Affinage

APOA1

Apolipoprotein A-I · UniProt P02647

Round 2 corrected
Length
267 aa
Mass
30.8 kDa
Annotated
2026-04-28
130 papers in source corpus 23 papers cited in narrative 23 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

APOA1, the principal structural and functional protein of high-density lipoproteins (HDL), orchestrates reverse cholesterol transport by activating lecithin:cholesterol acyltransferase (LCAT) through a helical-registry-dependent mechanism, accepting cholesterol and other lipids from peripheral cells via ABCA1-dependent efflux, and serving as a reservoir for exchangeable apolipoproteins that transfer between lipoprotein classes (PMID:4335615, PMID:4345202, PMID:29773713). On small HDL particles, the C-termini of antiparallel APOA1 molecules adopt a flipped conformation that engages ABCA1 to promote cholesterol efflux; LCAT-driven particle maturation converts this active conformation into a lipid-adherent helical bundle that suppresses efflux capacity, and myeloperoxidase-catalyzed oxidation of APOA1 independently impairs ABCA1-dependent efflux, rendering HDL dysfunctional (PMID:38018436, PMID:15314690). Beyond lipid transport, APOA1 suppresses glucagon secretion from pancreatic α-cells through SCARB1-mediated activation of the PI3K/Akt/FoxO1 cascade, improves glucose tolerance by increasing skeletal muscle glucose uptake independently of AMPKα2, and modulates amyloid-β transport across the blood–brain barrier via LRP family receptors (PMID:33086869, PMID:32244181, PMID:27232214). Germline loss-of-function variants in APOA1 cause low HDL cholesterol, and position-specific amyloidogenic mutations cause hereditary apolipoprotein A-I amyloidosis (AApoAI) with organ tropism determined by the mutation location (PMID:15297675, PMID:19324996).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1972 High

    Establishing that APOA1 is the obligate protein cofactor for LCAT resolved how plasma cholesterol esterification is catalyzed and positioned APOA1 as the central functional component of HDL-mediated lipid metabolism.

    Evidence In vitro reconstitution assay measuring LCAT activity with and without apolipoprotein fractions

    PMID:4335615

    Open questions at the time
    • Structural basis of LCAT activation by APOA1 was unknown
    • Which APOA1 domains are required for activation was not determined
  2. 1973 High

    Demonstrating that HDL/APOA1 particles donate exchangeable apolipoproteins (apoC) to chylomicrons during alimentary lipemia established HDL as a dynamic reservoir that facilitates triglyceride metabolism across lipoprotein classes.

    Evidence In vivo human metabolic study with apolipoprotein quantification across lipoprotein fractions before and after fat meals

    PMID:4345202

    Open questions at the time
    • Mechanism of apolipoprotein transfer between particles was not defined
    • Role of specific APOA1 domains in exchange was unknown
  3. 1989 Medium

    Quantifying APOA1 binding to triglyceride-rich emulsion particles and showing that excess cholesterol sharply reduces binding capacity revealed a lipid-composition-dependent gating mechanism for apolipoprotein redistribution.

    Evidence In vitro binding assay with Scatchard analysis on TG-phospholipid emulsions of varying cholesterol content

    PMID:2496752

    Open questions at the time
    • Whether this binding modulation occurs on native lipoproteins in vivo was not tested
    • Structural basis of cholesterol-induced reduction in binding sites was not resolved
  4. 2004 High

    Identifying myeloperoxidase as a direct binding partner that nitrates/chlorinates APOA1 on HDL and selectively impairs ABCA1-dependent cholesterol efflux established a molecular mechanism for generating dysfunctional HDL in atherosclerotic disease.

    Evidence Co-immunoprecipitation, mass spectrometry of oxidative modifications in lesion-derived APOA1, and macrophage cholesterol efflux assays

    PMID:15314690

    Open questions at the time
    • Which specific modified residues are responsible for efflux impairment was not fully resolved
    • Whether MPO-modified APOA1 gains toxic gain-of-function activities was not addressed
  5. 2004 High

    Population-based resequencing with functional validation showed that rare loss-of-function APOA1 variants collectively explain a substantial fraction of low HDL-C in the general population, establishing APOA1 as a direct genetic determinant of plasma HDL levels.

    Evidence Resequencing of APOA1 in extreme HDL-C phenotype groups with biochemical functional studies of variants

    PMID:15297675

    Open questions at the time
    • Effect sizes of individual rare variants on cardiovascular outcomes were not determined
    • Functional consequences beyond HDL-C levels (e.g., efflux capacity) were not measured for each variant
  6. 2009 High

    Mapping amyloidogenic APOA1 mutations to two hot-spot regions and correlating mutation position with organ-specific amyloid deposition established genotype–phenotype relationships for hereditary AApoAI amyloidosis.

    Evidence Germline sequencing and Congo red/immunohistochemistry-confirmed biopsy across multiple patients

    PMID:19324996

    Open questions at the time
    • Structural basis for why different regions produce different amyloid fibrils with different tissue tropism was unknown
    • Whether amyloid toxicity is from loss of HDL function or gain-of-function aggregation was not resolved
  7. 2011 High

    Determining that three APOA1 chains form a helical dimer-with-hairpin architecture on spherical HDL provided the first solution-phase structural model of mature HDL, resolving how a protein shell cradles a lipid core.

    Evidence Small-angle neutron scattering with contrast variation combined with chemical cross-linking/mass spectrometry on reconstituted spherical HDL

    PMID:21292766

    Open questions at the time
    • Atomic-resolution structure of full-length APOA1 on HDL was not achieved
    • Conformational dynamics during particle remodeling were not captured
  8. 2013 High

    Stable isotope kinetic studies in human APOA1 L202P carriers quantified, for the first time, the in vivo contribution of APOA1 to tissue cholesterol efflux (~19% reduction with mutation), while revealing substantial non-HDL reverse cholesterol transport pathways.

    Evidence In vivo ¹³C₂-cholesterol infusion with three-compartment kinetic modeling and fecal sterol recovery in mutation carriers versus controls

    PMID:23650622

    Open questions at the time
    • Identity of the non-HDL efflux pathways was not established
    • Whether the L202P mutation affects efflux capacity per particle or reduces particle number was not distinguished
  9. 2015 Medium

    SAXS analysis demonstrated that the N-terminal domain of full-length APOA1 integrates into the protein belt of discoidal HDL particles and accommodates cholesterol-induced bilayer thickening, clarifying its structural role beyond a separate globular domain.

    Evidence SAXS with constrained modeling of reconstituted APOA1-POPC-cholesterol discoidal particles compared to N-terminal-truncated nanodiscs

    PMID:26200866

    Open questions at the time
    • Mutagenesis to validate N-terminal integration was not performed
    • Dynamic conformational changes during cholesterol loading were not time-resolved
  10. 2016 Medium

    Multiple non-lipid functions of APOA1 were established: modulation of Aβ1-40 transport across a reconstituted blood–brain barrier via LRP family receptors, direct interaction with dengue NS1 to neutralize lipid raft remodeling and viral infection, and selective acceptance of vitamin E via ABCA1 from intestinal enterocytes.

    Evidence In vitro BBB Transwell model with LRP inhibitors; co-IP of APOA1 with dengue NS1 and infectivity assays; polarized Caco-2 monolayer tocopherol secretion with ABCA1 induction and MTP inhibition

    PMID:23946344 PMID:27232214 PMID:33827950

    Open questions at the time
    • In vivo relevance of APOA1-Aβ interaction for Alzheimer's disease progression was not tested
    • Structural basis of NS1-APOA1 interaction was not mapped
    • Whether selective tocopherol transfer occurs in vivo was not confirmed
  11. 2018 High

    Disulfide-locking experiments revealed that APOA1 activates LCAT through a reciprocating thumbwheel mechanism dependent on helical registry: the 5/5 registry is the predominant conformation, but a hybrid epitope spanning helices 5–7 and 3–4 of adjacent APOA1 molecules in the 5/5 registry is required for full catalytic activation.

    Evidence Engineered cysteine mutations to lock 5/2 versus 5/5 registries; LCAT cholesteryl ester formation assay and macrophage cholesterol efflux assay

    PMID:29773713

    Open questions at the time
    • Atomic structure of the APOA1-LCAT complex was not resolved
    • How registry shifts are regulated in vivo (e.g., by lipid composition) was not determined
  12. 2020 Medium

    APOA1 was shown to regulate glucose homeostasis through two distinct mechanisms: suppressing glucagon secretion from pancreatic α-cells via SCARB1/PI3K/Akt/FoxO1 signaling, and enhancing skeletal muscle glucose uptake through a systemic, AMPKα2-independent mechanism.

    Evidence Pharmacological inhibitor panel (Akt, PI3K, SCARB1 blockers) in αTC1 cells with in vivo validation; recombinant APOA1 injection in wild-type and AMPKα2 kinase-dead mice with radiolabeled glucose uptake

    PMID:32244181 PMID:33086869

    Open questions at the time
    • The systemic factor mediating muscle glucose uptake downstream of APOA1 was not identified
    • Whether the glucagon-suppressive effect is physiologically relevant at endogenous APOA1 concentrations was not established
  13. 2021 Medium

    Discovery that TRIM15 ubiquitinates APOA1 via its RING domain (recognized through the PRY/SPRY domain) for proteasomal degradation identified the first E3 ligase regulating APOA1 turnover and linked APOA1 loss to lipid droplet accumulation and pancreatic cancer metastasis via the LDLR axis.

    Evidence Mass spectrometry-identified interaction confirmed by co-IP, domain-mapping mutagenesis, ubiquitination assays, and invasion/migration assays in pancreatic cancer cells

    PMID:34311082

    Open questions at the time
    • Whether TRIM15-mediated APOA1 degradation occurs in hepatocytes or in circulation was not tested
    • In vivo significance of TRIM15-APOA1 axis for lipid metabolism was not demonstrated
    • Ubiquitination sites on APOA1 were not mapped
  14. 2023 High

    Resolving the C-terminal conformational switch between small and large HDL particles explained size-dependent cholesterol efflux: on small HDL the flipped C-termini engage ABCA1, while LCAT-driven maturation locks C-termini onto the lipid surface, inhibiting efflux — unifying the opposing roles of LCAT activation and efflux capacity.

    Evidence Cross-linking MS and MD simulation across four HDL sizes; ABCA1-dependent efflux assays; HDL from LCAT-deficient subjects incubated with recombinant LCAT

    PMID:38018436

    Open questions at the time
    • Whether the C-terminal flip is a therapeutic target for enhancing cholesterol efflux has not been tested
    • Structural details of the APOA1 C-terminus–ABCA1 interaction interface are not resolved
  15. 2024 Medium

    Identification of the FOXM1/METTL3/YTHDF2 axis regulating APOA1 mRNA stability via m6A methylation revealed an epitranscriptomic layer of APOA1 regulation, linking it to scleral fibroblast transdifferentiation in myopia.

    Evidence ChIP for FOXM1 at METTL3 promoter; Me-RIP and PAR-CLIP for m6A modification and METTL3 binding of APOA1 mRNA; knockdown/overexpression in human scleral fibroblasts under hypoxia

    PMID:38190128

    Open questions at the time
    • Whether m6A-mediated regulation of APOA1 occurs in hepatocytes (the major source of circulating APOA1) was not examined
    • In vivo relevance to myopia progression was not demonstrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the atomic-resolution structure of APOA1 in complex with LCAT and ABCA1, the identity of the systemic mediator of APOA1-induced muscle glucose uptake, and whether therapeutic manipulation of the C-terminal conformational switch or TRIM15-mediated degradation can enhance reverse cholesterol transport in vivo.
  • No high-resolution APOA1-LCAT or APOA1-ABCA1 co-structure exists
  • Systemic mediator of APOA1 glucose uptake effect unidentified
  • Therapeutic relevance of TRIM15-APOA1 axis untested in vivo

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 6 GO:0098772 molecular function regulator activity 3 GO:0140104 molecular carrier activity 3
Localization
GO:0005576 extracellular region 7 GO:0005811 lipid droplet 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-1430728 Metabolism 7 R-HSA-382551 Transport of small molecules 4 R-HSA-162582 Signal Transduction 1 R-HSA-392499 Metabolism of proteins 1
Partners
ABCA1LCATLDLRMPOSAASCARB1TRIM15
Complex memberships
HDL particle

Evidence

Reading pass · 23 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1972 APOA1 acts as a protein cofactor (activator) of lecithin:cholesterol acyltransferase (LCAT), stimulating the esterification of cholesterol in plasma. In vitro biochemical reconstitution assay measuring LCAT activity in the presence and absence of apolipoprotein fractions Biochemical and biophysical research communications High 4335615
1973 APOA1-containing high-density lipoproteins donate apolipoprotein C activators (lipoprotein lipase activators) to chylomicrons during alimentary lipemia, demonstrating that APOA1/HDL particles serve as a reservoir for exchangeable apolipoproteins that transfer between lipoprotein classes during triglyceride metabolism. In vivo metabolic study in humans measuring apolipoprotein distribution across lipoprotein fractions before and after fat meals; polyacrylamide gel electrophoresis and biochemical quantification The Journal of clinical investigation High 4345202
2004 APOA1 is a selective target for myeloperoxidase (MPO)-catalyzed nitration and chlorination in vivo; MPO binds directly to APOA1 on HDL particles, and MPO-mediated oxidative modification of APOA1 selectively inhibits ABCA1-dependent cholesterol efflux from macrophages, converting HDL into a dysfunctional, proatherogenic form. Cross-immunoprecipitation of MPO with apoA-I in plasma; mass spectrometry quantification of nitrotyrosine and chlorotyrosine in apoA-I from serum and atherosclerotic lesions; ABCA1-dependent [³H]-cholesterol efflux assays from macrophages; identification of MPO-apoA-I contact site The Journal of clinical investigation High 15314690
2004 Rare nonsynonymous variants in APOA1 (along with ABCA1 and LCAT) are significantly more common in individuals with low HDL-C (<5th percentile) than high HDL-C (>95th percentile), and most such variants are functionally important as demonstrated by biochemical studies, establishing that rare loss-of-function alleles in APOA1 collectively contribute substantially to low plasma HDL levels in the general population. Population-based resequencing of APOA1, ABCA1, and LCAT; biochemical functional studies of identified variants Science High 15297675
2009 Amyloidogenic APOA1 mutations cluster in two hot-spot regions (residues 50–93 and 170–178) of the mature protein; mutations in residues 1–75 predominantly cause hepatic and renal amyloidosis, while mutations in residues 173–178 cause cardiac, laryngeal, and cutaneous amyloidosis, establishing a genotype–phenotype correlation linking mutation position to organ tropism of AApoAI amyloid deposition. Sequencing of APOA1 germline mutations in patients with biopsy-confirmed amyloidosis; Congo red staining with polarized light; immunohistochemistry with anti-apoAI antibodies; identification of three novel frameshift and missense mutations The Journal of molecular diagnostics High 19324996
2011 On spherical HDL (sHDL), three APOA1 chains adopt a helical dimer with hairpin (HdHp) architecture as the most consistent global structure, forming a hollow protein shell that cradles a central compact lipid core, as determined by small-angle neutron scattering with contrast variation combined with chemical cross-linking and mass spectrometry. Small-angle neutron scattering (SANS) with contrast variation on reconstituted sHDL; chemical cross-linking followed by mass spectrometry to discriminate among three structural models (HdHp, 3Hp, iT) The Journal of biological chemistry High 21292766
2011 APOA1 synthesized by small intestinal enterocytes is secreted apically and deposits in the brush border membrane, where it associates with cholesterol in detergent-resistant lipid raft microdomains; bile salts (taurocholate) efficiently release brush-border APOA1 at sub-solubilizing concentrations, and this apically localized APOA1 is proposed to mediate transintestinal cholesterol efflux (TICE) into the gut lumen. Immunomicroscopy and subcellular fractionation of porcine small intestine; immunoisolation of microvillar vesicles; cholesterol detection in apoA-1 immunoisolates; detergent-resistant membrane (DRM) fractionation; treatment with phospholipase C, trypsin, bile salts; comparison with aminopeptidase N as transmembrane control Biochimica et biophysica acta Medium 22119776
2013 In vivo tissue cholesterol efflux (TCE) is reduced by 19% in carriers of the L202P mutation in APOA1 compared to controls with normal HDL-C, demonstrating that functional APOA1 directly mediates cholesterol efflux from peripheral tissues in humans; residual TCE and unaffected fecal sterol excretion indicate that non-HDL pathways also substantially contribute to reverse cholesterol transport. In vivo stable isotope infusion of ¹³C₂-cholesterol in APOA1 L202P mutation carriers and controls; three-compartment SAAM-II kinetic modeling of plasma and erythrocyte cholesterol enrichment; fecal ¹³C recovery measurement Journal of lipid research High 23650622
2015 The N-terminal domain of full-length APOA1 participates as an integrated part of the protein belt (not as a separate globular domain) stabilizing discoidal APOA1-POPC-cholesterol particles; upon cholesterol incorporation, the N-terminal domain allows bilayer thickness to increase while maintaining a flat bilayer structure, in contrast to the N-terminal-truncated nanodisc system which adopts an energetically strained lens shape. Small-angle X-ray scattering (SAXS) with molecular constrained data modeling of reconstituted APOA1-POPC-cholesterol discoidal particles; comparison with N-terminal truncated nanodisc system across increasing cholesterol concentrations Biophysical journal Medium 26200866
2018 APOA1 uses a reciprocating thumbwheel-like mechanism to activate LCAT on nascent discoidal HDL: most APOA1 adopts a 5/5 helical registry (helix 5 of one molecule across from helix 5 of the other), but a fraction adopts a 5/2 registry; the 5/2 registry, locked by engineered disulfide bonds, impairs LCAT cholesteryl esterification activity without affecting LCAT binding or macrophage cholesterol efflux, indicating that full LCAT activation requires a hybrid epitope composed of helices 5–7 on one APOA1 molecule and helices 3–4 on the other. Site-directed mutagenesis introducing cysteines at predicted interface positions; disulfide bond locking of specific helical registries; LCAT cholesteryl esterification assay; macrophage cholesterol efflux assay; chemical cross-linking studies Journal of lipid research High 29773713
2016 ApoA1 interacts directly with dengue virus (DENV) non-structural protein 1 (NS1); ApoA1-mediated depletion of lipid rafts from cell membranes inhibits DENV attachment to the cell surface, and ApoA1 neutralizes NS1-induced cell activation and NS1-mediated enhancement of DENV infection, identifying a mechanism by which ApoA1/HDL-mediated reverse cholesterol transport controls viral infection. Co-immunoprecipitation and binding assays between DENV NS1 and ApoA1; lipid raft quantification in cell membranes; DENV infectivity assays with ApoA1 and ApoA1 mimetic peptide 4F; cell activation assays Journal of virology Medium 33827950
2016 ApoA1 (and ApoJ/Clusterin) modulate amyloid-β1-40 transport across the blood-brain barrier (BBB) by distinct mechanisms: ApoA1 complexed with Aβ1-40 does not enhance Aβ efflux from the brain, but ApoA1 present in the apical (blood) compartment mobilizes Aβ1-40 from the basolateral (brain) side; both ApoA1 and ApoJ cross the BBB via a mechanism involving the LDL receptor-related protein family, but ApoA1 trafficking is restricted when bound to Aβ. In vitro BBB model using primary cerebral endothelial cells on Matrigel-coated Transwells; fluorescently labeled Aβ1-40 transport assays; LRP family inhibitor experiments; measurement of bidirectional transport of recombinant ApoA1 and ApoJ Journal of Alzheimer's disease Medium 27232214
2016 ApoA1 binds heparin simultaneously with serum amyloid A (SAA) on HDL isolated from inflamed mice, forming rapid complex aggregates; mass spectrometry of chemically cross-linked HDL-SAA particles detected multiple cross-links between ApoA1 and SAA, indicating these two proteins are in close proximity (within 25 Å) on the HDL surface, providing a structural basis for simultaneous heparin binding. Gel electrophoresis of heparin-HDL complexes; mass spectrometry analysis of chemically cross-linked apoA1-SAA peptides from inflammation-associated HDL Biochemical and biophysical research communications Medium 27105909
2020 ApoA-1 improves glucose tolerance in high-fat diet-fed mice by increasing glucose uptake into skeletal muscle (+110%) and heart (+100%) independently of AMPKα2 kinase activity; the insulin-independent component of this effect requires systemic factors not present in isolated muscle ex vivo, suggesting ApoA-1 acts through an indirect systemic mechanism rather than direct muscle cell signaling via AMPKα2. Recombinant human ApoA-1 injection in wild-type and AMPKα2 kinase-dead mice; glucose tolerance tests with/without insulin secretion block (epinephrine + propranolol); radiolabeled glucose uptake into isolated tissues; isolated skeletal muscle ex vivo glucose uptake assay Molecular metabolism High 32244181
2020 HDL and ApoA-1 suppress glucagon expression and secretion from pancreatic α-cells via binding to SCARB-1 (scavenger receptor class B type 1) and activating the PI3K/Akt/FoxO1 signaling cascade; pretreatment with Akt inhibitor VIII, PI3K inhibitor LY294002, or SCARB-1 inhibitor BLT-1 restores α-cell response to low glucose, establishing the receptor and downstream pathway. Treatment of αTC1 clone 6 cells with HDL or ApoA-1; glucagon expression (RT-PCR) and secretion assays; western blotting for Akt and FoxO1 phosphorylation; pharmacological inhibitors of Akt, PI3K, and SCARB-1; in vivo HDL/ApoA-1 injection in CD1 mice measuring glucagon response to insulin-induced hypoglycemia Arteriosclerosis, thrombosis, and vascular biology Medium 33086869
2021 TRIM15 interacts with APOA1 through its PRY/SPRY domain and promotes APOA1 polyubiquitination via its RING domain, leading to APOA1 proteasomal degradation; loss of APOA1 enhances lipid anabolism, promotes lipid droplet accumulation, and drives pancreatic cancer cell invasion and metastasis via the APOA1-LDLR axis regulating triglyceride synthesis. Mass spectrometry identification of TRIM15 binding partners; co-immunoprecipitation of TRIM15 and APOA1; domain-mapping experiments with PRY/SPRY and RING domain mutants; ubiquitination assay; lipid droplet staining; TRIM15 silencing with invasion/migration assays; LDLR pathway analysis Biochimica et biophysica acta. Molecular basis of disease Medium 34311082
2021 Targeting the Apoa1 locus in mouse liver with CRISPR-Cas9/AAV delivery achieves 6–16% targeted hepatocyte editing; the endogenous Apoa1 promoter drives robust and sustained hepatic expression of therapeutic transgenes (APOE, FAH), validating Apoa1 as a functional integration site for liver-directed gene therapy. AAV delivery of CRISPR-Cas9 targeting mouse Apoa1 locus; quantification of targeted integration rates; plasma lipid measurement in hypercholesterolemia model after APOE knock-in; phenotypic rescue of hereditary tyrosinemia type I by FAH knock-in Molecular therapy. Methods & clinical development Medium 34141821
2023 In small HDL particles, the C-termini of the two antiparallel APOA1 molecules are 'flipped' off the lipid surface, adopting an extended conformation that engages ABCA1 to promote cholesterol efflux; in larger HDL particles, the C-termini form a helical bundle that adheres strongly to the lipid surface, preventing productive ABCA1 interaction. LCAT activity converts small/extra-small HDL into larger particles and markedly inhibits cholesterol efflux capacity, confirming this structural mechanism. Tandem mass spectrometric analysis of chemically cross-linked peptides from reconstituted HDL of four sizes; molecular dynamics simulations of APOA1 conformations; macrophage ABCA1-dependent cholesterol efflux capacity assays; isolation of HDL from LCAT-deficient subjects; incubation with human LCAT to convert particle size distributions Circulation High 38018436
2024 In human scleral fibroblasts under hypoxia, FOXM1 represses METTL3 transcription (demonstrated by ChIP showing FOXM1 enrichment at the METTL3 promoter); reduced METTL3 decreases m6A methylation of APOA1 mRNA, reducing YTHDF2-mediated mRNA degradation and thereby stabilizing/increasing APOA1 expression; elevated APOA1 promotes myofibroblast transdifferentiation (elevated vinculin, paxillin, α-SMA) and inhibits collagen production, contributing to scleral remodeling in myopia. ChIP assay for FOXM1 at METTL3 promoter; Me-RIP to measure m6A modification of APOA1 mRNA; PAR-CLIP to examine METTL3-APOA1 mRNA binding; loss/gain-of-function experiments (siRNA knockdown, overexpression); western blotting and RT-qPCR for myofibroblast markers; CCK-8 proliferation and flow cytometry apoptosis assays Investigative ophthalmology & visual science Medium 38190128
2013 ABCA1-dependent vitamin E (tocopherol) secretion from Caco-2 intestinal cells to APOA1 (but not HDL) is vitamer-selective: T0901317-induced ABCA1 expression drives α- and γ-tocopherol secretion to apical APOA1 more efficiently than δ-tocopherol, while APOB-dependent secretion (accounting for ~80% of total) shows no such selectivity, establishing APOA1 as the acceptor that confers selective tocopherol secretion via the ABCA1 pathway. Caco-2 polarized monolayer system with apical co-incubation of three tocopherols; MTP inhibitor (BMS201038) to quantify apoB-dependent pathway; LXR agonist T0901317 to induce ABCA1; basolateral APOA1 acceptor assays; SR-BI blocking antibody; quantification of tocopherol and cholesterol secretion The Journal of nutrition Medium 23946344
1989 APOA1 binds to triglyceride-rich emulsion particles (model of triglyceride-rich lipoproteins) in a saturable manner with dissociation constant Kd = 7.4 × 10⁻⁷ M; when particle cholesterol content is elevated above the physiological range (>3.7% to 7.3%), the protein binding capacity (N) sharply decreases ~6-fold without changing Kd, suggesting that excess cholesterol content impairs apolipoprotein redistribution and remnant metabolism. Binding of APOA1 and ApoE-3 to isolated triglyceride-phospholipid emulsions of varying cholesterol content; negative stain EM; Scatchard analysis of saturable binding Biochemistry Medium 2496752
2016 Following neuronal injury, APOA1 expression increases in a delayed secondary phase response; exogenous ApoA1 treatment accelerates wound closure in a neuroblastoma scratch assay via activation of the ERK signaling pathway and actin polymerization, suggesting ApoA1 plays a functional role in post-injury neuronal healing through these downstream effectors. Proteomics of spinal cord injury tissue at multiple time points; scratch wound healing assay in neuroblastoma cells with ApoA1 treatment; western blotting for ERK pathway activation; actin polymerization assay Molecular and cellular biochemistry Low 27734225
2012 ApoA1 mimetic peptide L-4F increases insulin-receptor phosphorylation in mesenchymal stem cell-derived adipocytes via upregulation of heme oxygenase-1 (HO-1); HO activity inhibition reverses L-4F-induced effects on adipogenic markers (increases in WNT10b, decreases in Peg1/Mest), establishing that L-4F acts through an HO-1-dependent mechanism to restore adiponectin secretion, decrease inflammatory cytokines, and improve insulin sensitivity in obese mice. In vivo L-4F administration to ob/ob mice; western blotting for HO-1, insulin receptor phosphorylation, WNT10b, Peg1/Mest; HO activity inhibition pharmacological experiments; adiponectin and cytokine ELISA; cell cycle analysis of MSC-derived adipocytes Cell cycle Low 22306989

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Biological, clinical and population relevance of 95 loci for blood lipids. Nature 2873 20686565
2013 Discovery and refinement of loci associated with lipid levels. Nature genetics 2409 24097068
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2011 Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nature genetics 1493 21378990
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2008 Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Nature genetics 1310 18193043
2008 Six new loci associated with blood low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides in humans. Nature genetics 1130 18193044
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2008 Common variants at 30 loci contribute to polygenic dyslipidemia. Nature genetics 1113 19060906
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2004 Multiple rare alleles contribute to low plasma levels of HDL cholesterol. Science (New York, N.Y.) 829 15297675
2016 TREM2 Binds to Apolipoproteins, Including APOE and CLU/APOJ, and Thereby Facilitates Uptake of Amyloid-Beta by Microglia. Neuron 724 27477018
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2008 Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts. Nature genetics 695 19060911
1972 A protein cofactor of lecithin:cholesterol acyltransferase. Biochemical and biophysical research communications 694 4335615
2004 The human plasma proteome: a nonredundant list developed by combination of four separate sources. Molecular & cellular proteomics : MCP 658 14718574
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2003 Characterization of the proteins released from activated platelets leads to localization of novel platelet proteins in human atherosclerotic lesions. Blood 616 14630798
2008 Large-scale proteomics and phosphoproteomics of urinary exosomes. Journal of the American Society of Nephrology : JASN 607 19056867
2006 Functionally defective high-density lipoprotein: a new therapeutic target at the crossroads of dyslipidemia, inflammation, and atherosclerosis. Pharmacological reviews 579 16968945
2004 Apolipoprotein A-I is a selective target for myeloperoxidase-catalyzed oxidation and functional impairment in subjects with cardiovascular disease. The Journal of clinical investigation 575 15314690
2008 A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection. Science (New York, N.Y.) 573 19074352
2018 TREM2 Is a Receptor for β-Amyloid that Mediates Microglial Function. Neuron 571 29518356
1973 Interchange of apolipoproteins between chylomicrons and high density lipoproteins during alimentary lipemia in man. The Journal of clinical investigation 514 4345202
2003 Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides. Nature biotechnology 485 12665801
2015 Widespread macromolecular interaction perturbations in human genetic disorders. Cell 454 25910212
2002 Misdiagnosis of hereditary amyloidosis as AL (primary) amyloidosis. The New England journal of medicine 451 12050338
2014 The discovery of I-BET726 (GSK1324726A), a potent tetrahydroquinoline ApoA1 up-regulator and selective BET bromodomain inhibitor. Journal of medicinal chemistry 138 25249180
2021 APOA1: a Protein with Multiple Therapeutic Functions. Current atherosclerosis reports 137 33591433
2002 Polyunsaturated fatty acids modulate the effects of the APOA1 G-A polymorphism on HDL-cholesterol concentrations in a sex-specific manner: the Framingham Study. The American journal of clinical nutrition 117 11756058
2005 The APOA1/C3/A4/A5 gene cluster, lipid metabolism and cardiovascular disease risk. Current opinion in lipidology 112 15767855
2022 Leveraging knowledge of HDLs major protein ApoA1: Structure, function, mutations, and potential therapeutics. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 99 36063649
2009 Hereditary apolipoprotein AI-associated amyloidosis in surgical pathology specimens: identification of three novel mutations in the APOA1 gene. The Journal of molecular diagnostics : JMD 92 19324996
2004 In-depth haplotype analysis of ABCA1 gene polymorphisms in relation to plasma ApoA1 levels and myocardial infarction. Arteriosclerosis, thrombosis, and vascular biology 84 14962947
2016 ApoA1 and ApoA1-specific self-antibodies in cardiovascular disease. Laboratory investigation; a journal of technical methods and pathology 76 27183204
1988 DNA polymorphism haplotypes of the human apolipoprotein APOA1-APOC3-APOA4 gene cluster. Human genetics 70 2903847
2018 A thumbwheel mechanism for APOA1 activation of LCAT activity in HDL. Journal of lipid research 68 29773713
2011 Identification of Apo-A1 as a biomarker for early diagnosis of bladder transitional cell carcinoma. Proteome science 60 21496341
2010 D-4F, an apoA-1 mimetic, decreases airway hyperresponsiveness, inflammation, and oxidative stress in a murine model of asthma. Journal of lipid research 60 21131532
2019 KCNQ1OT1, HIF1A-AS2 and APOA1-AS are promising novel biomarkers for diagnosis of coronary artery disease. Clinical and experimental pharmacology & physiology 53 30941792
2014 Discovery of Apo-A1 as a potential bladder cancer biomarker by urine proteomics and analysis. Biochemical and biophysical research communications 53 24661883
1996 Haplotype analysis of two APOA1/MspI polymorphisms in relation to plasma levels of apo A-I and HDL-cholesterol. Atherosclerosis 53 9125316
2011 Increased risk of coronary artery disease in Caucasians with extremely low HDL cholesterol due to mutations in ABCA1, APOA1, and LCAT. Biochimica et biophysica acta 51 21875686
2010 Reduced plasma APOA1 level is associated with gastric tumor growth in MKN45 mouse xenograft model. Journal of proteomics 51 20399916
2016 Modulation of Amyloid-β1-40 Transport by ApoA1 and ApoJ Across an in vitro Model of the Blood-Brain Barrier. Journal of Alzheimer's disease : JAD 49 27232214
2020 The Positive Side of the Alzheimer's Disease Amyloid Cross-Interactions: The Case of the Aβ 1-42 Peptide with Tau, TTR, CysC, and ApoA1. Molecules (Basel, Switzerland) 48 32456156
2010 Effects of variations in the APOA1/C3/A4/A5 gene cluster on different parameters of postprandial lipid metabolism in healthy young men. Journal of lipid research 48 19592705
2021 TRIM15 promotes the invasion and metastasis of pancreatic cancer cells by mediating APOA1 ubiquitination and degradation. Biochimica et biophysica acta. Molecular basis of disease 45 34311082
2015 Decreased expression of the APOA1-APOC3-APOA4 gene cluster is associated with risk of Alzheimer's disease. Drug design, development and therapy 45 26491253
2011 The low resolution structure of ApoA1 in spherical high density lipoprotein revealed by small angle neutron scattering. The Journal of biological chemistry 44 21292766
2005 Kinetic stabilization and fusion of apolipoprotein A-2:DMPC disks: comparison with apoA-1 and apoC-1. Biophysical journal 43 15681655
2003 The study of APOA1, APOC3 and APOA4 variability in healthy ageing people reveals another paradox in the oldest old subjects. Annals of human genetics 42 12556235
2004 The effects of scale: variation in the APOA1/C3/A4/A5 gene cluster. Human genetics 39 15108119
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2012 Population-based resequencing of APOA1 in 10,330 individuals: spectrum of genetic variation, phenotype, and comparison with extreme phenotype approach. PLoS genetics 34 23209431
2021 ApoA1 Neutralizes Proinflammatory Effects of Dengue Virus NS1 Protein and Modulates Viral Immune Evasion. Journal of virology 33 33827950
2011 Mutation in APOA1 predicts increased risk of ischaemic heart disease and total mortality without low HDL cholesterol levels. Journal of internal medicine 33 21443680
2007 APOA1/C3/A5 haplotype and risk of hypertriglyceridemia in Taiwanese. Clinica chimica acta; international journal of clinical chemistry 33 18206649
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2006 Evidence for consistent intragenic and intergenic interactions between SNP effects in the APOA1/C3/A4/A5 gene cluster. Human heredity 31 16710093
2020 ApoA-1 improves glucose tolerance by increasing glucose uptake into heart and skeletal muscle independently of AMPKα2. Molecular metabolism 30 32244181
2015 HDL/ApoA-1 infusion and ApoA-1 gene therapy in atherosclerosis. Frontiers in pharmacology 30 26388776
2023 Flipped C-Terminal Ends of APOA1 Promote ABCA1-Dependent Cholesterol Efflux by Small HDLs. Circulation 28 38018436
2019 LCAT, ApoD, and ApoA1 Expression and Review of Cholesterol Deposition in the Cornea. Biomolecules 28 31779197
2018 Histone Deacetylase 3 Inhibitor Suppresses Hepatitis C Virus Replication by Regulating Apo-A1 and LEAP-1 Expression. Virologica Sinica 28 30328580
2015 Genetic association of the ApoB and ApoA1 gene polymorphisms with the risk for alcohol-induced osteonecrosis of femoral head. International journal of clinical and experimental pathology 28 26617857
2017 Increased prevalence of clinical and subclinical atherosclerosis in patients with damaging mutations in ABCA1 or APOA1. Journal of clinical lipidology 27 29150341
2012 Associations of polymorphisms in the apolipoprotein APOA1-C3-A5 gene cluster with acute coronary syndrome. Journal of biomedicine & biotechnology 27 22675253
2014 APOA1 mRNA expression in ovarian serous carcinoma effusions is a marker of longer survival. American journal of clinical pathology 26 24926085
2019 Long noncoding RNAs APOA1-AS, IFNG-AS1, RMRP and their related biomolecules in Egyptian patients with relapsing-remitting multiple sclerosis: Relation to disease activity and patient disability. Journal of advanced research 25 32071782
2004 Haplotypes in the APOA1-C3-A4-A5 gene cluster affect plasma lipids in both humans and baboons. Human molecular genetics 25 15044382
2018 Role of long non-coding RNAs expression (ANRIL, NOS3-AS, and APOA1-AS) in development of atherosclerosis in Egyptian systemic lupus erythematosus patients. Clinical rheumatology 24 30128915
2020 Alzheimer's disease in the gut-Major changes in the gut of 5xFAD model mice with ApoA1 as potential key player. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 23 32681583
2015 Design and synthesis of a novel candidate compound NTI-007 targeting sodium taurocholate cotransporting polypeptide [NTCP]-APOA1-HBx-Beclin1-mediated autophagic pathway in HBV therapy. Bioorganic & medicinal chemistry 23 25650312
2013 In vivo tissue cholesterol efflux is reduced in carriers of a mutation in APOA1. Journal of lipid research 22 23650622
2005 APOA1/C3/A4 gene cluster variability and lipid levels in Brazilian children. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas 22 15962178
2005 APOA1-75 G to A substitution associated with severe forms of CAD, lower levels of HDL and apoA-I among northern Indians. Disease markers 22 16403951
2022 Selective activation of ABCA1/ApoA1 signaling in the V1 by magnetoelectric stimulation ameliorates depression via regulation of synaptic plasticity. iScience 21 35479414
2021 LncRNA APOA1-AS facilitates proliferation and migration and represses apoptosis of VSMCs through TAF15-mediated SMAD3 mRNA stabilization. Cell cycle (Georgetown, Tex.) 21 34382908
2013 Vitamin E secretion by Caco-2 monolayers to APOA1, but not to HDL, is vitamer selective. The Journal of nutrition 21 23946344
2013 Plasma lipids, genetic variants near APOA1, and the risk of infantile hypertrophic pyloric stenosis. JAMA 21 23989729
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2015 Small-angle X-ray scattering of the cholesterol incorporation into human ApoA1-POPC discoidal particles. Biophysical journal 20 26200866
2014 The apoB/apoA1 ratio predicts future cardiovascular events in patients with rheumatoid arthritis. Scandinavian journal of rheumatology 20 24689997
2013 Gene-gene combination effect and interactions among ABCA1, APOA1, SR-B1, and CETP polymorphisms for serum high-density lipoprotein-cholesterol in the Japanese population. PloS one 20 24376512
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2005 Polymorphisms in APOA1 and LPL genes are statistically independently associated with fasting TG in men with CAD. European journal of human genetics : EJHG 20 15657615
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2012 The relationship between high-sensitivity C-reactive protein and ApoB, ApoB/ApoA1 ratio in general population of China. Endocrine 19 22246850
2012 ApoA1: mimetic peptide reverses adipocyte dysfunction in vivo and in vitro via an increase in heme oxygenase (HO-1) and Wnt10b. Cell cycle (Georgetown, Tex.) 19 22306989
2008 Increase levels of apo-A1 and apo B are associated in knee osteoarthritis: lack of association with VEGF-460 T/C and +405 C/G polymorphisms. Rheumatology international 19 18597093
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2016 APOA5 and APOA1 polymorphisms are associated with triglyceride levels in Mexican children. Pediatric obesity 18 27171122
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2016 Increased expression of ApoA1 after neuronal injury may be beneficial for healing. Molecular and cellular biochemistry 17 27734225
2013 The dyslipidemia-associated SNP on the APOA1/C3/A5 gene cluster predicts post-surgery poor outcome in Taiwanese breast cancer patients: a 10-year follow-up study. BMC cancer 17 23829168
2021 High prevalence of APOA1/C3/A4/A5 alterations in luminal breast cancers among young women in East Asia. NPJ breast cancer 16 34226567
2018 Role of rs670 variant of APOA1 gene on metabolic response after a high fat vs. a low fat hypocaloric diets in obese human subjects. Journal of diabetes and its complications 16 30467071
2013 Controlling the diameter, monodispersity, and solubility of ApoA1 nanolipoprotein particles using telodendrimer chemistry. Protein science : a publication of the Protein Society 16 23754445
2007 Polymorphisms in the APOA1/C3/A4/A5 gene cluster and cholesterol responsiveness to dietary change. Clinical chemistry and laboratory medicine 16 17378725
2021 Hsa_circ_0088212-mediated miR-520 h/APOA1 axis inhibits osteosarcoma progression. Translational oncology 15 34555726
2020 HDL (High-Density Lipoprotein) and ApoA-1 (Apolipoprotein A-1) Potentially Modulate Pancreatic α-Cell Glucagon Secretion. Arteriosclerosis, thrombosis, and vascular biology 15 33086869
2017 Interactions of six SNPs in APOA1 gene and types of obesity on low HDL-C disease in Xinjiang pastoral area of China. Lipids in health and disease 15 28969676
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2019 Antibodies Against the C-Terminus of ApoA-1 Are Inversely Associated with Cholesterol Efflux Capacity and HDL Metabolism in Subjects with and without Type 2 Diabetes Mellitus. International journal of molecular sciences 14 30744100
2019 Association of BUD13-ZNF259-APOA5-APOA1-SIK3 cluster polymorphism in 11q23.3 and structure of APOA5 with increased plasma triglyceride levels in a Korean population. Scientific reports 14 31165758
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2007 Effect of the combination of the variants -75G/A APOA1 and Trp64Arg ADRB3 on the risk of type 2 diabetes (DM2). Clinical endocrinology 14 17727676
2004 A prospective study of the APOA1 XmnI and APOC3 SstI polymorphisms in the APOA1/C3/A4 gene cluster and risk of incident myocardial infarction in men. Atherosclerosis 14 15488874
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