Affinage

LPA

Apolipoprotein(a) · UniProt P08519

Length
2040 aa
Mass
226.5 kDa
Annotated
2026-06-10
100 papers in source corpus 22 papers cited in narrative 22 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LPA encodes apolipoprotein(a) (apo(a)), a plasminogen-homologous, kringle-rich glycoprotein that assembles with apolipoprotein B-100 to form the lipoprotein particle Lp(a), a determinant of atherothrombotic and vascular pathobiology (PMID:6219896, PMID:2956279). The native particle is a disulfide-linked complex of apoB-100 and a ~350 kDa apo(a) glycoprotein that displays genetically determined size heterogeneity, with isoform size inversely correlating with plasma concentration and the phenotype controlled by a series of autosomal alleles at a single locus (PMID:6219896, PMID:2956279). Assembly is a two-step process: apo(a) and apoB first associate noncovalently through apo(a) lysine-binding sites 7 and 8 inside hepatocytes, where the two proteins colocalize in the ER, trans-Golgi, and early endosomes, and this interaction is required for coupled secretion of both chains (PMID:9520125, PMID:35045727); covalent disulfide bond formation is subsequently accelerated by a secreted, cofactor-dependent extracellular hepatoma oxidase activity kinetically analogous to but distinct from protein disulfide isomerase (PMID:16893192). A splice-site mutation in the apo(a) kringle IV type 8 intron produces a truncated apo(a) that is secreted but cannot form the covalent complex and is rapidly degraded, causing congenital Lp(a) deficiency (PMID:10484779). Lp(a) is catabolized via the VLDL receptor through apo(a)-mediated binding rather than the classical LDL receptor, while LDL receptor status nonetheless modulates plasma Lp(a) levels (PMID:6277537, PMID:9410893, PMID:9781014). Functionally, apo(a) engages cell-surface plasminogen receptor sites carrying C-terminal lysines, competing with plasminogen (PMID:7667829); its oxidized-phospholipid cargo drives proinflammatory IL-8 induction in macrophages through CD36/TLR2–MAPK–NF-κB/AP-1 signaling (PMID:26474593); and Lp(a) promotes endothelial VCAM-1/E-selectin expression via a calcium-dependent, receptor-independent mechanism (PMID:9837867). Lp(a) accumulates in arterial extracellular matrix through chondroitin sulfate proteoglycan and glycosaminoglycan interactions that promote foam cell formation (PMID:10323765, PMID:2146124), down-regulates glucocorticoid receptor expression in vascular smooth muscle cells (PMID:7649076), and in its oxidized form drives endothelial apoptosis and autophagy through ROS-dependent pathways (PMID:26407666, PMID:10201010).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 1983 High

    Establishing the molecular composition of Lp(a) was the first step: the question was what distinguishes Lp(a) from LDL, answered by showing it is apoB-100 disulfide-linked to a distinct high-molecular-weight glycoprotein.

    Evidence SDS-PAGE under reducing/non-reducing conditions with immunochemical and periodate-Schiff analysis

    PMID:6219896

    Open questions at the time
    • Did not localize the disulfide bond or define the apo(a) sequence
    • Site and timing of disulfide formation unaddressed
  2. 1987 High

    Defined the genetic basis of plasma Lp(a) variation by showing apo(a) size heterogeneity is allelic at a single locus and inversely related to concentration, framing LPA as the primary determinant of Lp(a) levels.

    Evidence Reducing SDS-PAGE/immunoblotting, neuraminidase treatment, and family studies

    PMID:2956279

    Open questions at the time
    • Did not establish the molecular mechanism linking isoform size to concentration
    • Sialic acid excluded but other structural contributors not defined
  3. 1981 High

    Tested whether Lp(a) uses the LDL receptor pathway and found it does not, opening the question of an alternative catabolic route.

    Evidence 125I-ligand binding/degradation in normal, FH-heterozygous, and LDL-receptor-negative fibroblasts

    PMID:6277537

    Open questions at the time
    • Did not identify the actual uptake receptor
    • Mechanism of Lp(a) inhibition of LDL degradation unresolved
  4. 1993 Medium

    Probed hepatic handling of Lp(a) and showed it binds hepatoma cells with low-affinity non-saturable kinetics and may be cleared by LDL-dependent 'hitchhiking', refining the catabolic model.

    Evidence Radioligand binding/degradation in HepG2 and Hep3B cells with antibody inhibition

    PMID:8318510

    Open questions at the time
    • Single lab
    • Molecular identity of the hepatic binding site not defined
  5. 1995 High

    Connected apo(a) structural homology to function by demonstrating Lp(a) binds plasminogen receptor sites bearing C-terminal lysines, providing a mechanism for interference with fibrinolysis.

    Evidence Saturation binding of radiolabeled Lp(a) on U937 and endothelial cells with ganglioside/enolase/lysine-analog competition

    PMID:7667829

    Open questions at the time
    • Did not quantify the functional impact on plasminogen activation in vivo
    • Specific receptor proteins not all identified
  6. 1997 High

    Identified the VLDL receptor as a genuine Lp(a) catabolic receptor, with apo(a) rather than apoB mediating binding, resolving the long-standing alternative-pathway question.

    Evidence Receptor-expressing vs deficient fibroblasts, antibody/RAP inhibition, VLDLR-deficient mouse clearance, lesion immunohistochemistry

    PMID:9410893

    Open questions at the time
    • Relative in vivo contribution of VLDLR vs other routes unquantified
    • Does not explain hepatic clearance of the core particle
  7. 1997 Medium

    Proposed a two-step assembly model (noncovalent kringle-LDL interaction then disulfide stabilization) plus renal proteolytic processing, framing where and how Lp(a) is built and cleared.

    Evidence Biochemical analysis of assembly intermediates, urinary apo(a) fragment identification, kringle-variant binding studies

    PMID:9520125

    Open questions at the time
    • Some steps inferred rather than directly demonstrated
    • Identity of the renal protease not established
  8. 2006 Medium

    Addressed how covalent assembly is catalyzed by identifying a secreted, cofactor-dependent hepatoma oxidase activity that accelerates disulfide bond formation, distinct from PDI.

    Evidence In vitro Lp(a) assembly assay with conditioned medium, heat/ultrafiltration/dialysis fractionation, ping-pong kinetic analysis

    PMID:16893192

    Open questions at the time
    • Molecular identity of the oxidase not established
    • Single lab; cofactor not identified
  9. 2022 High

    Localized the noncovalent assembly step inside hepatocytes and showed it governs coupled apo(a)/apoB secretion, integrating assembly with cellular trafficking and secretion control.

    Evidence Co-IP, co-IF, PLA, pulse-chase, APOB siRNA, PCSK9/lomitapide perturbation in hepatocellular carcinoma cells with LBS-mutant apo(a)

    PMID:35045727

    Open questions at the time
    • Did not identify the extracellular oxidase coupling to covalent assembly
    • Performed in a 17K isoform context
  10. 1999 High

    Defined a genetic cause of Lp(a) deficiency: a kringle IV-8 splice-donor mutation yielding truncated apo(a) that cannot form the covalent complex and is degraded, directly linking assembly competence to plasma persistence.

    Evidence RT-PCR of apo(a) transcription, expression of spliced cDNA in HepG2, plasma apo(a) immunoprecipitation

    PMID:10484779

    Open questions at the time
    • Did not establish disease/phenotypic consequences of deficiency
    • Why free truncated apo(a) is rapidly cleared not fully resolved
  11. 1998 Medium

    Demonstrated genetic epistasis between LDLR status and Lp(a) levels independent of apo(a) genotype, showing LDLR deficiency raises Lp(a) despite LDLR not being the catabolic receptor.

    Evidence Sib-pair IBD analysis at the apo(a) locus with LDLR genotyping across 367 family members

    PMID:9781014

    Open questions at the time
    • Mechanism reconciling LDLR effect on levels with non-LDLR catabolism unresolved
    • Single analysis
  12. 1990 Medium

    Linked Lp(a) to matrix retention and foam cell formation by showing enhanced proteoglycan/GAG complex formation driving macrophage cholesteryl ester accumulation, partly attributable to apo(a).

    Evidence In vitro GAG/PG complex formation, macrophage incubation, cholesteryl ester measurement with apo(a)-depleted controls

    PMID:2146124

    Open questions at the time
    • Single lab
    • Apo(a)-independent component of binding not fully explained
  13. 1999 Medium

    Showed cooperative matrix accumulation: smooth muscle cell chondroitin sulfate proteoglycans bind Lp(a) and pre-bound Lp(a) enhances subsequent LDL retention, a mechanism for lesional lipoprotein deposition.

    Evidence Radioligand binding to SMC matrix, chondroitinase analysis, binding affinity measurements

    PMID:10323765

    Open questions at the time
    • Non-ionic interaction partners not molecularly defined
    • Single lab
  14. 1998 Medium

    Identified an endothelial pro-adhesive function: Lp(a) induces VCAM-1/E-selectin via intracellular calcium, mediated by apo(a) and independent of known lipoprotein receptors.

    Evidence HCAEC culture, adhesion molecule measurement, BAPTA/AM chelation, recombinant apo(a) competition, multiple receptor-blocking controls

    PMID:9837867

    Open questions at the time
    • The receptor/sensor transducing the calcium signal not identified
    • Single lab
  15. 2015 High

    Defined the molecular basis of Lp(a) proinflammatory signaling, showing apo(a)-borne oxidized phospholipids drive IL-8 through CD36/TLR2–MAPK–NF-κB/AP-1, tying a structural cargo to a signaling output.

    Evidence siRNA receptor knockdown, MAPK inhibitors, IL-8 promoter luciferase mutants, enzymatic oxPL removal, LBS-mutant apo(a) in THP-1/U937

    PMID:26474593

    Open questions at the time
    • In vivo relevance of the macrophage pathway not established here
    • Contribution relative to other oxPL carriers unquantified
  16. 1995 Medium

    Revealed an effect on vascular smooth muscle signaling: Lp(a) selectively down-regulates glucocorticoid receptor expression, blunting the antiproliferative action of glucocorticoids.

    Evidence Nuclear GR radioligand binding, GR mRNA Northern blotting, proliferation assays across cell and lipoprotein types

    PMID:7649076

    Open questions at the time
    • Receptor/signal mediating GR down-regulation not identified
    • Single lab
  17. 1996 Medium

    Characterized Lp(a)-associated PAF-acetylhydrolase, showing most activity resides on the lipid/apoB core rather than apo(a) and is sensitive to particle oxidation.

    Evidence Density-gradient ultracentrifugation, DTT cleavage, PAF-AH activity and Cu2+-oxidation kinetics

    PMID:8831934

    Open questions at the time
    • Physiological consequence of isoform-dependent kinetics unresolved
    • Single lab
  18. 1991 Medium

    Explained the relative oxidation resistance of Lp(a) by attributing its extended lag phase to high sialic acid content, demonstrated by neuraminidase removal and NANA reconstitution.

    Evidence Paired Cu2+ lipid peroxidation of Lp(a) and LDL, neuraminidase treatment, NANA reconstitution, composition analysis

    PMID:1825020

    Open questions at the time
    • In vivo relevance of differential oxidation kinetics not addressed
    • Single lab
  19. 1999 Medium

    Linked oxidized Lp(a) to endothelial injury, showing oxLp(a) is more potent than oxLDL at inducing apoptosis via superoxide and high lysophosphatidylcholine content.

    Evidence DNA fragmentation, Annexin V, TUNEL, superoxide measurement, SOD/catalase and DDTC manipulation, lysoPC quantification in HUVECs and rabbit aorta

    PMID:10201010

    Open questions at the time
    • Upstream receptor/uptake route for oxLp(a) not defined
    • Single lab
  20. 2015 Medium

    Extended oxLp(a) endothelial signaling to autophagy, mapping a ROS-dependent PARP-1–LKB1–AMPK–mTOR axis.

    Evidence Autophagy and ROS assays, pathway inhibitor and SOD studies, Western blotting in HUVECs

    PMID:26407666

    Open questions at the time
    • Single cell type and lab
    • Functional outcome of autophagy for cell fate not resolved
  21. 1999 Medium

    Showed Lp(a) is a negative acute-phase reactant, declining during inflammation through decreased production rather than enhanced catabolism, integrating Lp(a) regulation with systemic inflammatory state.

    Evidence Serial plasma measurements in sepsis/burns patients, apo(a) fragment and urinary apo(a) assays, LPS-challenge mouse clearance study

    PMID:10764684

    Open questions at the time
    • Transcriptional/hepatic mechanism of decreased production not defined
    • Single lab
  22. 2017 Low

    Implicated Lp(a) in calcific aortic valve disease via interaction with autotaxin promoting valve mineralization, extending Lp(a) pathobiology beyond atherothrombosis.

    Evidence Mechanistic claim summarized in a review citing original work

    PMID:28816078

    Open questions at the time
    • Primary experimental detail not available in this entry
    • Direct Lp(a)–autotaxin interaction not independently characterized in the timeline

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular identity of the extracellular oxidase that catalyzes covalent Lp(a) assembly, and how it integrates with the intracellular noncovalent assembly step, remains unresolved.
  • Oxidase enzyme unidentified
  • Cofactor required for assembly unknown
  • Coupling between hepatocyte secretion and extracellular covalent assembly undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 3 GO:0098772 molecular function regulator activity 3 GO:0008092 cytoskeletal protein binding 2
Localization
GO:0005576 extracellular region 2 GO:0031012 extracellular matrix 2 GO:0005768 endosome 1 GO:0005783 endoplasmic reticulum 1 GO:0005794 Golgi apparatus 1
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 2
Partners
APOBCD36LDLRPLGTLR2VLDLR
Complex memberships
Lp(a) particle (apo(a)/apoB-100)

Evidence

Reading pass · 22 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1983 Lp(a) lipoprotein contains two polypeptide chains: apolipoprotein B-100 (identical to LDL apoB) and a high-molecular-weight glycoprotein (~350 kDa) carrying the specific Lp(a) immunoreactivity. These two components are linked by disulfide bonds in the native lipoprotein, as the unreduced delipidized protein moiety runs as a single ~700 kDa band on SDS-PAGE. SDS-polyacrylamide gel electrophoresis under reducing and non-reducing conditions, immunochemical analysis, periodate-Schiff staining FEBS letters High 6219896
1987 Lp(a) glycoprotein (apo(a)) exhibits inter- and intraindividual size heterogeneity (apparent MW ~400,000–700,000 Da), and phenotypic differences between apo(a) isoforms do not reside in the sialic acid moiety (neuraminidase treatment does not abolish size differences). Family studies indicate phenotypes are controlled by a series of autosomal alleles at a single locus, and isoform size is inversely associated with plasma Lp(a) concentration. SDS-gel electrophoresis under reducing conditions, immunoblotting with anti-Lp(a) serum, neuraminidase treatment, family studies The Journal of clinical investigation High 2956279
1981 Lp(a) lipoprotein enters cultured fibroblasts independently of the LDL receptor: processing of 125I-Lp(a) was not saturated at high concentrations, was largely receptor-independent (only slightly higher in normal vs. receptor-negative cells), and Lp(a) did not compete with 125I-LDL for receptor-mediated fibroblast association, although it inhibited LDL degradation in a time-dependent manner. 125I-labeled ligand binding and degradation assays in fibroblasts from normal, FH heterozygous, and LDL receptor-negative FH homozygous subjects Clinical genetics High 6277537
1997 The VLDL receptor mediates endocytosis and lysosomal degradation of Lp(a). Fibroblasts expressing human VLDL receptor catabolize Lp(a); receptor-deficient fibroblasts do not. Antibodies against VLDL receptor and RAP (a receptor antagonist) block Lp(a) degradation. Catabolism is inhibited by apolipoprotein(a) but not by LDL or anti-apoB antibodies, indicating that apo(a) mediates Lp(a) binding to the VLDL receptor. In vivo, Lp(a) clearance is delayed in VLDL receptor-deficient mice. Receptor-expressing vs. receptor-deficient fibroblast assays, antibody and RAP inhibition, in vivo mouse clearance studies, immunohistochemistry of human atherosclerotic lesions The Journal of clinical investigation High 9410893
1995 Lp(a) interacts directly with plasminogen binding sites on monocytoid U937 cells and endothelial cells in a time-dependent, specific, saturable, divalent ion-independent, and temperature-sensitive manner with affinity similar to plasminogen (Kd ~1–3 μM), but binds to ~10-fold fewer sites. Gangliosides and cell-surface proteins with C-terminal lysyl residues (including enolase) inhibit Lp(a) binding, indicating shared plasminogen receptor sites. Binding assays with radiolabeled Lp(a) on U937 and endothelial cells; competitive inhibition with gangliosides, enolase, and lysine analogs; saturation binding kinetics Thrombosis and haemostasis High 7667829
1999 A G→A substitution at the +1 donor splice site of the apo(a) kringle IV type 8 intron occurs in ~6% of Caucasians and causes congenital Lp(a) deficiency. This mutation leads to alternative splicing producing a truncated apo(a). The truncated apo(a) is secreted but cannot form the covalent Lp(a) complex (disulfide-linked apo(a)/apoB-100 complex), resulting in rapid degradation of free apo(a) in plasma. RT-PCR of apo(a) illegitimate transcription, expression of alternatively spliced cDNA in HepG2 cells, immunoprecipitation of plasma apo(a) Human molecular genetics High 10484779
2006 Cultured human hepatoma cells secrete an extracellular oxidase activity that dramatically enhances the rate of covalent (disulfide bond) Lp(a) assembly. This activity is heat-sensitive and protein-based (retained after ultrafiltration >5 kDa), requires a small-molecule cofactor (lost upon dialysis), and exhibits a ping-pong reaction mechanism kinetically analogous to protein disulfide isomerase. Protein disulfide isomerase itself was ruled out as the responsible enzyme. In vitro Lp(a) assembly assay with hepatoma cell-conditioned medium, heat inactivation, ultrafiltration, dialysis, kinetic analysis (Km, Vmax, rectangular hyperbola fitting) Biochemistry Medium 16893192
1997 Lp(a) assembly occurs via a two-step mechanism: (1) noncovalent interactions between apo(a) kringle domains (particularly T-6 and T-7) and circulating LDL, followed by (2) formation of a single disulfide bridge to stabilize the Lp(a) complex. Circulating Lp(a) interacts with kidney cells, where a collagenase-type protease cleaves the N-terminal ~2/3–3/4 of apo(a), with apo(a) fragments found in urine. The core Lp(a) particle is subsequently cleared by the liver. Biochemical analysis of Lp(a) assembly intermediates, identification of apo(a) fragments in urine, in vitro binding studies with kringle domain variants Clinical genetics Medium 9520125
2022 Apo(a) and apoB interact noncovalently within hepatocytes before Lp(a) is secreted. Noncovalent apo(a)/apoB complexes (but not covalent ones) are present in cell lysates. Apo(a) and apoB colocalize in the ER, trans-Golgi, and early endosomes. The noncovalent interaction (mediated by lysine-binding sites 7 and 8 of apo(a)) is required for coupling of apo(a) and Lp(a)-apoB secretion: PCSK9 treatment enhances and lomitapide reduces apo(a) secretion in a manner dependent on this interaction; siRNA knockdown of APOB reduces apo(a) secretion. Co-immunoprecipitation, co-immunofluorescence, proximity ligation assay, pulse-chase metabolic labeling, siRNA knockdown, pharmacological manipulation (PCSK9, lomitapide) in human hepatocellular carcinoma cells expressing wild-type and LBS-mutant 17K apo(a) Arteriosclerosis, thrombosis, and vascular biology High 35045727
1993 Lp(a) binding to hepatoma cells (HepG2) is predominantly of low affinity and non-saturable (unlike LDL which shows saturable high-affinity binding). Preincubation with Lp(a) or free apo(a) for 48–72 h paradoxically increases subsequent 125I-LDL binding (>2-fold) through a mechanism not involving the LDL receptor (not blocked by anti-LDL receptor antibodies). Coincubation with LDL significantly increases Lp(a) degradation by HepG2 cells, suggesting 'hitchhiking' uptake. Radioligand binding assays with 125I-LDL and 125I-Lp(a) in HepG2 and Hep3B cells, antibody inhibition, preincubation experiments Arteriosclerosis and thrombosis Medium 8318510
1999 Chondroitin sulfate proteoglycans in smooth muscle cell extracellular matrix bind both Lp(a) and LDL with high affinity. Lp(a) pre-bound to matrix increases subsequent LDL binding 2–3-fold, with the additional LDL held predominantly by strong non-ionic associations (vs. ~50% ionic for LDL-pretreated matrix), providing a mechanism for cooperative lipoprotein accumulation in arterial lesions. Radioligand binding assays with cultured human arterial smooth muscle cell matrix, chondroitinase/proteoglycan analysis, binding affinity measurements Arteriosclerosis, thrombosis, and vascular biology Medium 10323765
1990 Lp(a) forms complexes with glycosaminoglycans (GAG) and proteoglycans (PG) from human aorta with a higher GAG/lipoprotein ratio than LDL. The Lp(a) lacking apo(a) (Lpa-) shows intermediate reactivity between Lp(a) and LDL, indicating apo(a) contributes to but is not solely responsible for the enhanced proteoglycan binding. Lp(a)-glycan complexes incubated with mouse peritoneal macrophages cause cholesteryl ester accumulation and foam cell formation, with the degree of accumulation correlating with proteoglycan reactivity. In vitro complex formation assays with isolated GAG/PG and lipoproteins, macrophage incubation with lipoglycan complexes, cholesterol ester measurement European heart journal Medium 2146124
1998 Lp(a) stimulates expression of VCAM-1 and E-selectin in cultured human coronary artery endothelial cells (HCAEC) via a rise in intracellular free calcium. This effect is blocked by the intracellular calcium chelator BAPTA/AM. Recombinant apo(a) competes with Lp(a) and attenuates adhesion molecule expression, indicating apo(a) mediates this effect. The LDL receptor, VLDL receptor (RAP-insensitive), LDL receptor-related protein, cell-surface proteoglycans, and plasminogen receptors are not involved in this Lp(a)-induced adhesion molecule production. Cell culture with human coronary artery endothelial cells, VCAM-1/E-selectin protein measurement, intracellular calcium chelation (BAPTA/AM), competitive inhibition with recombinant apo(a), antibody/enzyme blocking of candidate receptors FASEB journal Medium 9837867
2015 Recombinant apo(a) containing 17 kringle IV domains induces IL-8 mRNA and protein expression in THP-1 and U937 macrophages via oxidized phospholipids (oxPL) carried on apo(a). Mutation of the lysine-binding site in kringle IV type 10 abolishes oxPL on apo(a) and blunts IL-8 induction. Enzymatic removal of oxPL from apo(a) significantly reduces this effect. The effect is mediated through CD36 and TLR2 receptors, downstream MAPK signaling (JNK and ERK1/2), and requires both NF-κB and AP-1 binding sites in the IL-8 promoter. siRNA receptor knockdown, MAPK inhibitors, luciferase reporter gene assays with IL-8 promoter mutants, enzymatic oxPL removal, trypsin digestion, LBS-mutant apo(a) in macrophage cell lines Journal of lipid research High 26474593
1996 PAF-acetylhydrolase (PAF-AH) activity is associated with Lp(a) particles in human plasma. Removal of apo(a) from Lp(a) by reductive cleavage with DTT releases only ~15% of total PAF-AH activity, indicating that most PAF-AH is associated with the lipid/apoB core of Lp(a) rather than with apo(a) itself. Kinetic constants (Km, Vmax) differ significantly between small and large apo(a) isoforms. During Cu2+-induced Lp(a) oxidation, PAF-AH Vmax decreases significantly and extensive phosphatidylcholine hydrolysis to lyso-PC occurs. Density gradient ultracentrifugation, DTT reductive cleavage, PAF-AH activity assay, Cu2+-induced oxidation kinetics, lipid analysis by phospholipid assay Atherosclerosis Medium 8831934
1991 Lp(a) is oxidized by Cu2+ more slowly than LDL from the same donor (1.2–2.4-fold longer lag phase). The extended lag phase of Lp(a) is attributable to its higher sialic acid (NANA) content: neuraminidase treatment drastically shortens the Lp(a) lag phase, and re-supplementation with NANA at physiological concentrations restores it. LDL lag phase is not significantly affected by neuraminidase. Paired Cu2+-induced lipid peroxidation assays on isolated Lp(a) and LDL, neuraminidase treatment, NANA reconstitution, fatty acid and antioxidant composition analysis Biochimica et biophysica acta Medium 1825020
1995 Lp(a) down-regulates glucocorticoid receptor (GR) gene expression and nuclear GR protein levels in human and rat vascular smooth muscle cells (SMC), but not in rat endothelial cells. GR mRNA decreases to 23% of control after 12 h Lp(a) treatment; nuclear GR protein falls to 55% after 48 h. LDL, VLDL, and HDL have no effect on GR in SMC. As a functional consequence, the antiproliferative effect of glucocorticoids on SMC is blunted by Lp(a) exposure. Radioligand binding assay for nuclear GR, Northern blotting for GR mRNA, cell proliferation assay, comparison across lipoprotein types and cell types Endocrinology Medium 7649076
1999 Lp(a) behaves as a negative acute-phase reactant: plasma Lp(a) concentrations decline abruptly and transiently during sepsis and major burns, inversely mirroring CRP levels and paralleling LDL-C changes. This decline is not accompanied by increases in plasma apo(a) fragments or urinary apo(a), suggesting decreased production rather than increased degradation/shedding. Mouse turnover studies show that LPS treatment retards Lp(a) clearance, indicating that the reduction is not due to enhanced catabolism. Serial plasma measurements in ICU patients (sepsis, burns), apo(a) fragment immunoassay, urinary apo(a) measurement, mouse Lp(a) clearance study with LPS challenge Arteriosclerosis, thrombosis, and vascular biology Medium 10764684
2015 Oxidized Lp(a) (oxLp(a)) induces autophagy in human umbilical vein endothelial cells (HUVECs) via a reactive oxygen species (ROS)-dependent mechanism. The PARP-1–LKB1–AMPK–mTOR and LKB1–AMPK–mTOR signaling pathways mediate this autophagic response. Superoxide dismutase (antioxidant) inhibits oxLp(a)-induced autophagy, confirming ROS dependence. Autophagy assays in HUVECs, ROS measurement, pathway inhibitor studies (PARP-1, LKB1, AMPK, mTOR), SOD treatment, Western blotting for pathway components Atherosclerosis Medium 26407666
2017 Autotaxin (ATX), a lysophospholipase D, interacts with Lp(a) and promotes mineralization of the aortic valve, linking Lp(a) to calcific aortic valve disease (CAVD) pathobiology. Referenced as recent mechanistic data in review; original experimental work cited within the review paper Expert review of cardiovascular therapy Low 28816078
1999 Lp(a) induces apoptosis in human umbilical vein endothelial cells (HUVECs) and rabbit aorta, with oxidized Lp(a) (oxLp(a)) being more potent than oxLDL. oxLp(a) stimulates superoxide (O2-) formation in HUVECs (356% increase) and rabbit aorta (294% increase). Apoptosis induction by oxLp(a) involves O2- as a mediator: it is enhanced by the SOD inhibitor DDTC and blunted by SOD and catalase. Lysophosphatidylcholine content is 7-fold higher in oxLp(a) vs. native Lp(a). DNA fragmentation assay, Annexin V assay, TUNEL staining, O2- measurement, SOD/catalase treatment, SOD inhibitor (DDTC), lysoPC quantification in HUVECs and rabbit aorta segments Kidney international Medium 10201010
1998 Elevated Lp(a) concentrations in patients with familial hypercholesterolemia (FH) are due to an effect of the LDL receptor deficiency on Lp(a) metabolism, independent of apo(a) genotype. Sib-pair analysis of siblings identical-by-descent at the apo(a) locus but differing in LDLR mutation status shows significantly higher Lp(a) in FH siblings, establishing a quantitative genetic interaction between LDLR status and Lp(a) levels. Sib-pair genetic analysis with IBD determination at apo(a) locus, LDLR mutation genotyping, Lp(a) plasma measurement in 367 family members of 60 index patients European journal of human genetics Medium 9781014

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Genetic variants associated with Lp(a) lipoprotein level and coronary disease. The New England journal of medicine 1276 20032323
1987 Lp(a) glycoprotein phenotypes. Inheritance and relation to Lp(a)-lipoprotein concentrations in plasma. The Journal of clinical investigation 835 2956279
1983 Protein composition of Lp(a) lipoprotein from human plasma. FEBS letters 242 6219896
1975 Lp(a) lipoprotein: relationship to sinking pre-beta lipoprotein hyperlipoproteinemia, and apolipoprotein B. Metabolism: clinical and experimental 164 168455
2008 Enhanced expression of Lp-PLA2 and lysophosphatidylcholine in symptomatic carotid atherosclerotic plaques. Stroke 148 18356547
1997 The atherogenic lipoprotein Lp(a) is internalized and degraded in a process mediated by the VLDL receptor. The Journal of clinical investigation 142 9410893
1989 Enzyme-linked immunoassay for Lp[a]. Journal of lipid research 132 2527286
1991 Oxidation of lipoprotein Lp(a). A comparison with low-density lipoproteins. Biochimica et biophysica acta 127 1825020
2004 Lp(a) lipoprotein and lipids in patients with rheumatoid arthritis: serum levels and relationship to inflammation. Rheumatology international 121 15290086
2021 Emerging RNA Therapeutics to Lower Blood Levels of Lp(a): JACC Focus Seminar 2/4. Journal of the American College of Cardiology 118 33766265
1995 Sequence polymorphisms in the apo(a) gene associated with specific levels of Lp(a) in plasma. Human molecular genetics 114 7757064
1999 Lp(a) and LDL induce apoptosis in human endothelial cells and in rabbit aorta: role of oxidative stress. Kidney international 113 10201010
1998 Expression of adhesion molecules by lp(a): a potential novel mechanism for its atherogenicity. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 93 9837867
2015 Mechanistic insights into Lp(a)-induced IL-8 expression: a role for oxidized phospholipid modification of apo(a). Journal of lipid research 91 26474593
1981 Lp(a) lipoprotein enters cultured fibroblasts independently of the plasma membrane low density lipoprotein receptor. Clinical genetics 88 6277537
2022 Beyond fibrinolysis: The confounding role of Lp(a) in thrombosis. Atherosclerosis 86 35606079
2005 Mediation of Epstein-Barr virus EBNA-LP transcriptional coactivation by Sp100. The EMBO journal 80 16177824
2011 Antioxidant and inflammatory aspects of lipoprotein-associated phospholipase A₂ (Lp-PLA₂): a review. Lipids in health and disease 75 21955667
2010 LP-211 is a brain penetrant selective agonist for the serotonin 5-HT(7) receptor. Neuroscience letters 75 20600619
1994 Lp(a): an acute-phase reactant? Chemistry and physics of lipids 72 7514505
2002 Lp-PLA2: an emerging biomarker of coronary heart disease. Expert review of molecular diagnostics 69 11963798
2000 Sequence and functional analysis of EBNA-LP and EBNA2 proteins from nonhuman primate lymphocryptoviruses. Journal of virology 67 10590127
2001 The mouse lp(A3)/Edg7 lysophosphatidic acid receptor gene: genomic structure, chromosomal localization, and expression pattern. Gene 62 11313151
2015 EBNA2 and Its Coactivator EBNA-LP. Current topics in microbiology and immunology 60 26428371
1999 Molecular basis of congenital lp(a) deficiency: a frequent apo(a) 'null' mutation in caucasians. Human molecular genetics 59 10484779
1995 Interaction of Lp(a) with plasminogen binding sites on cells. Thrombosis and haemostasis 56 7667829
2014 Pathophysiological role and clinical significance of lipoprotein-associated phospholipase A₂ (Lp-PLA₂) bound to LDL and HDL. Current pharmaceutical design 55 24953389
2000 Major reduction in plasma Lp(a) levels during sepsis and burns. Arteriosclerosis, thrombosis, and vascular biology 51 10764684
1994 Lp(a) lipoprotein: an overview. Chemistry and physics of lipids 50 8187248
1998 Concentrations of the atherogenic Lp(a) are elevated in FH. European journal of human genetics : EJHG 49 9781014
2001 EBNA-LP associates with cellular proteins including DNA-PK and HA95. Journal of virology 48 11160753
2017 Triglyceride Rich Lipoprotein -LPL-VLDL Receptor and Lp(a)-VLDL Receptor Pathways for Macrophage Foam Cell Formation. Journal of atherosclerosis and thrombosis 46 28428482
1999 Proteoglycans contribution to association of Lp(a) and LDL with smooth muscle cell extracellular matrix. Arteriosclerosis, thrombosis, and vascular biology 46 10323765
1996 PAF-acetylhydrolase activity of Lp(a) before and during Cu(2+)-induced oxidative modification in vitro. Atherosclerosis 46 8831934
2023 LP(a): Structure, Genetics, Associated Cardiovascular Risk, and Emerging Therapeutics. Annual review of pharmacology and toxicology 45 37506332
1995 Lp(a) lipoprotein levels as a predictor of risk for thrombogenic events in patients with Behçet's disease. Annals of the rheumatic diseases 45 7495343
1995 Lipid and lipoprotein factors associated with variation in Lp(a) density. Arteriosclerosis, thrombosis, and vascular biology 42 7749840
2021 Identification of Inflammation-Related Biomarker Lp-PLA2 for Patients With COPD by Comprehensive Analysis. Frontiers in immunology 41 34093570
2018 Oxidized phospholipids and lipoprotein-associated phospholipase A2 as important determinants of Lp(a) functionality and pathophysiological role. Journal of biomedical research 41 27346583
2018 Differential expression of Lp-PLA2 in obesity and type 2 diabetes and the influence of lipids. Diabetologia 41 29427237
2006 Lp-PLA2: a new kid on the block. Clinical chemistry 41 16873290
2002 Diagnostic value of CRP and Lp(a) in coronary heart disease. Acta cardiologica 40 12088177
2019 Prediction of cardiovascular risk by Lp(a) concentrations or genetic variants within the LPA gene region. Clinical research in cardiology supplements 38 30859385
2016 Lp(a) and cardiovascular risk: Investigating the hidden side of the moon. Nutrition, metabolism, and cardiovascular diseases : NMCD 38 27514608
1993 Interaction of Lp(a) and of apo(a) with liver cells. Arteriosclerosis and thrombosis : a journal of vascular biology 38 8318510
1992 Isolation and partial characterization of lipoprotein A-II (LP-A-II) particles of human plasma. Biochimica et biophysica acta 38 1606170
1991 Does lipoprotein(a) (Lp(a)) complete with plasminogen in human atherosclerotic lesions and thrombi? Atherosclerosis 38 1838924
2024 Antioxidant and anti-aging activities of Longan crude and purified polysaccharide (LP-A) in nematode Caenorhabditis elegans. International journal of biological macromolecules 37 38636747
2015 Ox-Lp(a) transiently induces HUVEC autophagy via an ROS-dependent PAPR-1-LKB1-AMPK-mTOR pathway. Atherosclerosis 35 26407666
2022 Exosome-Loaded Pro-efferocytic Vascular Stent with Lp-PLA2-Triggered Release for Preventing In-Stent Restenosis. ACS nano 34 36066255
2002 Immunohistological localization of the myelinating cell-specific receptor LP(A1). Glia 33 11948806
1999 Preparation of a stable fresh frozen primary lipoprotein[a] (Lp[a]) standard. Journal of lipid research 30 10588951
2022 Lp(a): a New Pathway to Target? Current atherosclerosis reports 29 36066785
2019 ApoB, small-dense LDL-C, Lp(a), LpPLA2 activity, and cognitive change. Neurology 29 31043469
2017 Specific Lp(a) apheresis: A tool to prove lipoprotein(a) atherogenicity. Atherosclerosis. Supplements 28 29096833
2006 [Inflammation, atherosclerosis and cardiovascular disease risk: PAPP-A, Lp-PLA2 and cystatin C. New insights or redundant information?]. Revista espanola de cardiologia 28 16712749
2003 Identification of AMSH-LP containing a Jab1/MPN domain metalloenzyme motif. Biochemical and biophysical research communications 28 12810066
2016 Genetic invalidation of Lp-PLA2 as a therapeutic target: Large-scale study of five functional Lp-PLA2-lowering alleles. European journal of preventive cardiology 27 27940953
2020 Characterization of LP-Z Lipoprotein Particles and Quantification in Subjects with Liver Disease Using a Newly Developed NMR-Based Assay. Journal of clinical medicine 26 32927635
2013 Lp-PLA2 is associated with structural valve degeneration of bioprostheses. European journal of clinical investigation 26 24328921
2006 Lp-PLA2 activity and PLA2G7 A379V genotype in patients with diabetes mellitus. Atherosclerosis 26 16438975
1990 Is the atherogenicity of Lp(a) caused by its reactivity with proteoglycans? European heart journal 26 2146124
2019 Individuals with familial hypercholesterolemia and cardiovascular events have higher circulating Lp(a) levels. Journal of clinical lipidology 25 31371270
2006 Genetics of the Lp(a)/apo(a) system in an autochthonous Black African population from the Gabon. European journal of human genetics : EJHG 25 16267501
2019 Looking at Lp(a) and Related Cardiovascular Risk: from Scientific Evidence and Clinical Practice. Current atherosclerosis reports 24 31350625
2009 Metalloproteases 2 and 9, Lp-PLA(2) and lipoprotein profile in coronary patients. Archives of medical research 24 19064127
2006 Catalysis of covalent Lp(a) assembly: evidence for an extracellular enzyme activity that enhances disulfide bond formation. Biochemistry 23 16893192
2010 Lp-PLA2: A new target for statin therapy. Current atherosclerosis reports 22 20425268
1997 Metabolism of Lp(a): assembly and excretion. Clinical genetics 22 9520125
2022 Apo(a) and ApoB Interact Noncovalently Within Hepatocytes: Implications for Regulation of Lp(a) Levels by Modulation of ApoB Secretion. Arteriosclerosis, thrombosis, and vascular biology 21 35045727
2021 Prevalence and influence of LPA gene variants and isoform size on the Lp(a)-lowering effect of pelacarsen. Atherosclerosis 21 33872986
2007 Effects of atorvastatin on Lp(a) and lipoprotein profiles in hemodialysis patients. The Annals of pharmacotherapy 21 18000162
2017 Heter-LP: A heterogeneous label propagation algorithm and its application in drug repositioning. Journal of biomedical informatics 20 28300647
1991 Lp(a) as a marker for coronary heart disease risk. Clinical cardiology 20 1828399
2025 Antibody evasion and receptor binding of SARS-CoV-2 LP.8.1.1, NB.1.8.1, XFG, and related subvariants. Cell reports 19 41091599
2022 Lp(a) and the Risk for Cardiovascular Disease: Focus on the Lp(a) Paradox in Diabetes Mellitus. International journal of molecular sciences 19 35408941
2016 The Lp_3561 and Lp_3562 Enzymes Support a Functional Divergence Process in the Lipase/Esterase Toolkit from Lactobacillus plantarum. Frontiers in microbiology 19 27486450
2011 Therapeutic modulation of lipoprotein-associated phospholipase A2 (Lp-PLA2). Current pharmaceutical design 19 22074435
1996 How often has Lp(a) evolved? Clinical genetics 19 8828980
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2017 Pathobiology of Lp(a) in calcific aortic valve disease. Expert review of cardiovascular therapy 18 28816078
1999 Plasma and Lp(a)-associated PAF-acetylhydrolase activity in uremic patients undergoing different dialysis procedures. Kidney international 18 10594806
2023 Developing an SI-traceable Lp(a) reference measurement system: a pilgrimage to selective and accurate apo(a) quantification. Critical reviews in clinical laboratory sciences 17 37128734
2008 Regulation of Sp100A subnuclear localization and transcriptional function by EBNA-LP and interferon. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 17 18844582
1992 Genetic basis and pathophysiological implications of high plasma Lp(a) levels. Journal of internal medicine 17 1535652
2025 Targeting Lp-PLA2 inhibits profibrotic monocyte-derived macrophages in silicosis through restoring cardiolipin-mediated mitophagy. Cellular & molecular immunology 16 40389600
2021 Lactobacillus plantarum GB LP-1 as a direct-fed microbial for neonatal calves. Journal of dairy science 16 33663862
2012 Inhibition of Lp(a)-induced functional impairment of endothelial cells and endothelial progenitor cells by hepatocyte growth factor. Biochemical and biophysical research communications 16 22634007
2006 Multiple QTL influence the serum Lp(a) concentration: a genome-wide linkage screen in the PROCARDIS study. European journal of human genetics : EJHG 16 17133260
1994 The relationship between infant and parent Lp(a) levels. Chemistry and physics of lipids 16 8187227
1988 Heterogeneity of lipoprotein Lp(a) and apolipoprotein(a). Clinical chemistry 16 2967739
2023 Structure of the N-RNA/P interface indicates mode of L/P recruitment to the nucleocapsid of human metapneumovirus. Nature communications 15 37993464
2010 Human SepSecS or SLA/LP: selenocysteine formation and autoimmune hepatitis. Biological chemistry 15 20623998
2024 Cryo-EM structure of Nipah virus L-P polymerase complex. Nature communications 14 39627254
2019 Homburgvirus LP-018 Has a Unique Ability to Infect Phage-Resistant Listeria monocytogenes. Viruses 14 31861087
1995 Glucocorticoid receptor expression is down-regulated by Lp(a) lipoprotein in vascular smooth muscle cells. Endocrinology 14 7649076
2022 Lp-PLA2 (Lipoprotein-Associated Phospholipase A2) Deficiency Lowers Cholesterol Levels and Protects Against Atherosclerosis in Rabbits. Arteriosclerosis, thrombosis, and vascular biology 13 36412196
2005 A novel human complement-related protein, C1r-like protease (C1r-LP), specifically cleaves pro-C1s. The Biochemical journal 13 15527420
2025 Lp(a)-Lowering Agents in Development: A New Era in Tackling the Burden of Cardiovascular Risk? Pharmaceuticals (Basel, Switzerland) 12 40430570
2025 Pelacarsen: Mechanism of action and Lp(a)-lowering effect. Journal of clinical lipidology 12 40781022

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