{"gene":"ANGPTL4","run_date":"2026-06-09T22:02:43","timeline":{"discoveries":[{"year":2000,"finding":"ANGPTL4 (FIAF) is a direct transcriptional target of PPARα and PPARγ. It is secreted into blood plasma, and its plasma levels increase with fasting and decrease with chronic high-fat feeding, indicating an endocrine function in metabolic regulation.","method":"Subtractive hybridization (SABRE), Western blotting of plasma, PPARα-null mouse model","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — identified by subtractive hybridization and validated in knockout mice, replicated across multiple conditions with orthogonal methods; foundational discovery paper","pmids":["10862772"],"is_preprint":false},{"year":2002,"finding":"Hypoxia induces ANGPTL4 (PGAR) expression in cardiomyocytes via HIF-1α, not via the PPARα/RXR pathway, as demonstrated by adenoviral overexpression of HIF-1α and pharmacological hypoxia mimetics.","method":"Adenoviral HIF-1α overexpression, CoCl2/desferrioxamine treatment, RT-PCR in neonatal rat cardiomyocytes","journal":"Journal of molecular and cellular cardiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal approaches (gain-of-function and chemical mimetics), single lab","pmids":["12099716"],"is_preprint":false},{"year":2004,"finding":"ANGPTL4 (FIAF) is present in human and mouse blood plasma in both a full-length and a truncated (cleaved) form. Differentiated 3T3-L1 adipocytes produce truncated FIAF, human liver produces truncated FIAF, and fenofibrate (PPARα agonist) treatment increases circulating truncated FIAF but not native FIAF. A functional PPAR response element was identified within intron 3 of the FIAF gene.","method":"Western blotting of plasma, chromatin immunoprecipitation (ChIP), gel shift/EMSA, transactivation assays, cell differentiation experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — ChIP, EMSA, transactivation, and protein analysis in multiple cell/tissue types; multiple orthogonal methods in a single rigorous study","pmids":["15190076"],"is_preprint":false},{"year":2007,"finding":"ANGPTL4 overexpression in mice inhibits LPL-dependent plasma triglyceride clearance by converting endothelial-bound LPL dimers to circulating LPL monomers, thereby reducing LPL activity and impairing cholesterol/fatty acid uptake into tissues, which secondarily upregulates hepatic cholesterol and fatty acid synthesis pathways.","method":"Angptl4-transgenic mouse model, post-heparin LPL activity assays, isotopic lipoprotein clearance studies","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo transgenic mouse model with multiple orthogonal metabolic readouts; mechanism of LPL dimer-to-monomer conversion directly measured","pmids":["17761937"],"is_preprint":false},{"year":2009,"finding":"ANGPTL4 forms dimers and tetramers intracellularly prior to secretion. After secretion, it is cleaved at a proprotein convertase site (RRKR161-164), releasing an oligomeric N-terminal domain and a monomeric C-terminal fibrinogen-like domain. Oligomerization (not cleavage) is required for LPL inhibition. The E40K variant is synthesized and processed normally but fails to accumulate as extracellular oligomers and cannot inhibit LPL activity.","method":"HEK-293A cell expression, oligomerization assays, LPL inhibition assays, proprotein convertase inhibition, E40K mutant analysis, parallel mouse experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution in cells and in vivo (mice), site-directed mutagenesis, functional LPL assays, multiple orthogonal methods in one study","pmids":["19270337"],"is_preprint":false},{"year":2010,"finding":"Hypothalamic ANGPTL4 suppresses food intake and increases energy expenditure by inhibiting hypothalamic AMPK activity. Intracerebroventricular administration of ANGPTL4 suppresses food intake and body weight gain; Angptl4-null mice show increased hypothalamic AMPK activity, increased food intake, and decreased energy expenditure.","method":"Intracerebroventricular (ICV) ANGPTL4 injection, Angptl4-null mouse model, AMPK activity assays, metabolic cage measurements","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function and gain-of-function approaches, multiple phenotypic readouts, ICV delivery placing ANGPTL4 upstream of hypothalamic AMPK","pmids":["20798332"],"is_preprint":false},{"year":2012,"finding":"Discrete tissue-specific cis-regulatory modules within ANGPTL4 intron 3 drive expression in the liver, pancreatic islet β-cells, and intestinal enterocytes. The microbiota suppresses the transcriptional activity of the intestine-specific regulatory module, reducing intestinal ANGPTL4 expression and thereby modulating peripheral fat storage.","method":"Zebrafish in vivo transgenic reporter assays, site-directed mutagenesis of regulatory modules, gnotobiotic zebrafish colonization experiments","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vivo transgenic reporter assays plus mutagenesis in a gnotobiotic vertebrate model; multiple tissue contexts tested","pmids":["22479192"],"is_preprint":false},{"year":2012,"finding":"PPARβ/δ drives ANGPTL4 transcription; synthetic inverse agonists of PPARβ/δ suppress ANGPTL4 expression and secretion by inducing a dominant transcriptional repressor complex at the ANGPTL4 transcription initiation site via a non-canonical, HDAC-independent mechanism. Suppression of ANGPTL4 transcription is functionally linked to reduced cancer cell invasion into 3D matrices.","method":"ChIP-Seq, microarray, inverse agonist treatment, ANGPTL4 knockdown, recombinant ANGPTL4 rescue, 3D invasion assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — ChIP-Seq identifies binding sites, multiple orthogonal methods (KD, rescue with recombinant protein, pharmacological), functional invasion assays","pmids":["23208498"],"is_preprint":false},{"year":2013,"finding":"Butyrate induces intestinal ANGPTL4 expression independently of PPARγ, using a butyrate-responsive element ~0.5 kb upstream of the transcription start site, while PPARγ agonists act via a distinct PPAR-responsive element downstream of the transcription start site; the two pathways are additive.","method":"PPARγ-independent reporter assays, PPAR agonist/antagonist treatment, germ-free mouse colonization with Clostridium tyrobutyricum, butyrate gavage","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo (germ-free mice), multiple orthogonal approaches, single lab","pmids":["23518684"],"is_preprint":false},{"year":2015,"finding":"Adipose ANGPTL4 is upregulated via PPARγ activation following glucagon receptor antagonist treatment and promotes α-cell proliferation specifically; glucagon receptor antagonist fails to induce α-cell proliferation in Angptl4-knockout mice, placing ANGPTL4 on the pathway linking adipose lipid metabolism to pancreatic α-cell expansion.","method":"Angptl4 knockout mice, glucagon receptor antagonist treatment, Angptl4 supplementation, adipose PPARγ activation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis using knockout mice plus pharmacological intervention, single lab","pmids":["26621734"],"is_preprint":false},{"year":2016,"finding":"Haematopoietic ANGPTL4 deficiency in macrophages promotes foam cell formation by enhancing CD36 expression and reducing ABCA1 surface localization, and increases common myeloid progenitor expansion (higher lipid raft content, increased proliferation, decreased apoptosis), leading to larger atherosclerotic plaques with bigger necrotic cores.","method":"Bone marrow transplantation (haematopoietic-specific KO), flow cytometry, CD36 and ABCA1 localization assays, atherosclerotic lesion analysis in hyperlipidemic mice","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific knockout with multiple orthogonal mechanistic readouts; localization and functional experiments","pmids":["27460411"],"is_preprint":false},{"year":2017,"finding":"ANGPTL4 mediates glucocorticoid-induced insulin resistance by promoting lipolysis in white adipose tissue, increasing hepatic ceramide concentrations (by inducing ceramide synthetic pathway enzymes), and activating PP2A and PKCζ downstream of ceramide. Angptl4-null mice are protected from glucocorticoid-induced glucose intolerance.","method":"Angptl4-knockout mouse model, metabolomic profiling, pharmacological inhibition of ceramide synthesis (myriocin) and PKCζ, PP2A/PKCζ activity assays","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — knockout mice + metabolomics + pharmacological inhibitors + pathway activity assays; multiple orthogonal methods establishing mechanistic axis","pmids":["28743803"],"is_preprint":false},{"year":2018,"finding":"Crystal structures of the fibrinogen-like (C-terminal) domains of ANGPTL4 and ANGPTL3 were solved, providing structural insights into known loss-of-function mutations and the mechanism of action of these proteins.","method":"X-ray crystallography","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure determination; structural basis for mechanistic interpretation of loss-of-function mutations","pmids":["29713054"],"is_preprint":false},{"year":2018,"finding":"Adipose tissue-specific deletion of ANGPTL4 results in enhanced LPL activity, rapid clearance of circulating TAGs, increased adipose lipolysis and FA oxidation, decreased FA synthesis, prevention of ectopic lipid deposition in liver and muscle, reduced nPKC membrane translocation, improved insulin signaling and glucose tolerance, and attenuated atherosclerosis.","method":"Adipose-specific Angptl4 knockout mice, LPL activity assays, metabolic turnover studies, nPKC translocation assays, glucose tolerance tests, atherosclerosis lesion analysis","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific KO with multiple mechanistic readouts across metabolic pathways; nPKC translocation links ANGPTL4-mediated lipid deposition to insulin signaling","pmids":["29563332"],"is_preprint":false},{"year":2018,"finding":"Brown adipose tissue (BAT)-specific deletion of ANGPTL4 results in enhanced LPL activity, increased circulating TAG clearance, increased FA oxidation, reduced FA synthesis, improved glucose tolerance, and enhanced thermogenesis during acute cold exposure.","method":"BAT-specific Angptl4 knockout mice, LPL activity assays, metabolic measurements, cold exposure experiments","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific KO, multiple metabolic phenotypic readouts, functional thermogenesis assay","pmids":["29627378"],"is_preprint":false},{"year":2019,"finding":"In mesenchymal stem cells (MSCs), ANGPTL4 expression is induced by RORα in response to inflammatory mediators (IL-1β). Secreted ANGPTL4 from MSCs suppresses macrophage polarization toward a proinflammatory phenotype; ANGPTL4-deficient MSCs fail to inhibit inflammatory macrophage polarization. Exogenous ANGPTL4 protein improves cardiac function following myocardial infarction.","method":"MSC-macrophage co-culture, ANGPTL4-deficient MSCs, RORα overexpression, ChIP showing RORα binding to ANGPTL4 promoter, peritonitis and MI animal models","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function co-culture, ChIP, multiple in vivo models, with mechanistic identification of upstream RORα","pmids":["31434807"],"is_preprint":false},{"year":2019,"finding":"ANGPTL4 deficiency in macrophages increases lipid uptake and cellular respiration without affecting LPL protein levels. Low levels of N-terminal ANGPTL4 (in hypomorphic mice) mitigate chylous ascites and acute-phase response compared with complete ANGPTL4 absence during high-fat feeding.","method":"Angptl4-knockout and Angptl4-hypomorphic mouse models, macrophage lipid uptake assays, LPL protein level measurement, respiratory assays, serum amyloid A measurement","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 2 / Strong — two complementary genetic mouse models with multiple orthogonal functional readouts","pmids":["31409739"],"is_preprint":false},{"year":2019,"finding":"ANGPTL4 is a direct transcriptional target of TAZ (Hippo pathway effector) and sensitizes ovarian cancer cells to ferroptosis by activating NOX2 (NADPH oxidase 2). TAZ removal confers ferroptosis resistance; TAZS89A overexpression sensitizes cells; ANGPTL4 loss abolishes TAZ-mediated ferroptosis sensitization.","method":"TAZ knockdown and overexpression, ANGPTL4 knockdown, genomic integration/transcriptomics, ferroptosis assays","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function and gain-of-function in cell lines, integrative genomic analysis, single lab","pmids":["31641008"],"is_preprint":false},{"year":2019,"finding":"ANGPTL4 inhibits LPL by triggering cooperative and sequential unfolding of LPL's α/β-hydrolase domain, resulting in irreversible collapse of the catalytic cavity. GPIHBP1 binding to LPL protects against ANGPTL4-mediated unfolding.","method":"Hydrogen-deuterium exchange/mass spectrometry, LPL thermal stability assays, GPIHBP1 protection assays (reviewed in detail in 2021 paper PMID:34336854 which cites earlier work)","journal":"Frontiers in cell and developmental biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — biophysical (HDX-MS) mapping of conformational changes plus functional assays; mechanistic model well-supported and cited as established","pmids":["34336854"],"is_preprint":false},{"year":2020,"finding":"ANGPTL8 forms complexes with ANGPTL4; the ANGPTL4/8 complex has >100-fold less LPL-inhibitory activity than ANGPTL4 alone (while ANGPTL3/8 is >100-fold more potent than ANGPTL3). Insulin increases ANGPTL4/8 secretion from adipocytes during feeding, locally blocking ANGPTL4-mediated LPL inhibition in adipose tissue, thereby directing FA toward fat rather than muscle.","method":"Immunoassay quantification of complexes in human serum, recombinant protein LPL-inhibitory activity assays, competition experiments, insulin treatment of hepatocytes and adipocytes","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — recombinant protein activity assays with quantitative kinetics, competition experiments, and cell-based validation; multiple orthogonal methods","pmids":["32487544"],"is_preprint":false},{"year":2020,"finding":"Fasting increases ANGPTL4 mRNA and protein levels in human adipose tissue and plasma, concurrent with decreased LPL activity (-60%), while LPL mRNA and protein remain unchanged. Decreased plasma insulin (which downregulates ANGPTL4 in primary human adipocytes) and increased cortisol and free fatty acids (which upregulate ANGPTL4) are the hormonal mediators.","method":"Human adipose tissue biopsies (fasting/fed), LPL activity assays, primary human adipocyte culture with insulin/cortisol/fatty acid treatments, plasma ANGPTL4 ELISA","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — human clinical study validated by primary human adipocyte mechanistic experiments; consistent with mouse data, multiple readouts","pmids":["32504883"],"is_preprint":false},{"year":2020,"finding":"ANGPTL4 depletion in CRC cells significantly inhibited c-Jun-mediated transactivation of NOX4 expression, reducing ROS, MMP-1, and MMP-9 levels and disrupting oleic acid-promoted CRC metastasis in vitro and in vivo.","method":"ANGPTL4 knockdown, NOX4 reporter/luciferase assays, ROS measurement, MMP knockdown, in vivo tumor metastasis assay","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown plus pathway assays in vitro and in vivo, single lab","pmids":["32641980"],"is_preprint":false},{"year":2021,"finding":"Hepatocyte-specific Angptl4 deficiency facilitates catabolism of TAG-rich lipoprotein remnants via increased hepatic lipase (HL) activity, significantly reducing circulating TAG and cholesterol. Loss of hepatic Angptl4 also promotes FA uptake, FA oxidation, ROS production, and AMPK activation. Liver-targeted pharmacologic inhibition of Angptl4 recapitulates these effects.","method":"Hepatocyte-specific Angptl4 mutant mice, metabolic turnover studies, HL activity assays, FA oxidation measurements, AMPK activation assays, liver-targeted ASO pharmacology","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific genetic model plus metabolic turnover studies plus pharmacologic validation; multiple orthogonal methods","pmids":["34255741"],"is_preprint":false},{"year":2021,"finding":"ANGPTL4 is an inhibitor of endothelial lipase (EL) and is a more potent EL inhibitor than ANGPTL3. Formation of the ANGPTL4/8 complex reduces EL-inhibitory activity of ANGPTL4, in contrast to ANGPTL3/8 which increases EL-inhibitory activity of ANGPTL3.","method":"Recombinant ANGPTL protein EL-inhibitory activity assays, comparison of complex vs. free forms","journal":"Heliyon","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstituted enzyme inhibition assays; single lab, single method type","pmids":["34504977"],"is_preprint":false},{"year":2021,"finding":"Genetic mimicry analysis in humans shows that ANGPTL4 suppression is highly concordant with LPL enhancement but not with HL or EL, demonstrating that ANGPTL4 modulates plasma metabolic parameters exclusively via LPL in humans.","method":"Human genetics/genetic mimicry analysis using UK Biobank (>110,000 participants) and 11 European cohorts; comparison of metabolic trait profiles for ANGPTL4 vs. LPL, LIPC, LIPG variants","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 2 / Strong — large-scale human genetic epistasis/mimicry analysis replicated across multiple cohorts; strong preponderance of evidence for LPL specificity","pmids":["36372100"],"is_preprint":false},{"year":2021,"finding":"ANGPTL4 inhibits LPL by promoting unfolding of LPL's hydrolase domain, leading to irreversible cleavage and degradation of LPL. ANGPTL8 binding to ANGPTL4 reduces this inhibitory activity, keeping LPL active in adipose tissue after feeding.","method":"Review synthesizing LPL unfolding studies, ANGPTL4/ANGPTL8 interaction studies, and tissue-specific LPL activity measurements (cited mechanistic studies)","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — synthesis of mechanistic studies including LPL unfolding assays and ANGPTL8 interaction studies; well-replicated across multiple labs","pmids":["34801488"],"is_preprint":false},{"year":2021,"finding":"Adipocyte-specific ANGPTL4 deficiency recapitulates the triglyceride phenotype of whole-body deficiency (increased adipose LPL activity, lower plasma TG, increased adipose TAG uptake), confirming adipocyte-derived ANGPTL4 as the primary source regulating plasma TG partitioning under normal diet conditions.","method":"Adipocyte-specific Angptl4 knockout mice (HFD and normal diet), LPL activity assays, triglyceride clearance and uptake assays, glucose homeostasis measurements","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — tissue-specific KO with functional assays; single lab, confirms findings from other adipose-KO studies","pmids":["33846453"],"is_preprint":false},{"year":2019,"finding":"Chronic dexamethasone (glucocorticoid) treatment induces an ANGPTL4-ceramide-PKCζ axis that activates hepatic de novo lipogenesis and triglyceride synthesis. Myriocin (ceramide synthesis inhibitor) and PKCζ inhibitor both reduce dexamethasone-induced lipid disorders in WT but not Angptl4-null mice, placing ceramide-PKCζ downstream of ANGPTL4.","method":"Stable isotope labeling for hepatic lipogenesis, Angptl4-null mice, myriocin treatment, AAV-shRNA targeting Sptlc2, PKCζ inhibitor (ACPD) treatment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — isotope labeling, genetic KO, multiple pharmacological interventions targeting different nodes of the pathway, single lab but multiple orthogonal methods","pmids":["31053639"],"is_preprint":false},{"year":2020,"finding":"ANGPTL4 exacerbates pancreatitis by activating macrophage infiltration via PI3K/AKT signaling, increasing complement component 5a (C5a) levels, which activates C5a receptor leading to hypercytokinemia and acinar cell damage. ANGPTL4 deficiency or neutralizing antibody mitigates pancreatitis severity.","method":"Angptl4 knockout mice, neutralizing antibody treatment, exogenous ANGPTL4 administration, C5a neutralizing antibody, LPS-activated macrophage assays, PI3K/AKT inhibition","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO, antibody neutralization, and pharmacological pathway inhibition; single lab with multiple approaches","pmids":["32638512"],"is_preprint":false},{"year":2020,"finding":"Calcineurin (CaN) inhibitors protect against PAN-induced podocyte injury by inhibiting NFAT (Nfatc1), which directly binds the Angptl4 promoter to drive Angptl4 expression. ANGPTL4 overexpression in podocytes induces cytoskeletal rearrangement, reduces synaptopodin, and enhances apoptosis.","method":"PAN-induced MCD rat model, CaN inhibitor treatment, Nfatc1 overexpression/knockdown, ChIP assay (Nfatc1 binding to Angptl4 promoter), ANGPTL4 overexpression/knockdown in podocytes","journal":"The Journal of pathology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — ChIP demonstrates direct NFAT binding to Angptl4 promoter; loss-of-function and gain-of-function in cell and animal models; mechanistic chain established","pmids":["32686149"],"is_preprint":false},{"year":2021,"finding":"G protein-coupled estrogen receptor (GPER) stimulates trophoblast cell invasion by activating YAP (Hippo pathway effector) via an MST1-independent mechanism, which in turn drives ANGPTL4 expression. ANGPTL4 is required for GPER-stimulated trophoblast invasion.","method":"GPER agonist (G1) treatment, RNA-seq, YAP pharmacological inhibitors, loss- and gain-of-function experiments, Transwell invasion assays","journal":"Communications biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-seq plus pharmacological and genetic loss/gain-of-function approaches; single lab","pmids":["34773076"],"is_preprint":false},{"year":2023,"finding":"APOC2 and ANGPTL4 bind overlapping sites on LPL (regions surrounding the catalytic pocket and lid-anchoring structures), but have opposite effects on LPL conformation: ANGPTL4 destabilizes lid-anchoring structures promoting LPL inactivation, while APOC2 stabilizes them and increases LPL thermal stability.","method":"Hydrogen-deuterium exchange/mass spectrometry (HDX-MS), LPL thermal stability assays, competition binding experiments","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — HDX-MS with mechanistic binding site mapping; rigorous biophysical characterization of opposing allosteric effects on LPL","pmids":["37094117"],"is_preprint":false},{"year":2024,"finding":"Recombinant protein assays demonstrate that ANGPTL3/8 complex potently inhibits GPIHBP1-bound LPL activity. CD-ANGPTL4 (C-terminal domain-containing fragment generated by furin or plasmin cleavage) is positively associated with cardiovascular mortality and inflammation in two large cohort studies; ANGPTL4/8 complex formation converts ANGPTL4 from a furin substrate to a plasmin substrate.","method":"Recombinant protein GPIHBP1-LPL activity assays, dedicated immunoassays in LURIC (n=2394) and getABI (n=6188) cohorts, cardiovascular mortality follow-up","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro reconstitution of GPIHBP1-LPL inhibition plus large-scale human cohort validation; two independent cohorts replicate the clinical associations","pmids":["39392008"],"is_preprint":false},{"year":2024,"finding":"Both podocyte- and tubule-derived ANGPTL4 are fibrogenic in diabetic kidneys. Secreted ANGPTL4 from these cells interacts with Integrin β1 and influences the association between DPP-4 and Integrin β1. ANGPTL4 mutant mice are protected from diabetes-accelerated fibrosis, showing reduced STING pathway activation, reduced EMT/EndoMT, and increased FA oxidation.","method":"Podocyte- and tubule-specific ANGPTL4 mutant mice, diabetic mouse model, Co-IP (ANGPTL4-Integrin β1), DPP-4/Integrin β1 association assays, kidney-targeted pharmacologic inhibition","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — cell type-specific genetic models, Co-IP identifying binding partners, pharmacologic validation; multiple orthogonal mechanistic readouts","pmids":["39630889"],"is_preprint":false},{"year":2023,"finding":"In atherosclerotic mice, ANGPTL4 protein treatment inhibits phenotypic transition of vascular smooth muscle cells into macrophage-like cells by downregulating NOX1 (NADPH oxidase 1) activation of KLF4, reducing KLF4-mediated SMC dedifferentiation and stabilizing atherosclerotic plaques.","method":"ANGPTL4 protein injection in Apoe-/- atherosclerotic mice, SMC isolation and phenotype analysis, NOX1 and KLF4 expression assays, fibrous cap thickness measurements","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — recombinant protein treatment in vivo with mechanistic pathway analysis; single lab, multiple readouts","pmids":["36782020"],"is_preprint":false},{"year":2024,"finding":"ANGPTL4 activates JAK2/STAT3 signaling in ovarian cancer cells to promote proliferation and invasion. ANGPTL4 also interacts with ESM1, which promotes ANGPTL4 binding to LPL (reprogramming lipid metabolism), and interferes with ANGPTL4 binding to integrin and VE-cadherin (stabilizing vascular integrity to promote angiogenesis).","method":"RNA-seq, Co-IP, molecular docking, MTT/EdU/wound healing/transwell assays, xenograft model, CAM assay, zebrafish model, Western blot for JAK2-STAT3 pathway","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and molecular docking identify interactions; multiple functional assays; single lab","pmids":["38212795"],"is_preprint":false},{"year":2019,"finding":"PPARβ/δ inverse agonist PT-S264 impairs ANGPTL4 transcription initiation by decreasing recruitment of activating Mediator subunits, RNA polymerase II, and TFIIB (but not TFIIA) to the ANGPTL4 promoter. NCOR is the main PT-S264-dependent interactor of PPARβ/δ, identified by mass spectrometry.","method":"ChIP for Mediator/PolII/TFIIB/TFIIA at ANGPTL4 promoter, mass spectrometry of PPARβ/δ interactors, PPARβ/δ basal-repression mutant reconstitution in KO cells","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — ChIP, mass spectrometry, and reconstitution experiments with mechanistic mutants; multiple orthogonal methods","pmids":["31428774"],"is_preprint":false},{"year":2021,"finding":"In macrophage foam cells, ANGPTL4 deficiency promotes foam cell formation through enhanced CD36 expression and reduced surface ABCA1; in macrophages, recombinant ANGPTL4 decreases lipid uptake. ANGPTL4 deficiency does not alter LPL protein levels in macrophages (negative finding for that specific mechanism).","method":"Recombinant ANGPTL4 treatment of macrophages, ANGPTL4-deficient macrophage lipid uptake assays, CD36/ABCA1 localization, LPL protein measurement","journal":"Nature communications / Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — recombinant protein and knockout approaches; confirmed in multiple papers (PMID:27460411, PMID:31409739); single phenotypic domain","pmids":["27460411","31409739"],"is_preprint":false},{"year":2018,"finding":"Angptl4 is required for exercise-induced AMPK activation in skeletal muscle. Angptl4 treatment of C2C12 myotubes increases AMPK and ACC phosphorylation and mitochondrial maximum respiratory capacity. Exercise-induced AMPK and ACC phosphorylation is attenuated in Angptl4-knockout mice, and endurance is reduced.","method":"Treadmill exercise in Angptl4-knockout vs. WT mice, recombinant Angptl4 treatment of myotubes, AMPK/ACC phosphorylation assays, Seahorse respirometry","journal":"Journal of applied physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mice plus cell-based gain-of-function; single lab, multiple phenotypic readouts","pmids":["29952246"],"is_preprint":false},{"year":2024,"finding":"TGF-β1 secreted by adipose-derived stem cells (ADSCs) activates SMAD3 in CRC cells, and SMAD3 directly binds the ANGPTL4 promoter (shown by ChIP) to drive ANGPTL4 transcription, which promotes glycolysis and anoikis resistance in CRC cells.","method":"RNA sequencing, ChIP assay (SMAD3 binding to ANGPTL4 promoter), co-culture experiments, in vivo intraperitoneal seeding model","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP directly shows SMAD3 binding to ANGPTL4 promoter; functional in vitro and in vivo validation; single lab","pmids":["38643448"],"is_preprint":false},{"year":2022,"finding":"Angptl4 regulates monocyte differentiation to macrophages during wound healing via a novel Angptl4-ifi202b axis. In Angptl4-deficient wounds, ifi202b is elevated and monocyte-to-macrophage transition is impaired. An unbiased kinase inhibitor screen revealed an Angptl4-mediated kinome network involving S6K, JAK, and CDK that modulates ifi202b expression. Silencing ifi202b in Angptl4-deficient monocytes rescues impaired monocyte-to-macrophage transition.","method":"Angptl4-knockout mice, single-cell RNA sequencing, flow cytometry, kinase inhibitor screen, ifi202b knockdown rescue experiments","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mice plus scRNA-seq plus pharmacological screen plus rescue experiments; single lab, complex multi-method study","pmids":["35210411"],"is_preprint":false},{"year":2024,"finding":"CAF-derived ANGPTL4 binds to IQGAP1 on PCa cell membranes, activating the Raf-MEK-ERK-PGC1α axis to promote mitochondrial biogenesis and OXPHOS metabolism, facilitating prostate cancer growth and chemoresistance.","method":"Proteomic analysis of conditioned media, GST pull-down, Co-IP (ANGPTL4-IQGAP1), metabolomics, drug screening (QGGP as IQGAP1 inhibitor)","journal":"Journal of advanced research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and GST pull-down identify ANGPTL4-IQGAP1 interaction; metabolomics and pathway assays; single lab","pmids":["39647634"],"is_preprint":false},{"year":2017,"finding":"The ANGPTL4 T266M variant in the C-terminal domain binds integrin α5β1 with reduced affinity compared to wild-type, leading to weaker activation of downstream signaling molecules, impaired tumor cell proliferation, anoikis resistance, and migratory capability. C-terminal ANGPTL4 also regulates Glut2 expression.","method":"Integrin α5β1 binding assays, signaling pathway analysis (downstream of integrin), proliferation/anoikis/migration assays, Glut2 expression measurement","journal":"Biochimica et biophysica acta. Molecular cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding affinity measurements plus functional assays with mutant protein; single lab","pmids":["28641978"],"is_preprint":false},{"year":2024,"finding":"SGLT2 inhibitor (SGLT2i) reduces ANGPTL4 expression by regulating the upstream transcription factor FOXO1, which directly drives ANGPTL4 transcription under hyperglycemia/hyperlipidemia conditions. ANGPTL4 knockdown reduces cardiomyocyte senescence; ANGPTL4 overexpression worsens it. ChIP-qPCR confirms FOXO1 binding to the ANGPTL4 promoter.","method":"DCM mouse model, AC16 human cardiomyocyte model, ANGPTL4 knockdown/overexpression, RNA-seq, ChIP-qPCR (FOXO1 binding to ANGPTL4 promoter), SGLT2i treatment","journal":"Cardiovascular diabetology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-qPCR identifies FOXO1 as direct upstream regulator of ANGPTL4; KD and OE with phenotypic readout; single lab","pmids":["39633372"],"is_preprint":false}],"current_model":"ANGPTL4 is a secreted glycoprotein that primarily functions as a context-dependent inhibitor of lipoprotein lipase (LPL): it binds LPL adjacent to the catalytic cavity, triggering cooperative irreversible unfolding of LPL's hydrolase domain, converting active LPL dimers to inactive monomers and thereby raising circulating triglycerides; this inhibitory activity requires N-terminal oligomerization, is opposed by ANGPTL8 (which forms a less-inhibitory complex with ANGPTL4) and GPIHBP1 (which stabilizes LPL against unfolding), and is abolished by the E40K loss-of-function variant. Transcriptionally, ANGPTL4 is induced by PPARα/β/δ/γ, HIF-1α, NFAT, RORα, TAZ/YAP, SMAD3, and FOXO1, and is suppressed by gut microbiota via an intronic cis-regulatory module. Beyond lipid metabolism, ANGPTL4 acts in the hypothalamus to suppress AMPK and food intake, mediates glucocorticoid-induced insulin resistance through a ceramide-PKCζ axis, modulates macrophage lipid uptake via CD36/ABCA1, binds Integrin β1 (in kidney fibrosis) and Integrin α5β1 (in cancer cells), activates NOX2 to sensitize cells to ferroptosis, regulates monocyte-to-macrophage differentiation during wound healing via an ifi202b axis, and promotes anti-inflammatory macrophage polarization and tissue repair through a RORα-dependent mechanism."},"narrative":{"mechanistic_narrative":"ANGPTL4 is a secreted, PPAR-regulated glycoprotein that governs the partitioning of circulating lipids across tissues by acting as a context-dependent inhibitor of lipoprotein lipase (LPL) [PMID:10862772, PMID:17761937]. Originally identified as a fasting-induced, PPARα/γ transcriptional target whose plasma levels track nutritional state [PMID:10862772], it is processed after secretion into an oligomeric N-terminal domain and a fibrinogen-like C-terminal domain, with N-terminal oligomerization—not proprotein-convertase cleavage—being required for LPL inhibition; the E40K variant is processed normally but fails to form extracellular oligomers and cannot inhibit LPL [PMID:19270337]. Mechanistically, ANGPTL4 binds LPL near the catalytic cavity and triggers cooperative, irreversible unfolding of the α/β-hydrolase domain, converting active endothelial-bound LPL dimers to inactive monomers and raising plasma triglycerides [PMID:17761937, PMID:34336854]; this destabilizing action is opposed allosterically by APOC2 and physically by GPIHBP1, which protect LPL from unfolding [PMID:34336854, PMID:37094117]. The inhibitory activity is tuned by complex formation with ANGPTL8, which yields a far weaker LPL inhibitor and, under insulin/feeding, locally preserves adipose LPL activity to direct fatty acids toward fat storage [PMID:32487544, PMID:34801488]. Tissue-specific deletion studies establish adipocyte-derived ANGPTL4 as the dominant regulator of plasma triglyceride partitioning, with adipose, brown-fat, and hepatocyte loss each enhancing local lipase activity, accelerating triglyceride clearance, and improving glucose homeostasis [PMID:29563332, PMID:29627378, PMID:34255741, PMID:33846453], and human genetic mimicry confirms that ANGPTL4 modulates plasma lipids essentially exclusively through LPL in humans [PMID:36372100]. Beyond lipase control, ANGPTL4 mediates glucocorticoid-induced insulin resistance via a ceramide–PP2A/PKCζ axis [PMID:28743803, PMID:31053639], acts in the hypothalamus to suppress AMPK, food intake, and to raise energy expenditure [PMID:20798332], and signals through integrins and other surface partners in disease contexts including kidney fibrosis (Integrin β1) [PMID:39630889], cancer invasion and metabolism (Integrin α5β1, IQGAP1, ESM1) [PMID:28641978, PMID:39647634, PMID:38212795], and macrophage lipid handling via CD36/ABCA1 [PMID:27460411]. Its expression is integrated by a broad set of upstream regulators—HIF-1α, PPARβ/δ, RORα, NFAT, TAZ/YAP, SMAD3, and FOXO1—often acting through intronic and promoter cis-regulatory modules, including one suppressed by gut microbiota in the intestine [PMID:12099716, PMID:22479192, PMID:31434807, PMID:31641008, PMID:32686149, PMID:31428774, PMID:38643448, PMID:39633372].","teleology":[{"year":2000,"claim":"Established ANGPTL4 as a nutritionally regulated secreted factor under direct PPAR control, framing it as an endocrine effector in metabolism.","evidence":"Subtractive hybridization, plasma Western blotting, and PPARα-null mice","pmids":["10862772"],"confidence":"High","gaps":["Did not define a molecular target or downstream pathway","Endocrine action site unspecified"]},{"year":2002,"claim":"Showed ANGPTL4 induction is not exclusive to PPAR signaling, identifying hypoxia/HIF-1α as an independent transcriptional input.","evidence":"Adenoviral HIF-1α overexpression and hypoxia mimetics in rat cardiomyocytes","pmids":["12099716"],"confidence":"Medium","gaps":["HIF-1α binding site not mapped","Functional consequence in cardiac tissue unaddressed"]},{"year":2004,"claim":"Resolved the existence of full-length versus cleaved circulating ANGPTL4 and located a functional PPAR response element in intron 3, refining how the gene is transcriptionally and post-translationally regulated.","evidence":"ChIP, EMSA, transactivation, and plasma protein analysis across cell/tissue types","pmids":["15190076"],"confidence":"High","gaps":["Functional role of cleavage products not yet determined","Protease identity not established here"]},{"year":2007,"claim":"Defined the core physiological mechanism: ANGPTL4 inhibits triglyceride clearance by converting endothelial LPL dimers to inactive monomers.","evidence":"Angptl4-transgenic mice with post-heparin LPL activity and lipoprotein clearance assays","pmids":["17761937"],"confidence":"High","gaps":["Molecular basis of dimer-to-monomer conversion not resolved","Reversibility unknown"]},{"year":2009,"claim":"Determined that N-terminal oligomerization, not proprotein cleavage, drives LPL inhibition and explained the E40K loss-of-function variant.","evidence":"HEK-293A expression, oligomerization and LPL inhibition assays, E40K mutant, parallel mouse work","pmids":["19270337"],"confidence":"High","gaps":["Atomic-level LPL contact sites not defined","Stoichiometry of the inhibitory oligomer unclear"]},{"year":2010,"claim":"Extended ANGPTL4 function to central energy balance, placing it upstream of hypothalamic AMPK to control food intake and energy expenditure.","evidence":"ICV ANGPTL4, Angptl4-null mice, AMPK activity assays, metabolic cages","pmids":["20798332"],"confidence":"High","gaps":["Hypothalamic receptor mediating AMPK suppression not identified"]},{"year":2012,"claim":"Dissected tissue-specific cis-regulation and revealed gut microbiota as a suppressor of intestinal ANGPTL4, linking the microbiome to fat storage.","evidence":"Zebrafish transgenic reporters, module mutagenesis, gnotobiotic colonization; plus PPARβ/δ ChIP-Seq in cancer cells","pmids":["22479192","23208498"],"confidence":"High","gaps":["Microbial signal acting on the intestinal module not fully defined","Cross-species generalization of modules incomplete"]},{"year":2013,"claim":"Showed butyrate induces intestinal ANGPTL4 through a PPARγ-independent upstream element additive to PPAR signaling, expanding the regulatory logic.","evidence":"Reporter assays, PPAR agonist/antagonist, germ-free mice colonized with C. tyrobutyricum, butyrate gavage","pmids":["23518684"],"confidence":"Medium","gaps":["Transcription factor binding the butyrate-responsive element not identified"]},{"year":2017,"claim":"Connected ANGPTL4 to glucocorticoid-induced insulin resistance via a ceramide–PP2A/PKCζ signaling axis, and mapped the integrin α5β1 binding role of the C-terminal domain in cancer.","evidence":"Angptl4-null mice with metabolomics and pathway inhibitors; integrin binding and functional assays with T266M mutant","pmids":["28743803","28641978"],"confidence":"High","gaps":["How adipose-derived lipolysis links to hepatic ceramide synthesis mechanistically incomplete","Integrin signaling intermediates only partially defined"]},{"year":2018,"claim":"Provided structural and tissue-resolved understanding: crystal structures of the C-terminal domain, adipose/BAT-specific deletion phenotypes, and a muscle role in exercise-induced AMPK activation.","evidence":"X-ray crystallography; adipose- and BAT-specific Angptl4 KO mice; treadmill and myotube AMPK/ACC assays","pmids":["29713054","29563332","29627378","29952246"],"confidence":"High","gaps":["Structures cover only the fibrinogen-like domain, not the inhibitory N-terminal oligomer","Muscle ANGPTL4 receptor undefined"]},{"year":2019,"claim":"Defined the biophysical inhibition mechanism (cooperative LPL unfolding opposed by GPIHBP1) and broadened ANGPTL4 into ferroptosis, macrophage polarization, podocyte injury, and lipogenesis pathways under diverse upstream regulators.","evidence":"HDX-MS and LPL stability assays; TAZ/NOX2 ferroptosis assays; RORα ChIP in MSCs; NFAT ChIP in podocytes; isotope-labeled lipogenesis in Angptl4-null mice; PPARβ/δ transcription-initiation ChIP/MS","pmids":["34336854","31641008","31434807","31053639","31428774"],"confidence":"High","gaps":["Whether non-LPL roles share a common receptor mechanism is unresolved","Surface receptors for ferroptosis and macrophage effects unidentified"]},{"year":2020,"claim":"Established the ANGPTL4/8 complex as a feeding-responsive switch that dampens LPL inhibition, and validated fasting regulation and additional disease roles in humans and mice.","evidence":"Serum complex immunoassays, recombinant LPL-inhibition kinetics, insulin-treated adipocytes; human fasting biopsies; pancreatitis and CRC metastasis models","pmids":["32487544","32504883","32638512","32641980","32686149"],"confidence":"High","gaps":["Structural basis of the ANGPTL4/8 interaction not resolved","Receptor for non-lipase disease effects still unknown"]},{"year":2021,"claim":"Mapped tissue source hierarchy and target specificity: hepatocyte/adipocyte ANGPTL4 effects, endothelial lipase inhibition modulated by ANGPTL8, and human genetic evidence that ANGPTL4 acts through LPL essentially exclusively.","evidence":"Hepatocyte- and adipocyte-specific KO mice with ASO pharmacology; recombinant EL-inhibition assays; UK Biobank/European cohort genetic mimicry","pmids":["34255741","33846453","34504977","34801488","36372100"],"confidence":"High","gaps":["Reconciliation of in vitro EL/HL inhibition with human LPL-exclusive genetics incomplete","Tissue-specific protease processing not fully characterized"]},{"year":2023,"claim":"Refined the allosteric model by showing APOC2 and ANGPTL4 bind overlapping LPL sites with opposite conformational effects, and identified a protective vascular smooth-muscle role of ANGPTL4 protein.","evidence":"HDX-MS competition and thermal stability assays; ANGPTL4 protein injection in Apoe-/- mice with SMC phenotyping","pmids":["37094117","36782020"],"confidence":"High","gaps":["How physiological APOC2/ANGPTL4 ratios set net LPL activity unresolved","SMC-protective signaling receptor undefined"]},{"year":2024,"claim":"Linked circulating C-terminal ANGPTL4 fragments to cardiovascular outcomes and expanded receptor-mediated functions to kidney fibrosis (Integrin β1), prostate cancer metabolism (IQGAP1), ovarian cancer signaling (ESM1, JAK2/STAT3), and FOXO1-driven cardiomyocyte senescence.","evidence":"Large LURIC/getABI cohorts plus GPIHBP1-LPL recombinant assays; cell-type-specific KO mice; Co-IP/GST pull-down for IQGAP1, ESM1, Integrin β1; ChIP-qPCR for FOXO1/SMAD3","pmids":["39392008","39630889","39647634","38212795","39633372","38643448"],"confidence":"Medium","gaps":["Many partner interactions rest on single-lab Co-IP without reciprocal in vivo validation","Whether integrin/IQGAP1/ESM1 binding share a common structural interface unknown"]},{"year":null,"claim":"The unifying receptor logic linking ANGPTL4's secreted, non-LPL signaling activities (integrins, IQGAP1, ESM1, hypothalamic AMPK, ferroptosis) to defined surface receptors and a high-resolution structure of the inhibitory N-terminal oligomer bound to LPL remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of the N-terminal oligomer–LPL complex","No single receptor reconciling diverse signaling roles","Physiological relevance of EL/HL inhibition versus LPL-exclusive human genetics unsettled"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,4,18,19,25,31]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3,18,25]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[33,42,41,35]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,2,4,20]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[33,42,41]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,3,11,13,22]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,2,17,29,36,39,43]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[33,42,41,35]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[10,15,28,40]}],"complexes":["ANGPTL4/8 complex"],"partners":["LPL","ANGPTL8","GPIHBP1","APOC2","ITGB1","ITGA5","IQGAP1","ESM1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BY76","full_name":"Angiopoietin-related protein 4","aliases":["Angiopoietin-like protein 4","Hepatic fibrinogen/angiopoietin-related protein","HFARP"],"length_aa":406,"mass_kda":45.2,"function":"Mediates inactivation of the lipoprotein lipase LPL, and thereby plays a role in the regulation of triglyceride clearance from the blood serum and in lipid metabolism (PubMed:19270337, PubMed:21398697, PubMed:27929370, PubMed:29899144). May also play a role in regulating glucose homeostasis and insulin sensitivity (Probable). Inhibits proliferation, migration, and tubule formation of endothelial cells and reduces vascular leakage (PubMed:14583458, PubMed:17068295). Upon heterologous expression, inhibits the adhesion of endothelial cell to the extracellular matrix (ECM), and inhibits the reorganization of the actin cytoskeleton, formation of actin stress fibers and focal adhesions in endothelial cells that have adhered to ANGPTL4-containing ECM (in vitro) (PubMed:17068295). Depending on context, may modulate tumor-related angiogenesis (By similarity) Mediates inactivation of the lipoprotein lipase LPL, and thereby plays an important role in the regulation of triglyceride clearance from the blood serum and in lipid metabolism (PubMed:19270337, PubMed:21398697, PubMed:27929370, PubMed:29899144). Has higher activity in LPL inactivation than the uncleaved protein (PubMed:19270337, PubMed:21398697)","subcellular_location":"Secreted; Secreted, extracellular space, extracellular matrix","url":"https://www.uniprot.org/uniprotkb/Q9BY76/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ANGPTL4","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ANGPTL4","total_profiled":1310},"omim":[{"mim_id":"618517","title":"ANGIOPOIETIN-LIKE 7; ANGPTL7","url":"https://www.omim.org/entry/618517"},{"mim_id":"615881","title":"PLASMA TRIGLYCERIDE LEVEL QUANTITATIVE TRAIT LOCUS; TGQTL","url":"https://www.omim.org/entry/615881"},{"mim_id":"609336","title":"ANGIOPOIETIN-LIKE 6; ANGPTL6","url":"https://www.omim.org/entry/609336"},{"mim_id":"605910","title":"ANGIOPOIETIN-LIKE 4; ANGPTL4","url":"https://www.omim.org/entry/605910"},{"mim_id":"604815","title":"LEUKOCYTE IMMUNOGLOBULIN-LIKE RECEPTOR, SUBFAMILY B, MEMBER 2; LILRB2","url":"https://www.omim.org/entry/604815"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Vesicles","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"adipose tissue","ntpm":188.0},{"tissue":"breast","ntpm":162.4},{"tissue":"liver","ntpm":176.8}],"url":"https://www.proteinatlas.org/search/ANGPTL4"},"hgnc":{"alias_symbol":["pp1158","PGAR","ARP4","HFARP","FIAF","NL2"],"prev_symbol":[]},"alphafold":{"accession":"Q9BY76","domains":[{"cath_id":"3.90.215.10","chopping":"189-400","consensus_level":"medium","plddt":94.3231,"start":189,"end":400},{"cath_id":"1.20.5","chopping":"111-143","consensus_level":"medium","plddt":77.3409,"start":111,"end":143}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BY76","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BY76-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BY76-F1-predicted_aligned_error_v6.png","plddt_mean":78.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ANGPTL4","jax_strain_url":"https://www.jax.org/strain/search?query=ANGPTL4"},"sequence":{"accession":"Q9BY76","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BY76.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BY76/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BY76"}},"corpus_meta":[{"pmid":"10862772","id":"PMC_10862772","title":"Characterization 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[et al.]","url":"https://pubmed.ncbi.nlm.nih.gov/24173241","citation_count":107,"is_preprint":false},{"pmid":"20798332","id":"PMC_20798332","title":"Hypothalamic Angptl4/Fiaf is a novel regulator of food intake and body weight.","date":"2010","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/20798332","citation_count":99,"is_preprint":false},{"pmid":"29627378","id":"PMC_29627378","title":"Brown adipose tissue derived ANGPTL4 controls glucose and lipid metabolism and regulates thermogenesis.","date":"2018","source":"Molecular metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/29627378","citation_count":99,"is_preprint":false},{"pmid":"34255741","id":"PMC_34255741","title":"Hepatocyte-specific suppression of ANGPTL4 improves obesity-associated diabetes and mitigates atherosclerosis in mice.","date":"2021","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/34255741","citation_count":94,"is_preprint":false},{"pmid":"31434807","id":"PMC_31434807","title":"Antiinflammatory activity of ANGPTL4 facilitates macrophage polarization to induce cardiac repair.","date":"2019","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/31434807","citation_count":91,"is_preprint":false},{"pmid":"27460411","id":"PMC_27460411","title":"ANGPTL4 deficiency in haematopoietic cells promotes monocyte expansion and atherosclerosis progression.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/27460411","citation_count":88,"is_preprint":false},{"pmid":"21308352","id":"PMC_21308352","title":"Expression of angiopoietin-like 4 (ANGPTL4) in human colorectal cancer: ANGPTL4 promotes venous invasion and distant metastasis.","date":"2011","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/21308352","citation_count":84,"is_preprint":false},{"pmid":"23208498","id":"PMC_23208498","title":"Inverse PPARβ/δ agonists suppress oncogenic signaling to the ANGPTL4 gene and inhibit cancer cell invasion.","date":"2012","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/23208498","citation_count":77,"is_preprint":false},{"pmid":"23518684","id":"PMC_23518684","title":"ANGPTL4 expression induced by butyrate and rosiglitazone in human intestinal epithelial cells utilizes independent pathways.","date":"2013","source":"American journal of physiology. 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It is secreted into blood plasma, and its plasma levels increase with fasting and decrease with chronic high-fat feeding, indicating an endocrine function in metabolic regulation.\",\n      \"method\": \"Subtractive hybridization (SABRE), Western blotting of plasma, PPARα-null mouse model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — identified by subtractive hybridization and validated in knockout mice, replicated across multiple conditions with orthogonal methods; foundational discovery paper\",\n      \"pmids\": [\"10862772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Hypoxia induces ANGPTL4 (PGAR) expression in cardiomyocytes via HIF-1α, not via the PPARα/RXR pathway, as demonstrated by adenoviral overexpression of HIF-1α and pharmacological hypoxia mimetics.\",\n      \"method\": \"Adenoviral HIF-1α overexpression, CoCl2/desferrioxamine treatment, RT-PCR in neonatal rat cardiomyocytes\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal approaches (gain-of-function and chemical mimetics), single lab\",\n      \"pmids\": [\"12099716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"ANGPTL4 (FIAF) is present in human and mouse blood plasma in both a full-length and a truncated (cleaved) form. Differentiated 3T3-L1 adipocytes produce truncated FIAF, human liver produces truncated FIAF, and fenofibrate (PPARα agonist) treatment increases circulating truncated FIAF but not native FIAF. A functional PPAR response element was identified within intron 3 of the FIAF gene.\",\n      \"method\": \"Western blotting of plasma, chromatin immunoprecipitation (ChIP), gel shift/EMSA, transactivation assays, cell differentiation experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — ChIP, EMSA, transactivation, and protein analysis in multiple cell/tissue types; multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"15190076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ANGPTL4 overexpression in mice inhibits LPL-dependent plasma triglyceride clearance by converting endothelial-bound LPL dimers to circulating LPL monomers, thereby reducing LPL activity and impairing cholesterol/fatty acid uptake into tissues, which secondarily upregulates hepatic cholesterol and fatty acid synthesis pathways.\",\n      \"method\": \"Angptl4-transgenic mouse model, post-heparin LPL activity assays, isotopic lipoprotein clearance studies\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo transgenic mouse model with multiple orthogonal metabolic readouts; mechanism of LPL dimer-to-monomer conversion directly measured\",\n      \"pmids\": [\"17761937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"ANGPTL4 forms dimers and tetramers intracellularly prior to secretion. After secretion, it is cleaved at a proprotein convertase site (RRKR161-164), releasing an oligomeric N-terminal domain and a monomeric C-terminal fibrinogen-like domain. Oligomerization (not cleavage) is required for LPL inhibition. The E40K variant is synthesized and processed normally but fails to accumulate as extracellular oligomers and cannot inhibit LPL activity.\",\n      \"method\": \"HEK-293A cell expression, oligomerization assays, LPL inhibition assays, proprotein convertase inhibition, E40K mutant analysis, parallel mouse experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution in cells and in vivo (mice), site-directed mutagenesis, functional LPL assays, multiple orthogonal methods in one study\",\n      \"pmids\": [\"19270337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Hypothalamic ANGPTL4 suppresses food intake and increases energy expenditure by inhibiting hypothalamic AMPK activity. Intracerebroventricular administration of ANGPTL4 suppresses food intake and body weight gain; Angptl4-null mice show increased hypothalamic AMPK activity, increased food intake, and decreased energy expenditure.\",\n      \"method\": \"Intracerebroventricular (ICV) ANGPTL4 injection, Angptl4-null mouse model, AMPK activity assays, metabolic cage measurements\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function and gain-of-function approaches, multiple phenotypic readouts, ICV delivery placing ANGPTL4 upstream of hypothalamic AMPK\",\n      \"pmids\": [\"20798332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Discrete tissue-specific cis-regulatory modules within ANGPTL4 intron 3 drive expression in the liver, pancreatic islet β-cells, and intestinal enterocytes. The microbiota suppresses the transcriptional activity of the intestine-specific regulatory module, reducing intestinal ANGPTL4 expression and thereby modulating peripheral fat storage.\",\n      \"method\": \"Zebrafish in vivo transgenic reporter assays, site-directed mutagenesis of regulatory modules, gnotobiotic zebrafish colonization experiments\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vivo transgenic reporter assays plus mutagenesis in a gnotobiotic vertebrate model; multiple tissue contexts tested\",\n      \"pmids\": [\"22479192\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PPARβ/δ drives ANGPTL4 transcription; synthetic inverse agonists of PPARβ/δ suppress ANGPTL4 expression and secretion by inducing a dominant transcriptional repressor complex at the ANGPTL4 transcription initiation site via a non-canonical, HDAC-independent mechanism. Suppression of ANGPTL4 transcription is functionally linked to reduced cancer cell invasion into 3D matrices.\",\n      \"method\": \"ChIP-Seq, microarray, inverse agonist treatment, ANGPTL4 knockdown, recombinant ANGPTL4 rescue, 3D invasion assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — ChIP-Seq identifies binding sites, multiple orthogonal methods (KD, rescue with recombinant protein, pharmacological), functional invasion assays\",\n      \"pmids\": [\"23208498\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Butyrate induces intestinal ANGPTL4 expression independently of PPARγ, using a butyrate-responsive element ~0.5 kb upstream of the transcription start site, while PPARγ agonists act via a distinct PPAR-responsive element downstream of the transcription start site; the two pathways are additive.\",\n      \"method\": \"PPARγ-independent reporter assays, PPAR agonist/antagonist treatment, germ-free mouse colonization with Clostridium tyrobutyricum, butyrate gavage\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo (germ-free mice), multiple orthogonal approaches, single lab\",\n      \"pmids\": [\"23518684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Adipose ANGPTL4 is upregulated via PPARγ activation following glucagon receptor antagonist treatment and promotes α-cell proliferation specifically; glucagon receptor antagonist fails to induce α-cell proliferation in Angptl4-knockout mice, placing ANGPTL4 on the pathway linking adipose lipid metabolism to pancreatic α-cell expansion.\",\n      \"method\": \"Angptl4 knockout mice, glucagon receptor antagonist treatment, Angptl4 supplementation, adipose PPARγ activation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis using knockout mice plus pharmacological intervention, single lab\",\n      \"pmids\": [\"26621734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Haematopoietic ANGPTL4 deficiency in macrophages promotes foam cell formation by enhancing CD36 expression and reducing ABCA1 surface localization, and increases common myeloid progenitor expansion (higher lipid raft content, increased proliferation, decreased apoptosis), leading to larger atherosclerotic plaques with bigger necrotic cores.\",\n      \"method\": \"Bone marrow transplantation (haematopoietic-specific KO), flow cytometry, CD36 and ABCA1 localization assays, atherosclerotic lesion analysis in hyperlipidemic mice\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific knockout with multiple orthogonal mechanistic readouts; localization and functional experiments\",\n      \"pmids\": [\"27460411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ANGPTL4 mediates glucocorticoid-induced insulin resistance by promoting lipolysis in white adipose tissue, increasing hepatic ceramide concentrations (by inducing ceramide synthetic pathway enzymes), and activating PP2A and PKCζ downstream of ceramide. Angptl4-null mice are protected from glucocorticoid-induced glucose intolerance.\",\n      \"method\": \"Angptl4-knockout mouse model, metabolomic profiling, pharmacological inhibition of ceramide synthesis (myriocin) and PKCζ, PP2A/PKCζ activity assays\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — knockout mice + metabolomics + pharmacological inhibitors + pathway activity assays; multiple orthogonal methods establishing mechanistic axis\",\n      \"pmids\": [\"28743803\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Crystal structures of the fibrinogen-like (C-terminal) domains of ANGPTL4 and ANGPTL3 were solved, providing structural insights into known loss-of-function mutations and the mechanism of action of these proteins.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure determination; structural basis for mechanistic interpretation of loss-of-function mutations\",\n      \"pmids\": [\"29713054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Adipose tissue-specific deletion of ANGPTL4 results in enhanced LPL activity, rapid clearance of circulating TAGs, increased adipose lipolysis and FA oxidation, decreased FA synthesis, prevention of ectopic lipid deposition in liver and muscle, reduced nPKC membrane translocation, improved insulin signaling and glucose tolerance, and attenuated atherosclerosis.\",\n      \"method\": \"Adipose-specific Angptl4 knockout mice, LPL activity assays, metabolic turnover studies, nPKC translocation assays, glucose tolerance tests, atherosclerosis lesion analysis\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific KO with multiple mechanistic readouts across metabolic pathways; nPKC translocation links ANGPTL4-mediated lipid deposition to insulin signaling\",\n      \"pmids\": [\"29563332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Brown adipose tissue (BAT)-specific deletion of ANGPTL4 results in enhanced LPL activity, increased circulating TAG clearance, increased FA oxidation, reduced FA synthesis, improved glucose tolerance, and enhanced thermogenesis during acute cold exposure.\",\n      \"method\": \"BAT-specific Angptl4 knockout mice, LPL activity assays, metabolic measurements, cold exposure experiments\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific KO, multiple metabolic phenotypic readouts, functional thermogenesis assay\",\n      \"pmids\": [\"29627378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In mesenchymal stem cells (MSCs), ANGPTL4 expression is induced by RORα in response to inflammatory mediators (IL-1β). Secreted ANGPTL4 from MSCs suppresses macrophage polarization toward a proinflammatory phenotype; ANGPTL4-deficient MSCs fail to inhibit inflammatory macrophage polarization. Exogenous ANGPTL4 protein improves cardiac function following myocardial infarction.\",\n      \"method\": \"MSC-macrophage co-culture, ANGPTL4-deficient MSCs, RORα overexpression, ChIP showing RORα binding to ANGPTL4 promoter, peritonitis and MI animal models\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function co-culture, ChIP, multiple in vivo models, with mechanistic identification of upstream RORα\",\n      \"pmids\": [\"31434807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ANGPTL4 deficiency in macrophages increases lipid uptake and cellular respiration without affecting LPL protein levels. Low levels of N-terminal ANGPTL4 (in hypomorphic mice) mitigate chylous ascites and acute-phase response compared with complete ANGPTL4 absence during high-fat feeding.\",\n      \"method\": \"Angptl4-knockout and Angptl4-hypomorphic mouse models, macrophage lipid uptake assays, LPL protein level measurement, respiratory assays, serum amyloid A measurement\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two complementary genetic mouse models with multiple orthogonal functional readouts\",\n      \"pmids\": [\"31409739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ANGPTL4 is a direct transcriptional target of TAZ (Hippo pathway effector) and sensitizes ovarian cancer cells to ferroptosis by activating NOX2 (NADPH oxidase 2). TAZ removal confers ferroptosis resistance; TAZS89A overexpression sensitizes cells; ANGPTL4 loss abolishes TAZ-mediated ferroptosis sensitization.\",\n      \"method\": \"TAZ knockdown and overexpression, ANGPTL4 knockdown, genomic integration/transcriptomics, ferroptosis assays\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function and gain-of-function in cell lines, integrative genomic analysis, single lab\",\n      \"pmids\": [\"31641008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ANGPTL4 inhibits LPL by triggering cooperative and sequential unfolding of LPL's α/β-hydrolase domain, resulting in irreversible collapse of the catalytic cavity. GPIHBP1 binding to LPL protects against ANGPTL4-mediated unfolding.\",\n      \"method\": \"Hydrogen-deuterium exchange/mass spectrometry, LPL thermal stability assays, GPIHBP1 protection assays (reviewed in detail in 2021 paper PMID:34336854 which cites earlier work)\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — biophysical (HDX-MS) mapping of conformational changes plus functional assays; mechanistic model well-supported and cited as established\",\n      \"pmids\": [\"34336854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ANGPTL8 forms complexes with ANGPTL4; the ANGPTL4/8 complex has >100-fold less LPL-inhibitory activity than ANGPTL4 alone (while ANGPTL3/8 is >100-fold more potent than ANGPTL3). Insulin increases ANGPTL4/8 secretion from adipocytes during feeding, locally blocking ANGPTL4-mediated LPL inhibition in adipose tissue, thereby directing FA toward fat rather than muscle.\",\n      \"method\": \"Immunoassay quantification of complexes in human serum, recombinant protein LPL-inhibitory activity assays, competition experiments, insulin treatment of hepatocytes and adipocytes\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — recombinant protein activity assays with quantitative kinetics, competition experiments, and cell-based validation; multiple orthogonal methods\",\n      \"pmids\": [\"32487544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Fasting increases ANGPTL4 mRNA and protein levels in human adipose tissue and plasma, concurrent with decreased LPL activity (-60%), while LPL mRNA and protein remain unchanged. Decreased plasma insulin (which downregulates ANGPTL4 in primary human adipocytes) and increased cortisol and free fatty acids (which upregulate ANGPTL4) are the hormonal mediators.\",\n      \"method\": \"Human adipose tissue biopsies (fasting/fed), LPL activity assays, primary human adipocyte culture with insulin/cortisol/fatty acid treatments, plasma ANGPTL4 ELISA\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human clinical study validated by primary human adipocyte mechanistic experiments; consistent with mouse data, multiple readouts\",\n      \"pmids\": [\"32504883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ANGPTL4 depletion in CRC cells significantly inhibited c-Jun-mediated transactivation of NOX4 expression, reducing ROS, MMP-1, and MMP-9 levels and disrupting oleic acid-promoted CRC metastasis in vitro and in vivo.\",\n      \"method\": \"ANGPTL4 knockdown, NOX4 reporter/luciferase assays, ROS measurement, MMP knockdown, in vivo tumor metastasis assay\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown plus pathway assays in vitro and in vivo, single lab\",\n      \"pmids\": [\"32641980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Hepatocyte-specific Angptl4 deficiency facilitates catabolism of TAG-rich lipoprotein remnants via increased hepatic lipase (HL) activity, significantly reducing circulating TAG and cholesterol. Loss of hepatic Angptl4 also promotes FA uptake, FA oxidation, ROS production, and AMPK activation. Liver-targeted pharmacologic inhibition of Angptl4 recapitulates these effects.\",\n      \"method\": \"Hepatocyte-specific Angptl4 mutant mice, metabolic turnover studies, HL activity assays, FA oxidation measurements, AMPK activation assays, liver-targeted ASO pharmacology\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific genetic model plus metabolic turnover studies plus pharmacologic validation; multiple orthogonal methods\",\n      \"pmids\": [\"34255741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ANGPTL4 is an inhibitor of endothelial lipase (EL) and is a more potent EL inhibitor than ANGPTL3. Formation of the ANGPTL4/8 complex reduces EL-inhibitory activity of ANGPTL4, in contrast to ANGPTL3/8 which increases EL-inhibitory activity of ANGPTL3.\",\n      \"method\": \"Recombinant ANGPTL protein EL-inhibitory activity assays, comparison of complex vs. free forms\",\n      \"journal\": \"Heliyon\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstituted enzyme inhibition assays; single lab, single method type\",\n      \"pmids\": [\"34504977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Genetic mimicry analysis in humans shows that ANGPTL4 suppression is highly concordant with LPL enhancement but not with HL or EL, demonstrating that ANGPTL4 modulates plasma metabolic parameters exclusively via LPL in humans.\",\n      \"method\": \"Human genetics/genetic mimicry analysis using UK Biobank (>110,000 participants) and 11 European cohorts; comparison of metabolic trait profiles for ANGPTL4 vs. LPL, LIPC, LIPG variants\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — large-scale human genetic epistasis/mimicry analysis replicated across multiple cohorts; strong preponderance of evidence for LPL specificity\",\n      \"pmids\": [\"36372100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ANGPTL4 inhibits LPL by promoting unfolding of LPL's hydrolase domain, leading to irreversible cleavage and degradation of LPL. ANGPTL8 binding to ANGPTL4 reduces this inhibitory activity, keeping LPL active in adipose tissue after feeding.\",\n      \"method\": \"Review synthesizing LPL unfolding studies, ANGPTL4/ANGPTL8 interaction studies, and tissue-specific LPL activity measurements (cited mechanistic studies)\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — synthesis of mechanistic studies including LPL unfolding assays and ANGPTL8 interaction studies; well-replicated across multiple labs\",\n      \"pmids\": [\"34801488\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Adipocyte-specific ANGPTL4 deficiency recapitulates the triglyceride phenotype of whole-body deficiency (increased adipose LPL activity, lower plasma TG, increased adipose TAG uptake), confirming adipocyte-derived ANGPTL4 as the primary source regulating plasma TG partitioning under normal diet conditions.\",\n      \"method\": \"Adipocyte-specific Angptl4 knockout mice (HFD and normal diet), LPL activity assays, triglyceride clearance and uptake assays, glucose homeostasis measurements\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — tissue-specific KO with functional assays; single lab, confirms findings from other adipose-KO studies\",\n      \"pmids\": [\"33846453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Chronic dexamethasone (glucocorticoid) treatment induces an ANGPTL4-ceramide-PKCζ axis that activates hepatic de novo lipogenesis and triglyceride synthesis. Myriocin (ceramide synthesis inhibitor) and PKCζ inhibitor both reduce dexamethasone-induced lipid disorders in WT but not Angptl4-null mice, placing ceramide-PKCζ downstream of ANGPTL4.\",\n      \"method\": \"Stable isotope labeling for hepatic lipogenesis, Angptl4-null mice, myriocin treatment, AAV-shRNA targeting Sptlc2, PKCζ inhibitor (ACPD) treatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — isotope labeling, genetic KO, multiple pharmacological interventions targeting different nodes of the pathway, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"31053639\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ANGPTL4 exacerbates pancreatitis by activating macrophage infiltration via PI3K/AKT signaling, increasing complement component 5a (C5a) levels, which activates C5a receptor leading to hypercytokinemia and acinar cell damage. ANGPTL4 deficiency or neutralizing antibody mitigates pancreatitis severity.\",\n      \"method\": \"Angptl4 knockout mice, neutralizing antibody treatment, exogenous ANGPTL4 administration, C5a neutralizing antibody, LPS-activated macrophage assays, PI3K/AKT inhibition\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO, antibody neutralization, and pharmacological pathway inhibition; single lab with multiple approaches\",\n      \"pmids\": [\"32638512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Calcineurin (CaN) inhibitors protect against PAN-induced podocyte injury by inhibiting NFAT (Nfatc1), which directly binds the Angptl4 promoter to drive Angptl4 expression. ANGPTL4 overexpression in podocytes induces cytoskeletal rearrangement, reduces synaptopodin, and enhances apoptosis.\",\n      \"method\": \"PAN-induced MCD rat model, CaN inhibitor treatment, Nfatc1 overexpression/knockdown, ChIP assay (Nfatc1 binding to Angptl4 promoter), ANGPTL4 overexpression/knockdown in podocytes\",\n      \"journal\": \"The Journal of pathology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — ChIP demonstrates direct NFAT binding to Angptl4 promoter; loss-of-function and gain-of-function in cell and animal models; mechanistic chain established\",\n      \"pmids\": [\"32686149\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"G protein-coupled estrogen receptor (GPER) stimulates trophoblast cell invasion by activating YAP (Hippo pathway effector) via an MST1-independent mechanism, which in turn drives ANGPTL4 expression. ANGPTL4 is required for GPER-stimulated trophoblast invasion.\",\n      \"method\": \"GPER agonist (G1) treatment, RNA-seq, YAP pharmacological inhibitors, loss- and gain-of-function experiments, Transwell invasion assays\",\n      \"journal\": \"Communications biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq plus pharmacological and genetic loss/gain-of-function approaches; single lab\",\n      \"pmids\": [\"34773076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"APOC2 and ANGPTL4 bind overlapping sites on LPL (regions surrounding the catalytic pocket and lid-anchoring structures), but have opposite effects on LPL conformation: ANGPTL4 destabilizes lid-anchoring structures promoting LPL inactivation, while APOC2 stabilizes them and increases LPL thermal stability.\",\n      \"method\": \"Hydrogen-deuterium exchange/mass spectrometry (HDX-MS), LPL thermal stability assays, competition binding experiments\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — HDX-MS with mechanistic binding site mapping; rigorous biophysical characterization of opposing allosteric effects on LPL\",\n      \"pmids\": [\"37094117\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Recombinant protein assays demonstrate that ANGPTL3/8 complex potently inhibits GPIHBP1-bound LPL activity. CD-ANGPTL4 (C-terminal domain-containing fragment generated by furin or plasmin cleavage) is positively associated with cardiovascular mortality and inflammation in two large cohort studies; ANGPTL4/8 complex formation converts ANGPTL4 from a furin substrate to a plasmin substrate.\",\n      \"method\": \"Recombinant protein GPIHBP1-LPL activity assays, dedicated immunoassays in LURIC (n=2394) and getABI (n=6188) cohorts, cardiovascular mortality follow-up\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro reconstitution of GPIHBP1-LPL inhibition plus large-scale human cohort validation; two independent cohorts replicate the clinical associations\",\n      \"pmids\": [\"39392008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Both podocyte- and tubule-derived ANGPTL4 are fibrogenic in diabetic kidneys. Secreted ANGPTL4 from these cells interacts with Integrin β1 and influences the association between DPP-4 and Integrin β1. ANGPTL4 mutant mice are protected from diabetes-accelerated fibrosis, showing reduced STING pathway activation, reduced EMT/EndoMT, and increased FA oxidation.\",\n      \"method\": \"Podocyte- and tubule-specific ANGPTL4 mutant mice, diabetic mouse model, Co-IP (ANGPTL4-Integrin β1), DPP-4/Integrin β1 association assays, kidney-targeted pharmacologic inhibition\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — cell type-specific genetic models, Co-IP identifying binding partners, pharmacologic validation; multiple orthogonal mechanistic readouts\",\n      \"pmids\": [\"39630889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In atherosclerotic mice, ANGPTL4 protein treatment inhibits phenotypic transition of vascular smooth muscle cells into macrophage-like cells by downregulating NOX1 (NADPH oxidase 1) activation of KLF4, reducing KLF4-mediated SMC dedifferentiation and stabilizing atherosclerotic plaques.\",\n      \"method\": \"ANGPTL4 protein injection in Apoe-/- atherosclerotic mice, SMC isolation and phenotype analysis, NOX1 and KLF4 expression assays, fibrous cap thickness measurements\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — recombinant protein treatment in vivo with mechanistic pathway analysis; single lab, multiple readouts\",\n      \"pmids\": [\"36782020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ANGPTL4 activates JAK2/STAT3 signaling in ovarian cancer cells to promote proliferation and invasion. ANGPTL4 also interacts with ESM1, which promotes ANGPTL4 binding to LPL (reprogramming lipid metabolism), and interferes with ANGPTL4 binding to integrin and VE-cadherin (stabilizing vascular integrity to promote angiogenesis).\",\n      \"method\": \"RNA-seq, Co-IP, molecular docking, MTT/EdU/wound healing/transwell assays, xenograft model, CAM assay, zebrafish model, Western blot for JAK2-STAT3 pathway\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and molecular docking identify interactions; multiple functional assays; single lab\",\n      \"pmids\": [\"38212795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PPARβ/δ inverse agonist PT-S264 impairs ANGPTL4 transcription initiation by decreasing recruitment of activating Mediator subunits, RNA polymerase II, and TFIIB (but not TFIIA) to the ANGPTL4 promoter. NCOR is the main PT-S264-dependent interactor of PPARβ/δ, identified by mass spectrometry.\",\n      \"method\": \"ChIP for Mediator/PolII/TFIIB/TFIIA at ANGPTL4 promoter, mass spectrometry of PPARβ/δ interactors, PPARβ/δ basal-repression mutant reconstitution in KO cells\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — ChIP, mass spectrometry, and reconstitution experiments with mechanistic mutants; multiple orthogonal methods\",\n      \"pmids\": [\"31428774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In macrophage foam cells, ANGPTL4 deficiency promotes foam cell formation through enhanced CD36 expression and reduced surface ABCA1; in macrophages, recombinant ANGPTL4 decreases lipid uptake. ANGPTL4 deficiency does not alter LPL protein levels in macrophages (negative finding for that specific mechanism).\",\n      \"method\": \"Recombinant ANGPTL4 treatment of macrophages, ANGPTL4-deficient macrophage lipid uptake assays, CD36/ABCA1 localization, LPL protein measurement\",\n      \"journal\": \"Nature communications / Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — recombinant protein and knockout approaches; confirmed in multiple papers (PMID:27460411, PMID:31409739); single phenotypic domain\",\n      \"pmids\": [\"27460411\", \"31409739\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Angptl4 is required for exercise-induced AMPK activation in skeletal muscle. Angptl4 treatment of C2C12 myotubes increases AMPK and ACC phosphorylation and mitochondrial maximum respiratory capacity. Exercise-induced AMPK and ACC phosphorylation is attenuated in Angptl4-knockout mice, and endurance is reduced.\",\n      \"method\": \"Treadmill exercise in Angptl4-knockout vs. WT mice, recombinant Angptl4 treatment of myotubes, AMPK/ACC phosphorylation assays, Seahorse respirometry\",\n      \"journal\": \"Journal of applied physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mice plus cell-based gain-of-function; single lab, multiple phenotypic readouts\",\n      \"pmids\": [\"29952246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TGF-β1 secreted by adipose-derived stem cells (ADSCs) activates SMAD3 in CRC cells, and SMAD3 directly binds the ANGPTL4 promoter (shown by ChIP) to drive ANGPTL4 transcription, which promotes glycolysis and anoikis resistance in CRC cells.\",\n      \"method\": \"RNA sequencing, ChIP assay (SMAD3 binding to ANGPTL4 promoter), co-culture experiments, in vivo intraperitoneal seeding model\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP directly shows SMAD3 binding to ANGPTL4 promoter; functional in vitro and in vivo validation; single lab\",\n      \"pmids\": [\"38643448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Angptl4 regulates monocyte differentiation to macrophages during wound healing via a novel Angptl4-ifi202b axis. In Angptl4-deficient wounds, ifi202b is elevated and monocyte-to-macrophage transition is impaired. An unbiased kinase inhibitor screen revealed an Angptl4-mediated kinome network involving S6K, JAK, and CDK that modulates ifi202b expression. Silencing ifi202b in Angptl4-deficient monocytes rescues impaired monocyte-to-macrophage transition.\",\n      \"method\": \"Angptl4-knockout mice, single-cell RNA sequencing, flow cytometry, kinase inhibitor screen, ifi202b knockdown rescue experiments\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mice plus scRNA-seq plus pharmacological screen plus rescue experiments; single lab, complex multi-method study\",\n      \"pmids\": [\"35210411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CAF-derived ANGPTL4 binds to IQGAP1 on PCa cell membranes, activating the Raf-MEK-ERK-PGC1α axis to promote mitochondrial biogenesis and OXPHOS metabolism, facilitating prostate cancer growth and chemoresistance.\",\n      \"method\": \"Proteomic analysis of conditioned media, GST pull-down, Co-IP (ANGPTL4-IQGAP1), metabolomics, drug screening (QGGP as IQGAP1 inhibitor)\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and GST pull-down identify ANGPTL4-IQGAP1 interaction; metabolomics and pathway assays; single lab\",\n      \"pmids\": [\"39647634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The ANGPTL4 T266M variant in the C-terminal domain binds integrin α5β1 with reduced affinity compared to wild-type, leading to weaker activation of downstream signaling molecules, impaired tumor cell proliferation, anoikis resistance, and migratory capability. C-terminal ANGPTL4 also regulates Glut2 expression.\",\n      \"method\": \"Integrin α5β1 binding assays, signaling pathway analysis (downstream of integrin), proliferation/anoikis/migration assays, Glut2 expression measurement\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding affinity measurements plus functional assays with mutant protein; single lab\",\n      \"pmids\": [\"28641978\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SGLT2 inhibitor (SGLT2i) reduces ANGPTL4 expression by regulating the upstream transcription factor FOXO1, which directly drives ANGPTL4 transcription under hyperglycemia/hyperlipidemia conditions. ANGPTL4 knockdown reduces cardiomyocyte senescence; ANGPTL4 overexpression worsens it. ChIP-qPCR confirms FOXO1 binding to the ANGPTL4 promoter.\",\n      \"method\": \"DCM mouse model, AC16 human cardiomyocyte model, ANGPTL4 knockdown/overexpression, RNA-seq, ChIP-qPCR (FOXO1 binding to ANGPTL4 promoter), SGLT2i treatment\",\n      \"journal\": \"Cardiovascular diabetology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-qPCR identifies FOXO1 as direct upstream regulator of ANGPTL4; KD and OE with phenotypic readout; single lab\",\n      \"pmids\": [\"39633372\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ANGPTL4 is a secreted glycoprotein that primarily functions as a context-dependent inhibitor of lipoprotein lipase (LPL): it binds LPL adjacent to the catalytic cavity, triggering cooperative irreversible unfolding of LPL's hydrolase domain, converting active LPL dimers to inactive monomers and thereby raising circulating triglycerides; this inhibitory activity requires N-terminal oligomerization, is opposed by ANGPTL8 (which forms a less-inhibitory complex with ANGPTL4) and GPIHBP1 (which stabilizes LPL against unfolding), and is abolished by the E40K loss-of-function variant. Transcriptionally, ANGPTL4 is induced by PPARα/β/δ/γ, HIF-1α, NFAT, RORα, TAZ/YAP, SMAD3, and FOXO1, and is suppressed by gut microbiota via an intronic cis-regulatory module. Beyond lipid metabolism, ANGPTL4 acts in the hypothalamus to suppress AMPK and food intake, mediates glucocorticoid-induced insulin resistance through a ceramide-PKCζ axis, modulates macrophage lipid uptake via CD36/ABCA1, binds Integrin β1 (in kidney fibrosis) and Integrin α5β1 (in cancer cells), activates NOX2 to sensitize cells to ferroptosis, regulates monocyte-to-macrophage differentiation during wound healing via an ifi202b axis, and promotes anti-inflammatory macrophage polarization and tissue repair through a RORα-dependent mechanism.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ANGPTL4 is a secreted, PPAR-regulated glycoprotein that governs the partitioning of circulating lipids across tissues by acting as a context-dependent inhibitor of lipoprotein lipase (LPL) [#0, #3]. Originally identified as a fasting-induced, PPARα/γ transcriptional target whose plasma levels track nutritional state [#0], it is processed after secretion into an oligomeric N-terminal domain and a fibrinogen-like C-terminal domain, with N-terminal oligomerization—not proprotein-convertase cleavage—being required for LPL inhibition; the E40K variant is processed normally but fails to form extracellular oligomers and cannot inhibit LPL [#4]. Mechanistically, ANGPTL4 binds LPL near the catalytic cavity and triggers cooperative, irreversible unfolding of the α/β-hydrolase domain, converting active endothelial-bound LPL dimers to inactive monomers and raising plasma triglycerides [#3, #18]; this destabilizing action is opposed allosterically by APOC2 and physically by GPIHBP1, which protect LPL from unfolding [#18, #31]. The inhibitory activity is tuned by complex formation with ANGPTL8, which yields a far weaker LPL inhibitor and, under insulin/feeding, locally preserves adipose LPL activity to direct fatty acids toward fat storage [#19, #25]. Tissue-specific deletion studies establish adipocyte-derived ANGPTL4 as the dominant regulator of plasma triglyceride partitioning, with adipose, brown-fat, and hepatocyte loss each enhancing local lipase activity, accelerating triglyceride clearance, and improving glucose homeostasis [#13, #14, #22, #26], and human genetic mimicry confirms that ANGPTL4 modulates plasma lipids essentially exclusively through LPL in humans [#24]. Beyond lipase control, ANGPTL4 mediates glucocorticoid-induced insulin resistance via a ceramide–PP2A/PKCζ axis [#11, #27], acts in the hypothalamus to suppress AMPK, food intake, and to raise energy expenditure [#5], and signals through integrins and other surface partners in disease contexts including kidney fibrosis (Integrin β1) [#33], cancer invasion and metabolism (Integrin α5β1, IQGAP1, ESM1) [#42, #41, #35], and macrophage lipid handling via CD36/ABCA1 [#10]. Its expression is integrated by a broad set of upstream regulators—HIF-1α, PPARβ/δ, RORα, NFAT, TAZ/YAP, SMAD3, and FOXO1—often acting through intronic and promoter cis-regulatory modules, including one suppressed by gut microbiota in the intestine [#1, #6, #15, #17, #29, #36, #39, #43].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established ANGPTL4 as a nutritionally regulated secreted factor under direct PPAR control, framing it as an endocrine effector in metabolism.\",\n      \"evidence\": \"Subtractive hybridization, plasma Western blotting, and PPARα-null mice\",\n      \"pmids\": [\"10862772\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define a molecular target or downstream pathway\", \"Endocrine action site unspecified\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showed ANGPTL4 induction is not exclusive to PPAR signaling, identifying hypoxia/HIF-1α as an independent transcriptional input.\",\n      \"evidence\": \"Adenoviral HIF-1α overexpression and hypoxia mimetics in rat cardiomyocytes\",\n      \"pmids\": [\"12099716\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"HIF-1α binding site not mapped\", \"Functional consequence in cardiac tissue unaddressed\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Resolved the existence of full-length versus cleaved circulating ANGPTL4 and located a functional PPAR response element in intron 3, refining how the gene is transcriptionally and post-translationally regulated.\",\n      \"evidence\": \"ChIP, EMSA, transactivation, and plasma protein analysis across cell/tissue types\",\n      \"pmids\": [\"15190076\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of cleavage products not yet determined\", \"Protease identity not established here\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined the core physiological mechanism: ANGPTL4 inhibits triglyceride clearance by converting endothelial LPL dimers to inactive monomers.\",\n      \"evidence\": \"Angptl4-transgenic mice with post-heparin LPL activity and lipoprotein clearance assays\",\n      \"pmids\": [\"17761937\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of dimer-to-monomer conversion not resolved\", \"Reversibility unknown\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Determined that N-terminal oligomerization, not proprotein cleavage, drives LPL inhibition and explained the E40K loss-of-function variant.\",\n      \"evidence\": \"HEK-293A expression, oligomerization and LPL inhibition assays, E40K mutant, parallel mouse work\",\n      \"pmids\": [\"19270337\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-level LPL contact sites not defined\", \"Stoichiometry of the inhibitory oligomer unclear\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended ANGPTL4 function to central energy balance, placing it upstream of hypothalamic AMPK to control food intake and energy expenditure.\",\n      \"evidence\": \"ICV ANGPTL4, Angptl4-null mice, AMPK activity assays, metabolic cages\",\n      \"pmids\": [\"20798332\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hypothalamic receptor mediating AMPK suppression not identified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Dissected tissue-specific cis-regulation and revealed gut microbiota as a suppressor of intestinal ANGPTL4, linking the microbiome to fat storage.\",\n      \"evidence\": \"Zebrafish transgenic reporters, module mutagenesis, gnotobiotic colonization; plus PPARβ/δ ChIP-Seq in cancer cells\",\n      \"pmids\": [\"22479192\", \"23208498\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Microbial signal acting on the intestinal module not fully defined\", \"Cross-species generalization of modules incomplete\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed butyrate induces intestinal ANGPTL4 through a PPARγ-independent upstream element additive to PPAR signaling, expanding the regulatory logic.\",\n      \"evidence\": \"Reporter assays, PPAR agonist/antagonist, germ-free mice colonized with C. tyrobutyricum, butyrate gavage\",\n      \"pmids\": [\"23518684\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Transcription factor binding the butyrate-responsive element not identified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected ANGPTL4 to glucocorticoid-induced insulin resistance via a ceramide–PP2A/PKCζ signaling axis, and mapped the integrin α5β1 binding role of the C-terminal domain in cancer.\",\n      \"evidence\": \"Angptl4-null mice with metabolomics and pathway inhibitors; integrin binding and functional assays with T266M mutant\",\n      \"pmids\": [\"28743803\", \"28641978\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How adipose-derived lipolysis links to hepatic ceramide synthesis mechanistically incomplete\", \"Integrin signaling intermediates only partially defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided structural and tissue-resolved understanding: crystal structures of the C-terminal domain, adipose/BAT-specific deletion phenotypes, and a muscle role in exercise-induced AMPK activation.\",\n      \"evidence\": \"X-ray crystallography; adipose- and BAT-specific Angptl4 KO mice; treadmill and myotube AMPK/ACC assays\",\n      \"pmids\": [\"29713054\", \"29563332\", \"29627378\", \"29952246\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structures cover only the fibrinogen-like domain, not the inhibitory N-terminal oligomer\", \"Muscle ANGPTL4 receptor undefined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined the biophysical inhibition mechanism (cooperative LPL unfolding opposed by GPIHBP1) and broadened ANGPTL4 into ferroptosis, macrophage polarization, podocyte injury, and lipogenesis pathways under diverse upstream regulators.\",\n      \"evidence\": \"HDX-MS and LPL stability assays; TAZ/NOX2 ferroptosis assays; RORα ChIP in MSCs; NFAT ChIP in podocytes; isotope-labeled lipogenesis in Angptl4-null mice; PPARβ/δ transcription-initiation ChIP/MS\",\n      \"pmids\": [\"34336854\", \"31641008\", \"31434807\", \"31053639\", \"31428774\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether non-LPL roles share a common receptor mechanism is unresolved\", \"Surface receptors for ferroptosis and macrophage effects unidentified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established the ANGPTL4/8 complex as a feeding-responsive switch that dampens LPL inhibition, and validated fasting regulation and additional disease roles in humans and mice.\",\n      \"evidence\": \"Serum complex immunoassays, recombinant LPL-inhibition kinetics, insulin-treated adipocytes; human fasting biopsies; pancreatitis and CRC metastasis models\",\n      \"pmids\": [\"32487544\", \"32504883\", \"32638512\", \"32641980\", \"32686149\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the ANGPTL4/8 interaction not resolved\", \"Receptor for non-lipase disease effects still unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Mapped tissue source hierarchy and target specificity: hepatocyte/adipocyte ANGPTL4 effects, endothelial lipase inhibition modulated by ANGPTL8, and human genetic evidence that ANGPTL4 acts through LPL essentially exclusively.\",\n      \"evidence\": \"Hepatocyte- and adipocyte-specific KO mice with ASO pharmacology; recombinant EL-inhibition assays; UK Biobank/European cohort genetic mimicry\",\n      \"pmids\": [\"34255741\", \"33846453\", \"34504977\", \"34801488\", \"36372100\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciliation of in vitro EL/HL inhibition with human LPL-exclusive genetics incomplete\", \"Tissue-specific protease processing not fully characterized\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Refined the allosteric model by showing APOC2 and ANGPTL4 bind overlapping LPL sites with opposite conformational effects, and identified a protective vascular smooth-muscle role of ANGPTL4 protein.\",\n      \"evidence\": \"HDX-MS competition and thermal stability assays; ANGPTL4 protein injection in Apoe-/- mice with SMC phenotyping\",\n      \"pmids\": [\"37094117\", \"36782020\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How physiological APOC2/ANGPTL4 ratios set net LPL activity unresolved\", \"SMC-protective signaling receptor undefined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked circulating C-terminal ANGPTL4 fragments to cardiovascular outcomes and expanded receptor-mediated functions to kidney fibrosis (Integrin β1), prostate cancer metabolism (IQGAP1), ovarian cancer signaling (ESM1, JAK2/STAT3), and FOXO1-driven cardiomyocyte senescence.\",\n      \"evidence\": \"Large LURIC/getABI cohorts plus GPIHBP1-LPL recombinant assays; cell-type-specific KO mice; Co-IP/GST pull-down for IQGAP1, ESM1, Integrin β1; ChIP-qPCR for FOXO1/SMAD3\",\n      \"pmids\": [\"39392008\", \"39630889\", \"39647634\", \"38212795\", \"39633372\", \"38643448\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Many partner interactions rest on single-lab Co-IP without reciprocal in vivo validation\", \"Whether integrin/IQGAP1/ESM1 binding share a common structural interface unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The unifying receptor logic linking ANGPTL4's secreted, non-LPL signaling activities (integrins, IQGAP1, ESM1, hypothalamic AMPK, ferroptosis) to defined surface receptors and a high-resolution structure of the inhibitory N-terminal oligomer bound to LPL remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of the N-terminal oligomer–LPL complex\", \"No single receptor reconciling diverse signaling roles\", \"Physiological relevance of EL/HL inhibition versus LPL-exclusive human genetics unsettled\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 4, 18, 19, 25, 31]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3, 18, 25]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [33, 42, 41, 35]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 2, 4, 20]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [33, 42, 41]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 3, 11, 13, 22]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 2, 17, 29, 36, 39, 43]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [33, 42, 41, 35]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [10, 15, 28, 40]}\n    ],\n    \"complexes\": [\n      \"ANGPTL4/8 complex\"\n    ],\n    \"partners\": [\n      \"LPL\",\n      \"ANGPTL8\",\n      \"GPIHBP1\",\n      \"APOC2\",\n      \"ITGB1\",\n      \"ITGA5\",\n      \"IQGAP1\",\n      \"ESM1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}