Affinage

LCAT

Phosphatidylcholine-sterol acyltransferase · UniProt P04180

Length
440 aa
Mass
49.6 kDa
Annotated
2026-06-10
100 papers in source corpus 34 papers cited in narrative 34 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

LCAT is a plasma α/β-hydrolase that esterifies cholesterol on lipoproteins and is the central enzyme driving maturation of high-density lipoprotein (HDL) (PMID:9541390, PMID:9054454). Catalysis proceeds through a Ser/Asp345/His377 triad with Phe103 and Leu182 forming the oxyanion hole and a lid domain (residues 50–74) controlling substrate access, an architecture confirmed by the 2.65 Å crystal structure that resolves a hydrolase core plus subdomains for interfacial activation and substrate-pocket shaping (PMID:9541390, PMID:26195816). The enzyme transfers an acyl chain from phosphatidylcholine to cholesterol; on HDL this requires apoA-I as an activator, acting through a defined helical registry—the active 5/5 thumbwheel configuration engaging helices 5–7 and 3–4, with negatively charged helix-6 residues attenuating activity—whereas apoA-II-bound particles are not substrates and apoE is the dominant activator on apoB-containing lipoproteins (PMID:29773713, PMID:15654758, PMID:15807534, PMID:7706940). Through this reaction LCAT, together with ABCA1, converts discoidal prebeta-HDL into mature spherical α-HDL and generates the bulk of plasma cholesteryl esters including the long-chain polyunsaturated species (PMID:17206937, PMID:23132909, PMID:12595510, PMID:11893779). Loss of LCAT in mice abolishes cholesterol esterification, collapses HDL cholesterol and apoA-I, and causes accumulation of the nephrotoxic vesicular lipoprotein X (LpX), which is taken up by glomerular cells via macropinocytosis, drives IL-6 secretion, and produces renal disease resembling familial LCAT deficiency; recombinant LCAT replacement reverses LpX accumulation and proteinuria (PMID:9054454, PMID:26919698, PMID:15466392, PMID:30563940). LCAT-derived cholesteryl ester additionally supplies cholesterol for adrenal steroidogenesis, supports HDL antiatherogenic and LPS-neutralizing functions, and its expression is regulated by IL-6 through a STAT3 element in the distal promoter and by estrogen via ESR1, the latter suppressing hepatocellular carcinoma by limiting SREBP2-driven cholesterol synthesis (PMID:12032172, PMID:25964513, PMID:38718297, PMID:26170061, PMID:23178225). Plasma LCAT is cleared as an enzymatically inactive complex with α2-macroglobulin recognized by the LRP receptor (PMID:11435418).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1993 Low

    Establishing whether LCAT loss-of-function arose from active-site lesions alone defined whether the protein had multiple functionally critical domains.

    Evidence Sequencing of all LCAT exons and mass/activity measurement in deficiency patients and heterozygotes

    PMID:8432868

    Open questions at the time
    • No in vitro functional characterization of individual mutants
    • Mechanism inferred from genotype–phenotype correlation only
  2. 1995 High

    Defining which apolipoproteins generate competent LCAT substrate particles established apolipoprotein specificity in HDL maturation.

    Evidence Cell-derived nascent apoA-I vs apoA-II lipid complexes incubated with purified LCAT, EM and native PAGE

    PMID:7706940

    Open questions at the time
    • Did not resolve the apoA-I structural features required for activation
    • In vitro reconstitution only
  3. 1997 High

    A clean knockout determined the in vivo necessity of LCAT for plasma cholesterol esterification and HDL homeostasis.

    Evidence Mouse LCAT gene disruption with FPLC and 2D-gel lipoprotein phenotyping under dietary challenge

    PMID:9054454

    Open questions at the time
    • Did not address downstream pathophysiology such as renal or steroidogenic consequences
    • Mouse-only physiology
  4. 1998 High

    Identifying the catalytic triad and oxyanion hole placed LCAT mechanistically within the α/β-hydrolase fold and defined its active site.

    Evidence Homology modeling plus site-directed mutagenesis expressed in Cos-1 cells with activity assays

    PMID:9541390

    Open questions at the time
    • Lid domain role proposed but not structurally resolved
    • No experimental 3D structure at this stage
  5. 2001 High

    Discovering the LCAT–α2-macroglobulin complex defined the receptor-mediated route for plasma LCAT clearance.

    Evidence Complex purification, radiolabeled binding assays, and internalization/degradation in LRP(+/+) vs LRP(−/−) cells

    PMID:11435418

    Open questions at the time
    • Physiological regulation of this clearance pathway not quantified
    • Binding interface on LCAT not mapped
  6. 2005 High

    Comparing apoE and apoA-I activation across genetic substrate backgrounds established apoE as the dominant activator on apoB-containing lipoproteins.

    Evidence apoA-I/apoE KO mouse plasma, in vitro LCAT assays on genotype-defined LDL/VLDL, apolipoprotein reconstitution

    PMID:15654758

    Open questions at the time
    • Structural basis of apoE-driven activation not defined
    • Did not address relative contribution in human lipoproteins
  7. 2007 High

    Genetic epistasis fixed LCAT's position downstream of ABCA1 in converting discoidal to spherical HDL across multiple apolipoprotein scaffolds.

    Evidence Adenoviral apoE4/apoA-IV plus LCAT transfer in ABCA1−/−, LCAT−/−, apoA-I−/− mice with EM verification

    PMID:17206937 PMID:23132909

    Open questions at the time
    • Did not dissect the molecular interface of LCAT with each apolipoprotein
    • Particle remodeling kinetics not resolved
  8. 2007 High

    Mapping disease and engineered apoA-I mutations that block LCAT activation showed impaired activation is the primary defect causing discoidal HDL accumulation.

    Evidence In vitro activation assays plus adenoviral mutant expression and LCAT rescue in apoA-I−/− mice with 2D-gel and EM readouts

    PMID:10787436 PMID:17506726 PMID:17711302

    Open questions at the time
    • Did not produce a co-structure of LCAT with apoA-I
    • Residue-level interaction inferred from activity, not direct binding
  9. 2018 High

    Disulfide-locking apoA-I registries demonstrated that activation depends on a specific helical configuration (5/5 thumbwheel) rather than on LCAT binding alone.

    Evidence Engineered disulfide-locked rHDL, esterification assays, and chemical cross-linking

    PMID:29773713

    Open questions at the time
    • The hybrid epitope model not confirmed by direct structure
    • Dynamics of the thumbwheel during catalysis unresolved
  10. 2015 High

    The crystal structure provided a definitive framework linking catalytic and interfacial-activation subdomains to disease mutations.

    Evidence X-ray crystallography at 2.65 Å with deglycosylation and Fab-complex crystallization

    PMID:26195816

    Open questions at the time
    • Structure lacks bound lipoprotein substrate
    • Lid conformational change during activation not captured
  11. 2016 High

    Defining LpX as the nephrotoxic species and its uptake route explained the renal pathology of LCAT deficiency at the cellular level.

    Evidence Synthetic LpX administration to WT and Lcat−/− mice, EM of kidney, IL-6 cytokine assays in glomerular cells

    PMID:15466392 PMID:26919698

    Open questions at the time
    • Receptor/macropinocytosis trigger on glomerular cells not molecularly identified
    • Link between IL-6 and proteinuria not fully causal
  12. 2018 Medium

    Enzyme-replacement experiments established that restoring esterification activity is sufficient to prevent LpX-driven renal injury.

    Evidence Intravenous rhLCAT in SREBP1a Tg × Lcat−/− mice with EM and albumin/creatinine readouts

    PMID:24140107 PMID:30563940

    Open questions at the time
    • Single lab in vivo rescue
    • Durability and dosing in human disease not established
  13. 2024 Medium

    Connecting estrogen/ESR1 regulation of LCAT to SREBP2-dependent cholesterol synthesis revealed a transcriptional and tumor-suppressive axis beyond lipoprotein metabolism.

    Evidence LCAT overexpression/knockdown in HCC cells, xenograft/orthotopic models, ovariectomized LCAT-KO mice, SREBF2 rescue

    PMID:38718297

    Open questions at the time
    • Direct ESR1 binding at the LCAT locus not demonstrated
    • Generality across cancer contexts unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How LCAT physically docks onto its lipoprotein substrate during interfacial activation, and the structural transitions of the lid coupled to apoA-I registry, remain unresolved.
  • No co-structure of LCAT with HDL or apoA-I
  • Conformational coupling between lid opening and catalysis not visualized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 4 GO:0016787 hydrolase activity 3
Localization
GO:0005576 extracellular region 3
Pathway
R-HSA-1430728 Metabolism 4 R-HSA-382551 Transport of small molecules 3
Partners
A2MAPOA1APOA4APOELRP1STAT3
Complex memberships
HDLLCAT–alpha2-macroglobulin complex

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 LCAT belongs to the α/β hydrolase fold family and contains a catalytic triad composed of Ser (active site), Asp345, and His377, with Phe103 and Leu182 forming the oxyanion hole. A potential 'lid' domain at residues 50–74 is proposed to be involved in enzyme–substrate interaction. These residues were identified by site-directed mutagenesis combined with expression in Cos-1 cells and enzymatic activity assays. Threading-based structural homology modeling, site-directed mutagenesis, expression in Cos-1 cells, ELISA for LCAT mass, enzymatic activity assays on rHDL, LDL, and monomeric substrate Protein science High 9541390
2015 The 2.65 Å crystal structure of human LCAT reveals an α/β hydrolase core with two additional subdomains: subdomain 1 contains the region required for interfacial activation, and subdomain 2 contains the lid and amino acids shaping the substrate-binding pocket. Mapping naturally occurring disease mutations onto the structure provides mechanistic insight into how they impair enzymatic activity. X-ray crystallography at 2.65 Å resolution; crystallization required enzymatic removal of N-linked glycans and complex formation with a Fab fragment Journal of lipid research High 26195816
1997 Targeted disruption of the mouse LCAT gene demonstrated that LCAT is essential for normal plasma cholesterol esterification, HDL cholesterol levels, and apoA-I levels. LCAT-null mice had >99% reduction in LCAT activity, markedly reduced HDL cholesterol (7% of normal) and apoA-I (12% of normal), elevated triglycerides in males, and accumulation of heterogeneous prebeta-migrating HDL particles. LCAT absence also attenuated the rise in apoB-containing lipoproteins in response to a high-fat/high-cholesterol diet. Gene knockout in mouse embryonic stem cells; plasma lipid/lipoprotein analysis by FPLC and two-dimensional gel electrophoresis; dietary challenge The Journal of biological chemistry High 9054454
2018 ApoA-I on nascent discoidal HDL can adopt at least two helical registries (5/5 and 5/2). HDL particles locked in the 5/2 registry by engineered disulfide bonds significantly impaired LCAT cholesteryl esterification activity despite equal LCAT binding, whereas the 5/5 registry supported full activity. Chemical cross-linking data suggest full LCAT activation requires a hybrid epitope composed of helices 5–7 on one apoA-I molecule and helices 3–4 on the other, consistent with a thumbwheel-like activation mechanism. Engineered disulfide bond formation at predicted registry positions, cholesterol efflux assays in macrophages, LCAT esterification activity assays, chemical cross-linking Journal of lipid research High 29773713
2001 LCAT directly binds α2-macroglobulin (α2M) in human plasma to form a complex (~18.5 nm diameter); ~40% of plasma LCAT-HDL is associated with α2M. LCAT associated with α2M is enzymatically inactive. The LCAT–α2M complex (but not free LCAT) binds to, is internalized by, and is degraded in LRP-expressing cells, identifying an α2M/LRP receptor-mediated pathway for LCAT clearance. Purification of plasma complex, radiolabeled rLCAT binding assays to native and methylamine-activated α2M in vitro, enzymatic activity assays, cell-based internalization/degradation assays in LRP(+/+) vs. LRP(-/-) cells The Journal of biological chemistry High 11435418
2005 ApoE is the major physiological activator of LCAT on apoB-containing lipoproteins. In apoA-I(-/-)apoE(-/-) mouse plasma, cholesterol esterification rate (CER) was <7% of wild-type despite retaining 1/3 of LCAT enzyme activity, demonstrating that substrate/cofactor deficiency rather than enzyme amount explained low CER. Reconstitution experiments showed that LDL particles lacking apoE were very poor LCAT substrates, and adding apoE to apoA-I(-/-)apoE(-/-) VLDL gave a 3-fold increase in CER, whereas adding apoA-I gave only an 80% increase. Genetic mouse models (apoA-I KO, apoE KO, combined KO), in vitro LCAT assays with isolated LDL/VLDL particles from each genotype, apolipoprotein reconstitution experiments, Western blot Biochemistry High 15654758
2000 Fish-eye disease (FED)-associated LCAT natural mutants T123I and N391S have decreased phospholipase A2 activity on rHDL, which accounts for their decreased acyltransferase activity specifically toward HDL. Engineered mutation F382A (designed from 3D model) phenocopied the T123I FED mutant. Residues T123 and F382 (N-terminal of helices α3-4 and αHis) contribute specifically to LCAT–HDL interaction, while residues N131 and N391 are critical for optimal orientation of amphipathic helices for lipoprotein substrate recognition. Site-directed mutagenesis of LCAT, overexpression in Cos-1 cells, esterase activity on monomeric substrate, phospholipase A2 activity on rHDL, acyltransferase activity on rHDL and LDL Journal of lipid research High 10787436
2005 Negatively charged residues in helix 6 of apoA-I attenuate LCAT activation. A strong inverse correlation (r = 0.85) was found between LCAT catalytic efficiency and apoA-I helix 6 net negative charge across engineered apoA-I mutants reconstituted into HDL particles of two different sizes, supporting direct protein–protein interaction between helix 6 and LCAT. Site-directed mutagenesis of apoA-I helix 6 charged residues, reconstituted HDL preparation of two sizes, in vitro LCAT kinetic assays (Km, Vmax, catalytic efficiency) Biochemistry High 15807534
1995 Nascent apoA-I-lipid discoidal complexes formed by apoA-I recruiting phospholipid and cholesterol from cell membranes serve as substrates for LCAT, which converts them into ~8.4 nm particles similar in size to plasma HDL3a LpA-I particles. In contrast, nascent apoA-II-lipid complexes could not serve as substrates for LCAT and did not undergo transformation, demonstrating apolipoprotein specificity of LCAT activation. Cell incubation with purified apoA-I or apoA-II to generate nascent HDL, incubation with purified LCAT, electron microscopy, non-denaturing PAGE gel analysis of particle sizes Journal of lipid research High 7706940
2007 ABCA1 is essential for apoE-containing HDL biogenesis (ABCA1-/- mice failed to form apoE-HDL particles after apoE4 adenovirus transfer). LCAT is required for the conversion of discoidal apoE-containing HDL into spherical HDL particles: co-infection with apoE4 and human LCAT adenoviruses converted discoidal HDL into spherical HDL and cleared triglyceride-rich lipoproteins in apoA-I-/- mice. Adenovirus-mediated gene transfer in apoA-I-/-, ABCA1-/-, and apoE-/- mice; electron microscopy of HDL particles; plasma lipid/lipoprotein analysis The Biochemical journal High 17206937
2012 Formation of spherical α-migrating apoA-IV-containing HDL particles requires both ABCA1 and LCAT. Gene transfer of apoA-IV in ABCA1-/- or LCAT-/- mice failed to generate spherical or α-migrating HDL particles, and co-expression of apoA-IV with LCAT in apoA-I-/- mice restored HDL-A-IV formation. Adenovirus-mediated gene transfer in ABCA1-/-, LCAT-/-, and apoA-I-/- mice; electron microscopy; lipid analysis Journal of lipid research High 23132909
2007 ApoA-I mutations Leu141Arg (Pisa) and Leu159Arg (FIN) diminish the capacity of apoA-I to activate LCAT in vitro and in vivo, causing accumulation of discoidal prebeta1-HDL. Co-treatment with human LCAT adenovirus normalized plasma apoA-I, HDL cholesterol, CE/TC ratio, and HDL subpopulations in apoA-I-/- mice expressing these mutants, demonstrating that impaired LCAT activation is the primary defect. In vitro LCAT activation assay, adenovirus-mediated gene transfer in apoA-I-/- mice, HDL subpopulation analysis, rescue with LCAT co-expression Biochemistry High 17711302
2007 ApoA-I mutations R151C (Paris), R160L (Oslo), and engineered R149A greatly reduce LCAT activation capacity in vitro and cause accumulation of discoidal HDL in vivo. Co-expression of LCAT with each mutant in apoA-I-/- mice normalized HDL cholesterol, apoA-I levels, CE/TC ratio, and converted discoidal to spherical HDL particles. In vitro LCAT activation assay, adenovirus gene transfer in apoA-I-/- mice, electron microscopy, 2D gel HDL subpopulation analysis, rescue with LCAT co-expression The Biochemical journal High 17506726
2016 Lipoprotein X (LpX), which accumulates when LCAT is absent, is nephrotoxic and causes all histological hallmarks of familial LCAT deficiency renal disease. An apoA-I- and LCAT-dependent pathway converts LpX to HDL-like particles and mediates normal plasma clearance. LpX is taken up by macropinocytosis into glomerular endothelial cells, podocytes, and mesangial cells, delivered to lysosomes for degradation, induces podocyte secretion of pro-inflammatory IL-6, and causes proteinuria when chronically administered to Lcat-/- mice. Synthetic LpX administration to wild-type and Lcat-/- mice, in vitro LpX-to-HDL conversion assay, EM (TEM/SEM) of kidney, proteinuria measurements, in vitro cytokine assays in podocytes and mesangial cells PloS one High 26919698
2004 Accumulation of LpX particles (vesicular lipoprotein X) in plasma in the absence of LCAT is strongly associated with spontaneous glomerulopathy. A novel mouse model (SREBP1a transgenic × LCAT-/- ) that selectively accumulates LpX developed glomerular lipid deposits, mesangial expansion, foam cell infiltrates, hyalinosis, and tubulointerstitial lipid deposits by 6–10 months, histologically similar to human LCAT deficiency nephropathy. SREBP1a Tg × lcat-/- mouse model, FPLC plasma lipoprotein fractionation, electron microscopy of LpX, renal histology, immunohistochemistry (RhoA) The American journal of pathology Medium 15466392
2018 Recombinant human LCAT (rhLCAT) enzyme replacement reduces LpX in plasma and kidneys and markedly decreases proteinuria in LCAT-deficient mice expressing abundant LpX, demonstrating that restoring LCAT esterification activity is sufficient to prevent LpX accumulation and renal injury. Intravenous rhLCAT injection in PRCL diet-fed SREBP1a Tg × Lcat-/- mice; plasma lipoprotein profiling; transmission EM; urine albumin/creatinine ratio measurement The Journal of pharmacology and experimental therapeutics Medium 30563940
2003 LCAT-dependent conversion of prebeta1-HDL to alpha-migrating HDL is the primary mechanism by which prebeta1-HDL is catabolized in plasma, as demonstrated by: (1) time-course incubation at 37°C showing LCAT-inhibitor-sensitive decrease in prebeta1-HDL, and (2) a positive correlation between LCAT activity and the rate of prebeta1-HDL decrease (r = 0.617, P<0.001) in hemodialysis patients vs. controls. Ex vivo plasma incubation at 37°C with and without LCAT inhibitor, prebeta1-HDL quantification by immunoassay, correlation analysis Journal of the American Society of Nephrology Medium 12595510
2002 LCAT is the only source of plasma long-chain polyunsaturated cholesteryl esters (20:4, 20:5n-3, 22:6n-3) in mouse plasma, demonstrating that LCAT generates a distinct subset of plasma cholesteryl ester species. Removal of functional LCAT from LDLr-/- mice caused a 7-fold increase in the saturated/polyunsaturated CE ratio in LDL due to complete absence of long-chain polyunsaturated CE. LCAT-/- × LDLr-/- and LCAT-/- × apoE-/- double-knockout mice; plasma cholesteryl ester fatty acid composition analysis Journal of lipid research Medium 11893779
2007 Decreased LCAT reactivity (not decreased LCAT protein or mRNA) with sphingomyelin-enriched HDL particles accounts for the functional LCAT deficiency observed in hA-ITg SR-BI-/- mice. HDL from these mice was enriched in sphingomyelin relative to phosphatidylcholine and had less associated LCAT radiolabel and endogenous LCAT activity, whereas LCAT protein, hepatic mRNA, and in vivo turnover were similar to controls. Radiolabeled LCAT turnover studies (35S), LCAT mass measurement, hepatic mRNA quantification, HDL lipid composition analysis, in vitro LCAT activity assays on isolated HDL fractions Journal of lipid research Medium 17272829
2021 LCAT is secreted predominantly in medium and small HDL (alpha2, alpha3, prebeta) fractions, and unlike PLTP and CETP, shows markedly delayed appearance on HDL after secretion, indicating that LCAT resides for a time outside systemic circulation before associating with HDL in plasma. Compartmental modeling of in vivo deuterium-labeled tracer data revealed these distinct metabolic properties. In vivo isotope tracer study with Orbitrap Fusion Lumos MS, compartmental modeling of protein kinetics on multiple HDL sizes from 6 participants JCI insight Medium 33351780
2002 IL-6 induces LCAT transcription via a minimal response element at −1514 to −1508 bp in the distal LCAT promoter with high homology to a STAT3 binding site. Overexpression of STAT3 significantly enhanced IL-6-induced LCAT promoter activity. Sequential deletion constructs mapped this element as sufficient for IL-6 responsiveness in transfected HepG2 cells. LCAT promoter-reporter deletion constructs, transfection in HepG2 cells, IL-6 treatment, STAT3 overexpression Journal of lipid research Medium 12032172
2015 Increased LCAT cholesterol esterification activity in Scarb1-/- × LCAT-transgenic mice reduced plasma free cholesterol/total cholesterol ratio to normal, decreased VLDL-cholesterol levels, and produced a 51% reduction in aortic sinus atherosclerosis compared to Scarb1-/- mice, demonstrating an antiatherogenic role for LCAT-mediated cholesterol esterification independent of SR-BI. Genetic mouse models (Scarb1-/- × LCAT-null and Scarb1-/- × LCAT-Tg), high-fat diet challenge, aortic sinus lesion quantification, plasma lipoprotein profiling, in vitro cholesterol efflux assay Journal of lipid research Medium 25964513
2010 A novel apoA-I mutation S36A, identified in a hypoalphalipoproteinemic patient, reduces apoA-I self-association (shifts from oligomeric to primarily monomeric form) and significantly impairs LCAT activation while preserving phospholipid vesicle solubilization and lipoprotein surface binding capacity, implicating the N-terminal region around S36 in apoA-I–LCAT interaction. Recombinant protein production, guanidine denaturation, native PAGE, chemical cross-linking, sedimentation equilibrium, phospholipid vesicle solubilization assay, in vitro LCAT activation assay Journal of lipid research Medium 20884842
2019 LCAT concentration and activity decrease significantly during STEMI (acute myocardial infarction), and this decrease correlates with impaired HDL-mediated endothelial NO production. In vitro addition of recombinant human LCAT to STEMI patient plasma restores HDL ability to promote endothelial NO production, associated with significant modification of HDL phospholipid classes. Prospective clinical measurement of LCAT mass and activity, in vitro rhLCAT supplementation of patient plasma, NO production assay in cultured endothelial cells, HDL phospholipid composition analysis Arteriosclerosis, thrombosis, and vascular biology Medium 30894011
1985 LCAT activity drives the in vitro conversion of HDL3 to lower-density HDL2a in whole plasma. Removal of VLDL/LDL by precipitation shifted the conversion toward higher-density particles, and adding back triglyceride-rich lipoproteins (TGRLP) at ratios ≥2.5:1 caused nearly complete conversion of HDL3 to HDL2b in an LCAT-dependent manner. In vitro incubation of whole plasma with and without active LCAT; selective lipoprotein precipitation; addition of TGRLP or Intralipid; analytical ultracentrifugation Journal of lipid research Medium 3989387
1995 In vitro glycation of HDL (the LCAT substrate) alters LCAT kinetics: moderate glycation increases both Km and Vmax but decreases overall enzyme reactivity (Vmax/Km); high glycation reduces both Km and Vmax markedly, further decreasing reactivity. The decrease is attributed to glycation of lysine residues in apoA-I rather than altered lipid or protein composition of HDL. In vitro HDL glycation with glucose/sodium cyanoborohydride, TNBS assay for glycation extent, kinetic analysis (Km, Vmax) of purified LCAT on glycated vs. native HDL Clinica chimica acta Low 7758222
2020 DS-8190a, a small-molecule LCAT activator, directly binds human LCAT protein (confirmed by affinity purification with immobilized DS-8190a beads and thermal shift assay) and activates human and cynomolgus monkey but not mouse LCAT in vitro. In vivo oral dosing in cynomolgus monkeys increased LCAT activity ~2-fold. In Ldlr-KO × hLcat-Tg mice, DS-8190a reduced atherosclerotic lesion area by 48% and enhanced reverse cholesterol transport. In vitro LCAT activation assay, affinity purification with compound-immobilized beads, thermal shift assay, photoaffinity labeling for binding site, oral dosing in cynomolgus monkeys, atherosclerosis lesion quantification, [3H]-cholesterol reverse cholesterol transport assay Arteriosclerosis, thrombosis, and vascular biology High 33086872
2013 Recombinant human LCAT (rhLCAT) corrects lipoprotein abnormalities in LCAT-deficient human plasma in vitro: reduces unesterified cholesterol by 30%, increases plasma cholesteryl esters by 210%, increases HDL-C by 89%, matures small prebeta-HDL into alpha-migrating particles, and converts abnormal phospholipid-rich LDL-region particles to normally sized LDL. In vitro incubation of LCAT-deficient plasma with rhLCAT; lipoprotein profiling; HDL subpopulation analysis Biologicals Medium 24140107
2024 Estrogen upregulates LCAT expression in liver in an ESR1-dependent manner. LCAT facilitates HDL-C production and uptake via LDLR and SCARB1 pathways. Enhanced HDL-C absorption induced by LCAT impairs SREBP2 maturation, suppressing cholesterol biosynthesis and dampening HCC cell proliferation. SREBF2 overexpression abolished LCAT's inhibitory activity on HCC cells. Transcriptomic analysis of mouse and human liver cancer, in vitro LCAT overexpression/knockdown in HCC cells, in vivo xenograft and orthotopic mouse models, LCAT-KO female mice with ovariectomy, HDL-C treatment, SREBP2 Western blot Cancer research Medium 38718297
2015 LCAT deficiency reduces the LPS-neutralizing capacity of HDL and enhances LPS-induced inflammation in mice. Lcat-/- HDL lacks significant amounts of apoA-I and apoA-II and is primarily composed of apoE. Reintroducing LCAT expression via adenovirus-mediated gene transfer reverted the enhanced inflammatory phenotype to wild-type. Lcat-/- mice also show increased circulating Cd11b+Ly6Cmed monocyte numbers. LPS challenge in Lcat-/- mice, ex vivo whole blood LPS stimulation, in vitro RAW264.7 macrophage TNFα assay with Lcat-/- serum/HDL/lipoprotein fractions, adenoviral LCAT rescue, flow cytometric immunophenotyping Biochimica et biophysica acta Medium 26170061
2012 HDL-cholesteryl ester deficiency in LCAT KO mice (complete absence of HDL-CE due to LCAT absence) results in a 40–50% lower glucocorticoid response to ACTH stimulation, endotoxemia, or fasting, despite normal basal corticosterone. Adrenal cells show compensatory upregulation of HMG-CoA reductase (516%) and LDL receptor (385%), indicating that HDL-derived CE is a major cholesterol source for adrenal steroidogenesis. LCAT KO mouse model, ACTH stimulation, endotoxemia, and fasting protocols; corticosterone measurement; quantitative gene expression of cholesterol metabolism genes; neutral lipid staining of adrenal tissue Journal of lipid research Medium 23178225
2013 An inhibitory anti-LCAT antibody in a patient's serum caused acquired LCAT deficiency with nephrotic syndrome histologically identical to familial LCAT deficiency. A mixing test and co-immunoprecipitation confirmed the presence of the antibody and its inhibitory effect. LCAT was detected by immunohistochemistry along glomerular capillary walls, indicating LCAT as a glomerular antigen. Steroid treatment restored LCAT activity and resolved the renal and lipid phenotype. Mixing test for LCAT inhibitory antibody, co-immunoprecipitation, renal biopsy histology/EM, LCAT immunohistochemistry/immunofluorescence, treatment with steroids Journal of the American Society of Nephrology Low 23620397
1993 Mutations dispersed throughout the LCAT gene (rather than clustered at the presumed active site) cause loss of enzymatic activity, suggesting multiple structurally important domains. In homozygous deficiency patients with missense mutations, residual LCAT mass was detectable but functionally inactive; null mutations (nonsense, frameshift) eliminated both mass and activity. DNA sequencing of all LCAT exons, mutagenic primer-based restriction analysis, LCAT activity and mass measurement in patients and family heterozygotes The Journal of clinical investigation Low 8432868
2020 ApoA-I in mouse cerebrospinal fluid originates from liver and intestine via plasma spherical HDL, which is regulated by ABCA1 and LCAT. Knockout of apoA-I in both intestine and liver virtually eliminated CSF apoA-I, and CSF apoA-I levels correlated with plasma spherical HDL levels regulated by ABCA1 and LCAT. Tissue-specific Apoa1 knockout mice (intestine-specific, liver-specific, double-KO); immunoassay for apoA-I in plasma and CSF; plasma HDL profiling FEBS letters Low 33020907

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Role of apoA-I, ABCA1, LCAT, and SR-BI in the biogenesis of HDL. Journal of molecular medicine (Berlin, Germany) 297 16501936
1997 The molecular pathology of lecithin:cholesterol acyltransferase (LCAT) deficiency syndromes. Journal of lipid research 260 9162740
2003 Increased low-density lipoprotein oxidation and impaired high-density lipoprotein antioxidant defense are associated with increased macrophage homing and atherosclerosis in dyslipidemic obese mice: LCAT gene transfer decreases atherosclerosis. Circulation 146 12668499
2005 Compromised LCAT function is associated with increased atherosclerosis. Circulation 135 16061733
1981 Lecithin:cholesterol acyltransferase (LCAT) mass; its relationship to LCAT activity and cholesterol esterification rate. Journal of lipid research 105 7320631
1997 Targeted disruption of the mouse lecithin:cholesterol acyltransferase (LCAT) gene. Generation of a new animal model for human LCAT deficiency. The Journal of biological chemistry 101 9054454
1995 Recruitment of cell phospholipids and cholesterol by apolipoproteins A-II and A-I: formation of nascent apolipoprotein-specific HDL that differ in size, phospholipid composition, and reactivity with LCAT. Journal of lipid research 95 7706940
1998 A proposed architecture for lecithin cholesterol acyl transferase (LCAT): identification of the catalytic triad and molecular modeling. Protein science : a publication of the Protein Society 86 9541390
2007 Pathway of biogenesis of apolipoprotein E-containing HDL in vivo with the participation of ABCA1 and LCAT. The Biochemical journal 84 17206937
1996 Increased prebeta-HDL levels, cholesterol efflux, and LCAT-mediated esterification in mice expressing the human cholesteryl ester transfer protein (CETP) and human apolipoprotein A-I (apoA-I) transgenes. Journal of lipid research 83 8808761
1993 Genetic and phenotypic heterogeneity in familial lecithin: cholesterol acyltransferase (LCAT) deficiency. Six newly identified defective alleles further contribute to the structural heterogeneity in this disease. The Journal of clinical investigation 79 8432868
2002 Altered activities of anti-atherogenic enzymes LCAT, paraoxonase, and platelet-activating factor acetylhydrolase in atherosclerosis-susceptible mice. Journal of lipid research 76 11893784
1994 Modification of LCAT activity and HDL structure. New links between cigarette smoke and coronary heart disease risk. Arteriosclerosis and thrombosis : a journal of vascular biology 74 8305416
2018 A thumbwheel mechanism for APOA1 activation of LCAT activity in HDL. Journal of lipid research 69 29773713
2003 LCAT-dependent conversion of prebeta1-HDL into alpha-migrating HDL is severely delayed in hemodialysis patients. Journal of the American Society of Nephrology : JASN 67 12595510
1997 Molecular phylogeny of rodents, with special emphasis on murids: evidence from nuclear gene LCAT. Molecular phylogenetics and evolution 65 9417899
2016 Lipoprotein X Causes Renal Disease in LCAT Deficiency. PloS one 64 26919698
2008 Functional LCAT is not required for macrophage cholesterol efflux to human serum. Atherosclerosis 64 18922527
1982 Population-based reference values for lecithin-cholesterol acyltransferase (LCAT). Atherosclerosis 58 7115467
1975 Genetics of LCAT (lecithin: cholesterol acyltransferase) deficiency. Annals of human genetics 55 806250
2015 Role of LCAT in Atherosclerosis. Journal of atherosclerosis and thrombosis 54 26607351
1996 Two novel molecular defects in the LCAT gene are associated with fish eye disease. Arteriosclerosis, thrombosis, and vascular biology 50 8620346
2003 Hepatic lipase expression in macrophages contributes to atherosclerosis in apoE-deficient and LCAT-transgenic mice. The Journal of clinical investigation 48 12897204
2012 Very low levels of HDL cholesterol and atherosclerosis, a variable relationship--a review of LCAT deficiency. Vascular health and risk management 47 22701329
2024 Estrogen Induces LCAT to Maintain Cholesterol Homeostasis and Suppress Hepatocellular Carcinoma Development. Cancer research 46 38718297
1998 Decreased postprandial high density lipoprotein cholesterol and apolipoproteins A-I and E in normolipidemic smoking men: relations with lipid transfer proteins and LCAT activities. Journal of lipid research 45 9684753
1996 Potential gene therapy for lecithin-cholesterol acyltransferase (LCAT)-deficient and hypoalphalipoproteinemic patients with adenovirus-mediated transfer of human LCAT gene. Circulation 45 8901669
1993 Two different allelic mutations in the lecithin:cholesterol acyltransferase (LCAT) gene resulting in classic LCAT deficiency: LCAT (tyr83-->stop) and LCAT (tyr156-->asn). Journal of lipid research 45 8445342
2020 Genetic, biochemical, and clinical features of LCAT deficiency: update for 2020. Current opinion in lipidology 44 32618730
2000 LCAT modulates atherogenic plasma lipoproteins and the extent of atherosclerosis only in the presence of normal LDL receptors in transgenic rabbits. Arteriosclerosis, thrombosis, and vascular biology 41 10669643
1988 Familial LCAT deficiency and fish-eye disease. Journal of inherited metabolic disease 41 3141686
1985 The in vitro formation of HDL2 during the action of LCAT: the role of triglyceride-rich lipoproteins. Journal of lipid research 41 3989387
2003 Effects of intravenous apolipoprotein A-I/phosphatidylcholine discs on LCAT, PLTP, and CETP in plasma and peripheral lymph in humans. Arteriosclerosis, thrombosis, and vascular biology 40 12893687
1980 Effects of dietary protein and fat sources on plasma cholesterol parameters, LCAT activity and amino acid levels and on tissue lipid content of growing pigs. The Journal of nutrition 39 7441375
2005 Apolipoprotein E is the major physiological activator of lecithin-cholesterol acyltransferase (LCAT) on apolipoprotein B lipoproteins. Biochemistry 38 15654758
2022 LCAT- targeted therapies: Progress, failures and future. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 37 35121343
2015 The high-resolution crystal structure of human LCAT. Journal of lipid research 37 26195816
2000 The bushlike radiation of muroid rodents is exemplified by the molecular phylogeny of the LCAT nuclear gene. Molecular phylogenetics and evolution 37 11083941
2015 Increased plasma cholesterol esterification by LCAT reduces diet-induced atherosclerosis in SR-BI knockout mice. Journal of lipid research 36 25964513
2020 Apigenin, flavonoid component isolated from Gentiana veitchiorum flower suppresses the oxidative stress through LDLR-LCAT signaling pathway. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 35 32504920
2019 Recombinant LCAT (Lecithin:Cholesterol Acyltransferase) Rescues Defective HDL (High-Density Lipoprotein)-Mediated Endothelial Protection in Acute Coronary Syndrome. Arteriosclerosis, thrombosis, and vascular biology 35 30894011
2012 ApoA-IV promotes the biogenesis of apoA-IV-containing HDL particles with the participation of ABCA1 and LCAT. Journal of lipid research 35 23132909
2015 Lack of LCAT reduces the LPS-neutralizing capacity of HDL and enhances LPS-induced inflammation in mice. Biochimica et biophysica acta 34 26170061
2005 Apolipoprotein A-I helix 6 negatively charged residues attenuate lecithin-cholesterol acyltransferase (LCAT) reactivity. Biochemistry 33 15807534
2004 A novel in vivo lecithin-cholesterol acyltransferase (LCAT)-deficient mouse expressing predominantly LpX is associated with spontaneous glomerulopathy. The American journal of pathology 33 15466392
2002 Transgenic overexpression of human lecithin: cholesterol acyltransferase (LCAT) in mice does not increase aortic cholesterol deposition. Atherosclerosis 33 12208474
2001 Interaction of lecithin:cholesterol acyltransferase (LCAT).alpha 2-macroglobulin complex with low density lipoprotein receptor-related protein (LRP). Evidence for an alpha 2-macroglobulin/LRP receptor-mediated system participating in LCAT clearance. The Journal of biological chemistry 33 11435418
2002 In vivo contribution of LCAT to apolipoprotein B lipoprotein cholesteryl esters in LDL receptor and apolipoprotein E knockout mice. Journal of lipid research 32 11893779
1998 Molecular genetic study of Finns with hypoalphalipoproteinemia and hyperalphalipoproteinemia: a novel Gly230 Arg mutation (LCAT[Fin]) of lecithin:cholesterol acyltransferase (LCAT) accounts for 5% of cases with very low serum HDL cholesterol levels. Arteriosclerosis, thrombosis, and vascular biology 32 9555865
1995 Reactivity of lecithin-cholesterol acyl transferase (LCAT) towards glycated high-density lipoproteins (HDL). Clinica chimica acta; international journal of clinical chemistry 32 7758222
1978 Lecithin-cholesterol acyltransferase (LCAT) activity in chronic uremia. Kidney international. Supplement 32 278893
2018 Loss of LCAT activity in the golden Syrian hamster elicits pro-atherogenic dyslipidemia and enhanced atherosclerosis. Metabolism: clinical and experimental 31 29526535
2015 A novel protein glycan biomarker and LCAT activity in metabolic syndrome. European journal of clinical investigation 31 26081900
2014 Increased risk of premature coronary artery disease in Egyptians with ABCA1 (R219K), CETP (TaqIB), and LCAT (4886C/T) genes polymorphism. Journal of clinical lipidology 31 25110219
2004 HMG-CoA reductase inhibition reverses LCAT and LDL receptor deficiencies and improves HDL in rats with chronic renal failure. American journal of physiology. Renal physiology 31 15507547
1985 Effects of antihypertensive agents propranolol, metoprolol, nadolol, prazosin, and chlorthalidone on ACAT activity in rabbit and rat aortas and on LCAT activity in human plasma in vitro. Journal of cardiovascular pharmacology 31 2410671
2013 Nephrotic syndrome caused by immune-mediated acquired LCAT deficiency. Journal of the American Society of Nephrology : JASN 29 23620397
2004 ACAT inhibition reverses LCAT deficiency and improves plasma HDL in chronic renal failure. American journal of physiology. Renal physiology 29 15280162
1987 The isolation and characterisation of a cDNA clone for human lecithin:cholesterol acyl transferase and its use to analyse the genes in patients with LCAT deficiency and fish eye disease. Biochemical and biophysical research communications 29 2823801
2019 LCAT, ApoD, and ApoA1 Expression and Review of Cholesterol Deposition in the Cornea. Biomolecules 28 31779197
1991 Molecular defect in familial lecithin:cholesterol acyltransferase (LCAT) deficiency: a single nucleotide insertion in LCAT gene causes a complete deficient type of the disease. Biochemical and biophysical research communications 28 1662503
1991 Lecithin-cholesterol acyltransferase (LCAT) deficiency with a missense mutation in exon 6 of the LCAT gene. Biochemical and biophysical research communications 28 1859405
2009 An apoA-I mimetic peptide increases LCAT activity in mice through increasing HDL concentration. International journal of biological sciences 27 19680471
2007 LCAT can rescue the abnormal phenotype produced by the natural ApoA-I mutations (Leu141Arg)Pisa and (Leu159Arg)FIN. Biochemistry 27 17711302
2000 Relationship between structure and biochemical phenotype of lecithin:cholesterol acyltransferase (LCAT) mutants causing fish-eye disease. Journal of lipid research 27 10787436
1997 Adenovirus-mediated expression of hepatic lipase in LCAT transgenic mice. Journal of lipid research 27 9323591
1987 The structural gene for lecithin:cholesterol acyl transferase (LCAT) maps to 16q22. Annals of human genetics 27 3674753
2012 Patients with low HDL-cholesterol caused by mutations in LCAT have increased arterial stiffness. Atherosclerosis 26 23078883
2007 Naturally occurring and bioengineered apoA-I mutations that inhibit the conversion of discoidal to spherical HDL: the abnormal HDL phenotypes can be corrected by treatment with LCAT. The Biochemical journal 26 17506726
1997 Reduced lecithin: cholesterol acyltransferase (LCAT) and Na+, K+, ATPase activity in diabetic patients. Clinical biochemistry 25 9127701
1981 Genetic control of lecithin-cholesterol acyltransferase (LCAT): measurement of LCAT mass in a large kindred with LCAT deficiency. American journal of human genetics 25 7294021
2003 HMG-CoA reductase, cholesterol 7alpha-hydroxylase, LCAT, ACAT, LDL receptor, and SRB-1 in hereditary analbuminemia. Kidney international 24 12787409
1982 Lecithin: cholesterol acyl transferase (LCAT). Clinical biochemistry 24 6762928
2021 LCAT deficiency: a systematic review with the clinical and genetic description of Mexican kindred. Lipids in health and disease 23 34256778
2013 Recombinant human LCAT normalizes plasma lipoprotein profile in LCAT deficiency. Biologicals : journal of the International Association of Biological Standardization 23 24140107
2020 Progression of chronic kidney disease in familial LCAT deficiency: a follow-up of the Italian cohort. Journal of lipid research 22 32998975
2010 Novel N-terminal mutation of human apolipoprotein A-I reduces self-association and impairs LCAT activation. Journal of lipid research 22 20884842
1975 Lipoproteins in lecithin-cholesterol-acyltransferase(LCAT)-deficiency. II. Further studies on the abnormal high-density-lipoproteins. Humangenetik 22 168146
2018 LCAT Enzyme Replacement Therapy Reduces LpX and Improves Kidney Function in a Mouse Model of Familial LCAT Deficiency. The Journal of pharmacology and experimental therapeutics 21 30563940
1992 A DNA polymorphism for LCAT is associated with altered LCAT activity and high density lipoprotein size distributions in baboons. Arteriosclerosis and thrombosis : a journal of vascular biology 21 1350465
2012 LCAT deficiency in mice is associated with a diminished adrenal glucocorticoid function. Journal of lipid research 20 23178225
2017 Depletion in LpA-I:A-II particles enhances HDL-mediated endothelial protection in familial LCAT deficiency. Journal of lipid research 19 28351888
2013 Amelioration of circulating lipoprotein profile and proteinuria in a patient with LCAT deficiency due to a novel mutation (Cys74Tyr) in the lid region of LCAT under a fat-restricted diet and ARB treatment. Atherosclerosis 19 23522979
2013 Characteristic kidney pathology, gene abnormality and treatments in LCAT deficiency. Clinical and experimental nephrology 19 24174160
2021 Metabolism of PLTP, CETP, and LCAT on multiple HDL sizes using the Orbitrap Fusion Lumos. JCI insight 18 33351780
2007 Functional LCAT deficiency in human apolipoprotein A-I transgenic, SR-BI knockout mice. Journal of lipid research 18 17272829
2020 Apolipoprotein A-I in mouse cerebrospinal fluid derives from the liver and intestine via plasma high-density lipoproteins assembled by ABCA1 and LCAT. FEBS letters 17 33020907
2020 Novel LCAT (Lecithin:Cholesterol Acyltransferase) Activator DS-8190a Prevents the Progression of Plaque Accumulation in Atherosclerosis Models. Arteriosclerosis, thrombosis, and vascular biology 17 33086872
1995 CETP and LCAT activities are unrelated to smoking and moderate alcohol consumption in healthy normolipidemic men. Japanese circulation journal 17 7474298
1995 Two novel point mutations in the lecithin:cholesterol acyltransferase (LCAT) gene resulting in LCAT deficiency: LCAT (G873 deletion) and LCAT (Gly344-->Ser). Journal of lipid research 17 8656071
2011 Homozygous lecithin:cholesterol acyltransferase (LCAT) deficiency due to a new loss of function mutation and review of the literature. Journal of clinical lipidology 16 22108153
1997 Familial lecithin:cholesterol acyltransferase deficiency: molecular analysis of a compound heterozygote: LCAT (Arg147 --> Trp) and LCAT (Tyr171 --> Stop). Atherosclerosis 16 9180249
1982 Plasma LCAT activities in renal allograft recipients. Clinica chimica acta; international journal of clinical chemistry 16 6754140
2021 Current Status of Familial LCAT Deficiency in Japan. Journal of atherosclerosis and thrombosis 15 33867422
2020 Common plasma protein marker LCAT in aggressive human breast cancer and canine mammary tumor. BMB reports 15 33298249
2002 Identification of an IL-6 response element in the human LCAT promoter. Journal of lipid research 15 12032172
2001 Alteration of plasma HDL cholesteryl ester composition with transgenic expression of a point mutation (E149A) of human LCAT. Journal of lipid research 15 11590219
2000 Physical and genetic mapping of the macular corneal dystrophy locus on chromosome 16q and exclusion of TAT and LCAT as candidate genes. Molecular vision 15 10869098
1997 Molecular basis of fish-eye disease in a patient from Spain. Characterization of a novel mutation in the LCAT gene and lipid analysis of the cornea. Arteriosclerosis, thrombosis, and vascular biology 15 9261271
1988 Familial lecithin: cholesterol acyltransferase (LCAT) deficiency. An updated review Spring 1988. Ophthalmic paediatrics and genetics 14 3068599

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