concordant with LPL enhancement but not with hepatic lipase or EL suppression, indicating ANGPTL4 modulates plasma lipid parameters exclusively via LPL in humans. Human genetic mimicry analysis using UK Biobank (>110,000 subjects) and validation in 11 European populations; variant-level concordance analysis across 248 metabolic parameters Journal of lipid research High 36372100
2023 ANGPTL4 inhibits LPL by destabilizing lid-anchoring structures via binding overlapping with the APOC2 binding site on LPL; ANGPTL4 decreases LPL thermal stability and promotes irreversible unfolding of LPL's α/β-hydrolase domain, whereas APOC2 binding to the same region stabilizes LPL and protects it from unfolding. Hydrogen-deuterium exchange mass spectrometry (HDX-MS) mapping of binding sites on LPL; thermal stability assays; comparison of ANGPTL4 and APOC2 effects on LPL conformation Proceedings of the National Academy of Sciences of the United States of America High 37094117
2023 TGFβ stimulates ANGPTL4 vesicle trafficking and secretion through formin-like 2 (FMNL2); PKC-dependent phosphorylation of FMNL2 downstream of TGFβ is required; FMNL2 directly polymerizes actin at ANGPTL4-containing vesicles (associated with Rab8a and myosin Vb) to facilitate their mobility and cancer cell invasion. Super-resolution microscopy; FMNL2 knockdown and phosphorylation mutants; PKC inhibition; co-localization studies; actin polymerization assays at vesicles; invasion assays Advanced science Medium 36691769
2023 ANGPTL4 treatment in atherosclerotic Apoe−/− mice reduces vascular smooth muscle cell (SMC) phenotypic transition to macrophage-like cells by reducing TNFα-induced NOX1 activation, thereby suppressing KLF4 expression and preventing SMC dedifferentiation; this stabilizes atherosclerotic plaques by increasing fibrous cap thickness. ANGPTL4 protein injection in Apoe−/− mice; SMC phenotype assays (α-SMA, SM22α, KLF4, CD68 staining); NOX1 assays; fibrotic cap morphometry Experimental & molecular medicine Medium 36782020
2024 Podocyte- and tubule-secreted ANGPTL4 interacts with Integrin β1 and influences the association between dipeptidyl peptidase-4 (DPP4) and Integrin β1; this interaction drives fibrogenic signaling including STING pathway activation, pro-inflammatory cytokine expression, EMT, and mitochondrial damage in diabetic kidney disease. Podocyte- and tubule-specific Angptl4 mutant mice; diabetes model; co-IP/binding assays between ANGPTL4, Integrin β1, and DPP4; STING pathway assays; kidney-targeted antisense inhibition Science advances Medium 39630889
2020 Fasting in humans increases ANGPTL4 mRNA (+90%) and protein (+46%) in subcutaneous adipose tissue coincident with a 60% reduction in adipose LPL activity, without changes in LPL mRNA or protein; cortisol and fatty acids upregulate ANGPTL4 in primary human adipocytes while insulin downregulates it. Human clinical study with adipose biopsies before and after 26-h fast; LPL activity assay; ANGPTL4 mRNA and protein quantification; primary human adipocyte treatment with cortisol, fatty acids, and insulin Molecular metabolism High 32504883
2020 ANGPTL4 deficiency in haematopoietic cells promotes monocyte/myeloid progenitor expansion and atherosclerosis; macrophage ANGPTL4 deficiency increases CD36 expression and reduces ABCA1 surface localization, promoting foam cell formation; ANGPTL4-deficient common myeloid progenitors have higher lipid raft content and are more proliferative and less apoptotic. Bone marrow transplantation; atherosclerosis quantification; flow cytometry of myeloid progenitors; CD36 and ABCA1 expression and localization assays; lipid raft staining Nature communications High 27460411
2019 PPARβ/δ represses ANGPTL4 transcription in the absence of ligands by recruiting NCOR (identified as the main interactor by mass spectrometry), which reduces recruitment of Mediator subunits, RNA polymerase II, and TFIIB to the ANGPTL4 promoter; this repression is partially HDAC-independent. ChIP assays; mass spectrometry identification of PPARβ/δ interactors; PPARβ/δ mutant reconstitution in KO cells; RNA polymerase II and general transcription factor occupancy assays Nucleic acids research Medium 31428774
2020 Calcineurin (CaN) inhibitors reduce ANGPTL4 expression in podocytes via suppression of Nfatc1; ChIP assays demonstrate that Nfatc1 directly binds the Angptl4 promoter and increases its transcription; overexpression of ANGPTL4 in podocytes induces cytoskeletal rearrangement, reduces synaptopodin, and enhances apoptosis. PAN-induced nephrotic syndrome rat model; CaN inhibitor treatment; Nfatc1 overexpression and knockdown; ChIP assays; podocyte cytoskeletal and apoptosis assays The Journal of pathology Medium 32686149
2024 CAF-secreted ANGPTL4 binds to IQGAP1 on prostate cancer cell membranes, activating the Raf-MEK-ERK-PGC1α axis to promote mitochondrial biogenesis and oxidative phosphorylation metabolism, thereby facilitating cancer cell growth and chemoresistance. GST pull-down assay; Co-IP; proteomics of conditioned media; metabolomics; IQGAP1 inhibitor screening; in vitro and in vivo cancer models Journal of advanced research Medium 39647634
2024 SMAD3 (activated by TGF-β1 secreted by adipose-derived stem cells) directly binds to the ANGPTL4 promoter as shown by chromatin immunoprecipitation, upregulating ANGPTL4 transcription in colorectal cancer cells to promote glycolysis and anoikis resistance. ChIP assay; RNA sequencing; co-culture with adipose-derived stem cells; ANGPTL4 knockdown; in vivo peritoneal seeding model Cellular and molecular life sciences : CMLS Medium 38643448
2024 ANGPTL4/8 complex and the C-terminal domain-containing ANGPTL4 (CD-ANGPTL4) fragment are positively associated with inflammation (CRP), diabetes prevalence, and cardiovascular mortality in two independent large cohorts; ANGPTL3/8 potently inhibits GPIHBP1-bound LPL activity in recombinant protein assays. Recombinant protein LPL activity assay with GPIHBP1; dedicated immunoassays for ANGPTL3/8, ANGPTL4/8, CD-ANGPTL4 in 2394 LURIC and 6188 getABI participants; longitudinal outcome analysis Circulation Medium 39392008
2022 Angptl4 modulates monocyte-to-macrophage differentiation during wound healing via regulation of interferon activated gene ifi202b; Angptl4-mediated kinome signaling (involving S6K, JAK, CDK) controls ifi202b expression; silencing ifi202b in Angptl4-deficient monocytes rescues impaired monocyte-to-macrophage transition in vitro. Flow cytometry; single-cell RNA sequencing; unbiased kinase inhibitor screen; siRNA rescue experiments; Angptl4 knockout and LysM-specific knockout mice; wound healing models Cell death & disease Medium 35210411
2009 Induction of ANGPTL4 expression in airway smooth muscle cells by PKC activators requires activation of the Ras-MEK1/2-ERK1/2 pathway and the JNK pathway, but not the p38 MAPK pathway; knockdown of PKCα, MEK1/2, or JNK1/2 inhibits PMA-induced ANGPTL4 upregulation. PKC inhibitors; specific kinase inhibitors (U0126, SP600125, manumycin A); siRNA knockdown of PKCs, MEK1/2, JNK1/2; phosphorylation assays in HASM cells Experimental cell research Medium 20025870

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Characterization of the fasting-induced adipose factor FIAF, a novel peroxisome proliferator-activated receptor target gene. The Journal of biological chemistry 475 10862772
2016 Inactivating Variants in ANGPTL4 and Risk of Coronary Artery Disease. The New England journal of medicine 412 26933753
2016 Coding Variation in ANGPTL4, LPL, and SVEP1 and the Risk of Coronary Disease. The New England journal of medicine 412 26934567
2005 Transgenic angiopoietin-like (angptl)4 overexpression and targeted disruption of angptl4 and angptl3: regulation of triglyceride metabolism. Endocrinology 362 16081640
2019 A TAZ-ANGPTL4-NOX2 Axis Regulates Ferroptotic Cell Death and Chemoresistance in Epithelial Ovarian Cancer. Molecular cancer research : MCR 256 31641008
2014 Regulation of lipoprotein lipase by Angptl4. Trends in endocrinology and metabolism: TEM 164 24397894
2017 Potential Role of ANGPTL4 in the Cross Talk between Metabolism and Cancer through PPAR Signaling Pathway. PPAR research 137 28182091
2020 Angiopoietin-like protein 8 differentially regulates ANGPTL3 and ANGPTL4 during postprandial partitioning of fatty acids. Journal of lipid research 132 32487544
2020 ANGPTL4: a multifunctional protein involved in metabolism and vascular homeostasis. Current opinion in hematology 122 32205586
2021 Role and mechanism of the action of angiopoietin-like protein ANGPTL4 in plasma lipid metabolism. Journal of lipid research 113 34801488
2018 Absence of ANGPTL4 in adipose tissue improves glucose tolerance and attenuates atherogenesis. JCI insight 113 29563332
2014 Fatty acid-inducible ANGPTL4 governs lipid metabolic response to exercise. Proceedings of the National Academy of Sciences of the United States of America 113 24591600
2009 Genetic variation in ANGPTL4 provides insights into protein processing and function. The Journal of biological chemistry 112 19270337
1999 The nuclear actin-related protein of Saccharomyces cerevisiae, Act3p/Arp4, interacts with core histones. Molecular biology of the cell 107 10436015
2013 Role of Angptl4 in vascular permeability and inflammation. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 106 24173241
2010 Hypothalamic Angptl4/Fiaf is a novel regulator of food intake and body weight. Diabetes 98 20798332
2018 Brown adipose tissue derived ANGPTL4 controls glucose and lipid metabolism and regulates thermogenesis. Molecular metabolism 97 29627378
2019 RREB1-induced upregulation of the lncRNA AGAP2-AS1 regulates the proliferation and migration of pancreatic cancer partly through suppressing ANKRD1 and ANGPTL4. Cell death & disease 95 30814490
2012 Angiopoietin-like 4 (Angptl4) protein is a physiological mediator of intracellular lipolysis in murine adipocytes. The Journal of biological chemistry 94 22267746
2021 Hepatocyte-specific suppression of ANGPTL4 improves obesity-associated diabetes and mitigates atherosclerosis in mice. The Journal of clinical investigation 92 34255741
2019 Antiinflammatory activity of ANGPTL4 facilitates macrophage polarization to induce cardiac repair. JCI insight 88 31434807
2016 ANGPTL4 deficiency in haematopoietic cells promotes monocyte expansion and atherosclerosis progression. Nature communications 87 27460411
2015 Silencing Angiopoietin-Like Protein 4 (ANGPTL4) Protects Against Lipopolysaccharide-Induced Acute Lung Injury Via Regulating SIRT1 /NF-kB Pathway. Journal of cellular physiology 75 25727991
2013 ANGPTL4 expression induced by butyrate and rosiglitazone in human intestinal epithelial cells utilizes independent pathways. American journal of physiology. Gastrointestinal and liver physiology 73 23518684
2020 Pharmacological aspects of ANGPTL3 and ANGPTL4 inhibitors: New therapeutic approaches for the treatment of atherogenic dyslipidemia. Pharmacological research 68 31931117
2018 The Arp8 and Arp4 module acts as a DNA sensor controlling INO80 chromatin remodeling. Nature communications 64 30120252
2017 Hypoxia-induced ANGPTL4 sustains tumour growth and anoikis resistance through different mechanisms in scirrhous gastric cancer cell lines. Scientific reports 57 28894280
2020 Fasting induces ANGPTL4 and reduces LPL activity in human adipose tissue. Molecular metabolism 56 32504883
2010 Expression of angiopoietin-like 4 in human gastric cancer: ANGPTL4 promotes venous invasion. Oncology reports 56 20664963
2020 Oleic acid-induced NOX4 is dependent on ANGPTL4 expression to promote human colorectal cancer metastasis. Theranostics 54 32641980
2023 Dual role of ANGPTL4 in inflammation. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 52 37300585
2018 Increased plasma and adipose tissue levels of ANGPTL8/Betatrophin and ANGPTL4 in people with hypertension. Lipids in health and disease 46 29490644
2017 The glucocorticoid-Angptl4-ceramide axis induces insulin resistance through PP2A and PKCζ. Science signaling 44 28743803
2018 Structures of Angptl3 and Angptl4, modulators of triglyceride levels and coronary artery disease. Scientific reports 43 29713054
2017 The long non-coding RNA PVT1 represses ANGPTL4 transcription through binding with EZH2 in trophoblast cell. Journal of cellular and molecular medicine 43 29193797
2022 ANGPTL4 regulate glutamine metabolism and fatty acid oxidation in nonsmall cell lung cancer cells. Journal of cellular and molecular medicine 41 35285130
2017 Paeoniflorin ameliorates Adriamycin-induced nephrotic syndrome through the PPARγ/ANGPTL4 pathway in vivo and vitro. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 41 28972886
2012 Heterocomplex formation by Arp4 and β-actin is involved in the integrity of the Brg1 chromatin remodeling complex. Journal of cell science 41 22573825
2016 ANGPTL4 Correlates with NSCLC Progression and Regulates Epithelial-Mesenchymal Transition via ERK Pathway. Lung 40 27166634
2012 Intronic cis-regulatory modules mediate tissue-specific and microbial control of angptl4/fiaf transcription. PLoS genetics 37 22479192
2011 Angiopoietin-like 4 (ANGPTL4) gene polymorphisms and risk of brain arteriovenous malformations. Cerebrovascular diseases (Basel, Switzerland) 37 21212665
2021 Regulation of plasma triglyceride partitioning by adipose-derived ANGPTL4 in mice. Scientific reports 36 33846453
2023 Eucommia bark/leaf extract improves HFD-induced lipid metabolism disorders via targeting gut microbiota to activate the Fiaf-LPL gut-liver axis and SCFAs-GPR43 gut-fat axis. Phytomedicine : international journal of phytotherapy and phytopharmacology 35 36638713
2002 Correlation between chromatin association and transcriptional regulation for the Act3p/Arp4 nuclear actin-related protein of Saccharomyces cerevisiae. Nucleic acids research 35 11937627
2023 ANGPTL4 stabilizes atherosclerotic plaques and modulates the phenotypic transition of vascular smooth muscle cells through KLF4 downregulation. Experimental & molecular medicine 34 36782020
2020 Secreted Factors from Adipose Tissue Reprogram Tumor Lipid Metabolism and Induce Motility by Modulating PPARα/ANGPTL4 and FAK. Molecular cancer research : MCR 34 32859692
2023 Cancer-associated mesothelial cell-derived ANGPTL4 and STC1 promote the early steps of ovarian cancer metastasis. JCI insight 33 36795484
2012 AKT3, ANGPTL4, eNOS3, and VEGFA associations with high altitude sickness in Han and Tibetan Chinese at the Qinghai-Tibetan Plateau. International journal of hematology 33 22729570
2004 BAF53/Arp4 homolog Alp5 in fission yeast is required for histone H4 acetylation, kinetochore-spindle attachment, and gene silencing at centromere. Molecular biology of the cell 32 15483052
2021 The Pathogenic Role of Long Non-coding RNA H19 in Atherosclerosis via the miR-146a-5p/ANGPTL4 Pathway. Frontiers in cardiovascular medicine 31 34820432
2015 Angptl4 links α-cell proliferation following glucagon receptor inhibition with adipose tissue triglyceride metabolism. Proceedings of the National Academy of Sciences of the United States of America 31 26621734
2017 Serum level of ANGPTL4 as a potential biomarker in renal cell carcinoma. Urologic oncology 30 28110976
2020 ANGPTL4 exacerbates pancreatitis by augmenting acinar cell injury through upregulation of C5a. EMBO molecular medicine 29 32638512
2024 Adipose-derived stem cells promote glycolysis and peritoneal metastasis via TGF-β1/SMAD3/ANGPTL4 axis in colorectal cancer. Cellular and molecular life sciences : CMLS 28 38643448
2018 HDL-apoA-I induces the expression of angiopoietin like 4 (ANGPTL4) in endothelial cells via a PI3K/AKT/FOXO1 signaling pathway. Metabolism: clinical and experimental 28 29928895
2014 ANGPTL4 regulates the metastatic potential of oral squamous cell carcinoma. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 27 25060575
2007 Actin-related protein Arp4 functions in kinetochore assembly. Nucleic acids research 27 17452364
2015 Regulation and clinical significance of the hypoxia-induced expression of ANGPTL4 in gastric cancer. Oncology letters 26 26893686
2016 ANGPTL4 variants E40K and T266M are associated with lower fasting triglyceride levels and predicts cardiovascular disease risk in Type 2 diabetic Tunisian population. Lipids in health and disease 25 27004807
2021 ANGPTL4 accelerates KRASG12D-Induced acinar to ductal metaplasia and pancreatic carcinogenesis. Cancer letters 24 34311032
2021 DNA methylation mediated down-regulation of ANGPTL4 promotes colorectal cancer metastasis by activating the ERK pathway. Journal of Cancer 24 34405010
2024 Single-cell transcriptomic profiling of heart reveals ANGPTL4 linking fibroblasts and angiogenesis in heart failure with preserved ejection fraction. Journal of advanced research 23 38346487
2024 Renal Angptl4 is a key fibrogenic molecule in progressive diabetic kidney disease. Science advances 23 39630889
2021 Angiopoietin-like protein 4 (ANGPTL4) is an inhibitor of endothelial lipase (EL) while the ANGPTL4/8 complex has reduced EL-inhibitory activity. Heliyon 23 34504977
2020 Calcineurin inhibitors ameliorate PAN-induced podocyte injury through the NFAT-Angptl4 pathway. The Journal of pathology 23 32686149
2012 Mechanisms involved in biological behavior changes associated with Angptl4 expression in colon cancer cell lines. Oncology reports 23 22307217
2025 Safety and efficacy of a novel ANGPTL4 inhibitory antibody for lipid lowering: results from phase 1 and phase 1b/2a clinical studies. Lancet (London, England) 22 40383129
2020 Curcumin enhances chemotherapeutic effects and suppresses ANGPTL4 in anoikis-resistant cholangiocarcinoma cells. Heliyon 22 32051864
2020 ANGPTL4 Promotes the Proliferation of Papillary Thyroid Cancer via AKT Pathway. OncoTargets and therapy 22 32231436
2015 Lactobacillus rhamnosus CNCMI-4317 Modulates Fiaf/Angptl4 in Intestinal Epithelial Cells and Circulating Level in Mice. PloS one 22 26439630
2014 Promising role of ANGPTL4 gene in diabetic wound healing. The international journal of lower extremity wounds 22 24659626
2009 Induction of ANGPTL4 expression in human airway smooth muscle cells by PMA through activation of PKC and MAPK pathways. Experimental cell research 22 20025870
2024 Cancer-associated fibroblasts regulate mitochondrial metabolism and inhibit chemosensitivity via ANGPTL4-IQGAP1 axis in prostate cancer. Journal of advanced research 21 39647634
2022 Single-cell analysis of skin immune cells reveals an Angptl4-ifi20b axis that regulates monocyte differentiation during wound healing. Cell death & disease 21 35210411
2022 Genetic Mimicry Analysis Reveals the Specific Lipases Targeted by the ANGPTL3-ANGPTL8 Complex and ANGPTL4. Journal of lipid research 21 36372100
2021 Research Progress on the Involvement of ANGPTL4 and Loss-of-Function Variants in Lipid Metabolism and Coronary Heart Disease: Is the "Prime Time" of ANGPTL4-Targeted Therapy for Coronary Heart Disease Approaching? Cardiovascular drugs and therapy 21 32500296
2022 ANGPTL4 Regulates Psoriasis via Modulating Hyperproliferation and Inflammation of Keratinocytes. Frontiers in pharmacology 20 35860030
2018 Role of Angptl4/Fiaf in exercise-induced skeletal muscle AMPK activation. Journal of applied physiology (Bethesda, Md. : 1985) 20 29952246
2016 The downregulation of ANGPTL4 inhibits the migration and proliferation of tongue squamous cell carcinoma. Archives of oral biology 20 27505034
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 ANGPTL4 Regulates Lung Adenocarcinoma Pyroptosis and Apoptosis via NLRP3\ASC\Caspase 8 Signaling Pathway to Promote Resistance to Gefitinib. Journal of oncology 19 36467503
2020 MNK1 signaling induces an ANGPTL4-mediated gene signature to drive melanoma progression. Oncogene 19 32132651
2023 Inverse effects of APOC2 and ANGPTL4 on the conformational dynamics of lid-anchoring structures in lipoprotein lipase. Proceedings of the National Academy of Sciences of the United States of America 18 37094117
2021 Chronic high-fat feeding and prolonged fasting in liver-specific ANGPTL4 knockout mice. American journal of physiology. Endocrinology and metabolism 18 34396783
2021 Nickel chloride regulates ANGPTL4 via the HIF-1α-mediated TET1 expression in lung cells. Toxicology letters 18 34571076
2019 PRSS21/testisin inhibits ovarian tumor metastasis and antagonizes proangiogenic angiopoietins ANG2 and ANGPTL4. Journal of molecular medicine (Berlin, Germany) 18 30911775
2022 ANGPTL4 attenuates palmitic acid-induced endothelial cell injury by increasing autophagy. Cellular signalling 17 35843572
2023 ANGPTL4 inhibits granulosa cell proliferation in polycystic ovary syndrome by EGFR/JAK1/STAT3-mediated induction of p21. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 16 36607250
2021 ANGPTL4 Attenuates Ang II-Induced Atrial Fibrillation and Fibrosis in Mice via PPAR Pathway. Cardiology research and practice 16 34422410
2020 Danlou Tablet Improves Chronic Intermittent Hypoxia-Induced Dyslipidemia and Arteriosclerosis by HIF-1α-Angptl4 mRNA Signaling Pathway. Chinese journal of integrative medicine 16 32623702
2019 PPARβ/δ recruits NCOR and regulates transcription reinitiation of ANGPTL4. Nucleic acids research 16 31428774
2023 STAT2-induced linc02231 promotes tumorigenesis and angiogenesis through modulation of hnRNPA1/ANGPTL4 in colorectal cancer. The journal of gene medicine 15 36994700
2020 Growth hormone upregulates ANGPTL4 mRNA and suppresses lipoprotein lipase via fatty acids: Randomized experiments in human individuals. Metabolism: clinical and experimental 15 32084431
2024 SGLT2 inhibitor downregulates ANGPTL4 to mitigate pathological aging of cardiomyocytes induced by type 2 diabetes. Cardiovascular diabetology 14 39633372
2023 Vesicle-Associated Actin Assembly by Formins Promotes TGFβ-Induced ANGPTL4 Trafficking, Secretion and Cell Invasion. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 14 36691769
2023 HIF-1α regulates osteoclastogenesis and alveolar bone resorption in periodontitis via ANGPTL4. Archives of oral biology 14 37290266
2022 ANGPTL4, IL-6 and TNF-α as regulators of lipid metabolism during a marathon run. Scientific reports 14 36402848
2020 Aberrant hydroxymethylation of ANGPTL4 is associated with selective intrauterine growth restriction in monochorionic twin pregnancies. Epigenetics 14 32114885
2020 EZH2 inhibition promotes ANGPTL4/CREB1 to suppress the progression of ulcerative colitis. Life sciences 14 32194081
2020 The Actin-Family Protein Arp4 Is a Novel Suppressor for the Formation and Functions of Nuclear F-Actin. Cells 14 32204557