Affinage

ACAT1

Acetyl-CoA acetyltransferase, mitochondrial · UniProt P24752

Length
427 aa
Mass
45.2 kDa
Annotated
2026-04-28
100 papers in source corpus 27 papers cited in narrative 27 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ACAT1 (also called SOAT1) is an ER-resident integral membrane acyltransferase that esterifies cholesterol using acyl-CoA substrates, serving as the predominant cholesterol-esterifying enzyme in liver, adrenal gland, macrophages, and kidney, while also functioning as a mitochondrial acetyltransferase that modifies metabolic enzymes including PDHA1, PDP1, ME2, and METTL3 (PMID:9717734, PMID:24486017, PMID:39951294, PMID:36890220). Structurally, ACAT1 assembles as a dimer-of-dimers tetramer with nine transmembrane helices per protomer, enclosing a cytosolic tunnel for acyl-CoA entry and a transmembrane tunnel for cholesterol access that converge at a catalytic site defined by residues H460, S456, D400, and Y518 (PMID:32433614, PMID:32433613, PMID:18480028). ACAT1 activity is allosterically activated by cholesterol at a stereospecific site distinct from the substrate site, and upon cholesterol loading in macrophages the enzyme redistributes into ER-derived vesicles where it exhibits approximately three-fold higher specific activity, amplifying esterification capacity without changes in protein level (PMID:15992359, PMID:20460577). Beyond lipid metabolism, ACAT1 loss alters intracellular cholesterol distribution across organelles with broad physiological consequences including enhanced microglial Aβ clearance via TFEB-dependent autophagy, restraint of hematopoietic progenitor proliferation, suppression of CD8+ T cell effector function, NLRP3-dependent cutaneous xanthomatosis, and amelioration of neurodegeneration in Alzheimer's and Niemann-Pick type C disease models (PMID:25339759, PMID:20133765, PMID:35507892, PMID:23846496, PMID:37879607, PMID:30354239).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1996 High

    Identifying that a single-residue substitution (S265L) abolishes ACAT1 enzymatic activity, while complementation restores cholesteryl ester synthesis but not SREBP regulation, established that ACAT1 cholesterol esterification is genetically separable from sterol-sensing signaling pathways.

    Evidence Molecular characterization and cDNA complementation of SRD-4 hamster cells

    PMID:8662991

    Open questions at the time
    • Identity of the sterol-regulatory defect gene in SRD-4 cells remained unresolved
    • No structural explanation for why S265L inactivates the enzyme
  2. 1998 High

    Quantitative immunodepletion across human tissues established ACAT1 as the dominant cholesterol-esterifying enzyme in liver, adrenal gland, macrophages, and kidney, while revealing a minor role in intestine where ACAT2 predominates.

    Evidence Immunodepletion of ACAT1 from tissue homogenates with residual activity measurement

    PMID:9717734

    Open questions at the time
    • Mechanism of tissue-specific ACAT1 vs. ACAT2 expression not addressed
    • Post-translational regulation not examined
  3. 1998 Medium

    The adrenocortical lipid depletion (ald) phenotype in AKR mice was mapped to mutations in the Acat1 gene, providing a natural mammalian loss-of-function model and showing that a truncated ACAT1 protein can retain partial activity.

    Evidence Genetic mapping, complementation cross with Acat1-KO, immunoblotting, cDNA sequencing in AKR mice

    PMID:9422770

    Open questions at the time
    • The post-translational modifying factors proposed to explain the adrenal phenotype were not identified
    • Only one inbred strain examined
  4. 2000 High

    Immunoelectron microscopy resolved the subcellular site of ACAT1 action to rough ER tubules and showed that cholesterol loading induces redistribution into ER-derived vesicles, providing a cell-biological framework for foam cell cholesterol ester accumulation.

    Evidence Immunoelectron microscopy and immunofluorescence with GRP78 co-localization in human macrophages

    PMID:10623671

    Open questions at the time
    • Mechanism of ER vesiculation was unknown
    • Whether vesicle-associated ACAT1 has altered enzymatic properties was not tested
  5. 2001 Medium

    ACAT1-deficient macrophages revealed that cholesterol esterification by ACAT1 routes cholesterol away from efflux pathways, as knockout cells accumulated free cholesterol and showed altered vesicular trafficking despite ABCA1 upregulation.

    Evidence Acat1−/− peritoneal macrophages with radiolabeled cholesterol efflux assay and electron microscopy

    PMID:15499044

    Open questions at the time
    • Mechanism by which ACAT1 influences vesicular cholesterol routing was not defined
    • Compensatory ABCA1 upregulation mechanism not elucidated
  6. 2005 High

    Demonstration that ACAT1 possesses a stereospecific allosteric activator site distinct from its substrate site explained how macrophage cholesterol loading amplifies esterification activity without increasing ACAT1 protein levels.

    Evidence In vitro enzyme assay with enantiomeric cholesterol and sterol analogs combined with intact-cell cholesterol loading

    PMID:15992359

    Open questions at the time
    • Structural location of allosteric site was unknown at this time
    • Identity of endogenous allosteric activator(s) in vivo not confirmed
  7. 2008 High

    Systematic mutagenesis defined the ACAT1 catalytic triad (S456, H460, D400) and the essential residue Y518, establishing a serine-based catalytic mechanism for acyl transfer.

    Evidence Site-directed mutagenesis with in vitro enzyme activity assays

    PMID:18480028

    Open questions at the time
    • No crystal or cryo-EM structure was available to place these residues architecturally
    • Role of the FYXDWWN motif beyond Y518 was not mechanistically dissected
  8. 2009 Medium

    Inflammatory signals — TNF-α via NF-κB and leptin via JAK2/PI3K — were shown to transcriptionally upregulate ACAT1 in monocytes/macrophages, linking inflammatory milieu to foam cell formation and cholesterol ester accumulation.

    Evidence Promoter-reporter assays with NF-κB site mapping; JAK2/PI3K inhibitor experiments in human monocyte-derived macrophages

    PMID:19189937 PMID:19625677

    Open questions at the time
    • In vivo relevance of inflammatory ACAT1 upregulation not demonstrated genetically
    • Epigenetic regulation of the ACAT1 promoter not explored
  9. 2010 High

    Two parallel advances showed that (1) vesicle-associated ACAT1 has ~3-fold higher specific activity than ER-resident ACAT1, explaining amplified esterification in cholesterol-loaded macrophages, and (2) ACAT1 deletion in AD model mice reduces APP and amyloid burden while altering brain cholesterol homeostasis via 24-hydroxycholesterol.

    Evidence Subcellular fractionation with reconstituted enzyme assay in macrophages; Acat1 KO crossed with 3XTg-AD mice with sterol synthesis and APP measurements

    PMID:20133765 PMID:20460577

    Open questions at the time
    • Mechanism by which vesicle environment enhances ACAT1 activity was not established
    • Downstream link between 24-hydroxycholesterol and APP reduction was correlative
  10. 2013 Medium

    Global Acat1 knockout revealed a role in restraining hematopoietic stem/progenitor cell proliferation, expanding the known functions of ACAT1 beyond cholesterol esterification into immune cell homeostasis.

    Evidence Acat1 KO mice with flow cytometric analysis of bone marrow LSK populations

    PMID:23846496

    Open questions at the time
    • Whether the proliferation phenotype is cell-autonomous or due to altered bone marrow niche cholesterol was not resolved
    • Downstream signaling mechanism not identified
  11. 2014 High

    Discovery that mitochondrial ACAT1 functions as a protein acetyltransferase — acetylating PDHA1 (K321) and PDP1 (K202) to suppress the pyruvate dehydrogenase complex — established a second enzymatic activity for ACAT1 that promotes the Warburg effect in cancer.

    Evidence Co-IP, mass spectrometry, in vitro acetyltransferase assay, mutagenesis, ACAT1 knockdown with tumor growth readout

    PMID:24486017

    Open questions at the time
    • Mechanism by which ACAT1 is targeted to mitochondria was not defined
    • Relationship between ER cholesterol esterification and mitochondrial acetyltransferase activities was unexplored
  12. 2014 High

    ACAT1 inhibition in microglia was shown to stimulate TFEB-mediated autophagy and lysosomal degradation of oligomeric Aβ, providing a mechanistic basis for the neuroprotective effects of ACAT1 loss in Alzheimer's models.

    Evidence Acat1 gene KO and pharmacological inhibitor K604 with autophagy and Aβ uptake/degradation assays in microglia

    PMID:25339759

    Open questions at the time
    • How cholesterol ester depletion triggers TFEB activation (mTOR-independent pathway) was not fully resolved
    • Long-term in vivo microglial-specific effects not tested
  13. 2018 High

    Genetic epistasis demonstrated that free cholesterol accumulation in ACAT1-deficient macrophages drives NLRP3 inflammasome activation, which is the primary cause of cutaneous xanthomatosis in hyperlipidemic settings, clarifying the deleterious consequences of macrophage ACAT1 loss under high-cholesterol conditions.

    Evidence Bone marrow transplantation with Acat1/Nlrp3 double KO in LDLR-null mice

    PMID:30354239

    Open questions at the time
    • Whether this inflammasome activation contributes to atherosclerotic plaque instability was not tested
    • Threshold of free cholesterol accumulation needed for NLRP3 triggering was not quantified
  14. 2019 High

    Myeloid-specific Acat1 knockout protected against diet-induced obesity by impairing monocyte integrin-β1-mediated infiltration into adipose tissue, extending ACAT1's functional scope to metabolic inflammation and adipose tissue homeostasis.

    Evidence Myeloid-specific Acat1 KO mice with adoptive transfer, flow cytometry, and pharmacological ACAT1 inhibition

    PMID:29533741

    Open questions at the time
    • How ACAT1 loss reduces integrin-β1 expression at the molecular level was not determined
    • Whether lipid composition of monocyte membranes mediates the integrin effect was not tested
  15. 2020 High

    Two independent cryo-EM structures of the ACAT1 tetramer revealed the architecture of the nine-transmembrane protomer with dual substrate tunnels converging at the catalytic histidine, providing a structural explanation for acyl-chain selectivity and enabling rational understanding of inhibitor binding.

    Evidence Two independent cryo-EM structures (with and without nevanimibe inhibitor) with structure-guided mutagenesis

    PMID:32433613 PMID:32433614

    Open questions at the time
    • No structure with bound cholesterol substrate was obtained
    • Mechanism of allosteric activation by cholesterol was not structurally resolved
    • Conformational dynamics during catalysis remain unknown
  16. 2022 High

    ACAT1 knockout in Niemann-Pick type C (Npc1 mutant) mice extended lifespan by 34% and corrected cholesterol misdistribution across late endosomes, TGN, and mitochondria, establishing ACAT1 as a critical node governing inter-organelle cholesterol routing in lysosomal storage disease.

    Evidence Genetic Acat1 KO crossed with Npc1 mutant mice; fibroblast cholesterol fractionation and organelle marker immunolocalization

    PMID:35507892

    Open questions at the time
    • Whether ACAT1 inhibitors can replicate the lifespan extension pharmacologically was not tested
    • Mechanism by which ACAT1 loss redirects cholesterol from late endosomes was not defined
  17. 2023 High

    Multiple 2023 studies expanded ACAT1's functional reach: oxysterol-activated ACAT1 depletes accessible plasma membrane cholesterol to mediate antimicrobial defense; ACAT1 blockade enriches cholesterol at the MAM and strengthens ER-mitochondria contacts; and ACAT1-mediated cholesterol esterification suppresses CD8+ T cell effector function via the SCD1-ACAT1 axis.

    Evidence ACAT-deficient cell lines with viral/bacterial infection assays; MAM proteomics with electron microscopy; SCD1/ACAT1 inhibitors with T cell functional assays and tumor models

    PMID:36695568 PMID:36982602 PMID:37879607

    Open questions at the time
    • Structural basis for oxysterol-specific allosteric ACAT1 activation is unknown
    • Whether MAM enrichment of ACAT1 has functional consequences for mitochondrial metabolism was not shown
    • In vivo confirmation of SCD1-ACAT1 T cell axis in human patients is lacking
  18. 2025 Medium

    ACAT1 was shown to acetylate ME2 at K156, potentiating malate-to-lactate conversion and driving lactylation of DNA repair proteins to promote chemoresistance, extending the mitochondrial acetyltransferase function beyond the pyruvate dehydrogenase complex.

    Evidence Co-IP, mass spectrometry, K156 mutagenesis, in vitro ME2 activity assay, in vivo ovarian cancer models

    PMID:39951294

    Open questions at the time
    • Independent replication in a second cancer type is needed
    • Whether SIRT3 opposes ME2-K156 acetylation as it does for PDHA1 was not tested
    • Structural basis for ACAT1 substrate recognition of diverse acetyltransferase targets is unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for cholesterol allosteric activation, the determinants of ACAT1 mitochondrial targeting versus ER retention, whether the ER cholesterol esterification and mitochondrial acetyltransferase activities are coordinated or independent, and how ACAT1 activity is precisely tuned in immune cells to balance protective cholesterol esterification against pathological free cholesterol accumulation.
  • No structure of ACAT1 with cholesterol bound at the allosteric site
  • Mitochondrial targeting signal or import mechanism not identified
  • Regulatory logic connecting the two enzymatic activities is unstudied

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 5 GO:0140096 catalytic activity, acting on a protein 3 GO:0008289 lipid binding 2
Localization
GO:0005783 endoplasmic reticulum 4 GO:0005739 mitochondrion 2 GO:0031410 cytoplasmic vesicle 2
Pathway
R-HSA-1430728 Metabolism 5 R-HSA-168256 Immune System 4 R-HSA-1643685 Disease 3 R-HSA-9612973 Autophagy 1
Partners
ME2METTL3NLRP3PDHA1PDP1SIRT3

Evidence

Reading pass · 27 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 Cryo-EM structure of human ACAT1 reveals it forms a dimer-of-dimers tetramer, with each protomer containing nine transmembrane segments enclosing a cytosolic tunnel and a transmembrane tunnel that converge at the catalytic site; structure-guided mutagenesis indicates acyl-CoA enters through the cytosolic tunnel while cholesterol enters through the transmembrane tunnel, rationalizing preference for unsaturated acyl chains. Cryo-EM structure determination + structure-guided mutagenesis Nature High 32433614
2020 Cryo-EM structure of human ACAT1 in complex with the inhibitor nevanimibe shows the holoenzyme as a tetramer of two homodimers, with each monomer containing nine transmembrane helices (TM4-TM9 forming the inhibitor-binding cavity); the cavity contains a catalytically essential histidine residue and accommodates an endogenous acyl-CoA, providing a structural basis for cholesterol esterification and inhibitor interaction. Cryo-EM structure determination + biochemical analysis Nature High 32433613
2008 Mutagenesis identified the putative catalytic triad of ACAT1 as S456, H460, and D400; mutation of any of these residues abolished enzymatic activity, and ACAT1 is sensitive to serine-modifying reagents, supporting a serine-based catalytic mechanism. Additionally, Y518 and the conserved FYXDWWN motif tyrosine are required for ACAT1 activity. Site-directed mutagenesis + in vitro enzyme activity assays Journal of lipid research High 18480028
2014 Mitochondrial ACAT1 functions as an acetyltransferase that acetylates PDHA1 at K321 (inhibiting it by recruiting PDK1) and PDP1 at K202 (inhibiting it by dissociating its substrate PDHA1), thereby suppressing the pyruvate dehydrogenase complex (PDC) and promoting the Warburg effect; SIRT3 acts as the corresponding deacetylase, and Y381 phosphorylation of PDP1 toggles recruitment between SIRT3 and ACAT1 at the PDC. Co-IP, mass spectrometry, in vitro acetyltransferase assay, site-directed mutagenesis, ACAT1 knockdown with tumor growth readout Molecular cell High 24486017
2005 ACAT1 has two distinct sterol-binding sites: a substrate-binding site and an allosteric activator site. Stereochemistry of the 3-hydroxyl group is critical for a sterol to serve as substrate but less critical for activation; enantiomeric cholesterol fails to activate ACAT1, demonstrating stereospecific interaction at the allosteric site independent of membrane biophysical effects. Cholesterol loading of macrophages increases ACAT1 activity without increasing ACAT1 protein, consistent with allosteric activation via increased ER cholesterol. In vitro ACAT enzyme assay with sterol analogs + intact cell cholesterol loading experiments The Biochemical journal High 15992359
1998 Immunodepletion with anti-ACAT1 antibodies demonstrated that ACAT1 protein is responsible for ~90% of cholesterol esterification activity in human liver, ~98% in adrenal gland, ~91% in macrophages, and ~80% in kidney, but only ~19% in intestine, establishing the tissue-specific catalytic role of ACAT1. Immunodepletion of ACAT1 protein from tissue homogenates followed by residual enzyme activity measurement Journal of lipid research High 9717734
2000 Immunoelectron microscopy and immunofluorescence of human macrophages showed ACAT1 localizes predominantly to tubular rough endoplasmic reticulum under normal conditions; upon cholesterol loading, ~30-40% of ACAT1 immunoreactivity redistributes into ER-derived small vesicles also enriched in GRP78, linking ER vesiculation to foam cell formation. Immunoelectron microscopy, immunofluorescence, subcellular fractionation with GRP78 co-localization The American journal of pathology High 10623671
2010 In cholesterol-loaded macrophages, ACAT1 redistributes from high-density ER membranes into lower-density ER-derived vesicles bearing both ER and trans-Golgi network markers; when normalized per equal ACAT1 protein mass, vesicle-associated ACAT1 shows ~3-fold higher enzymatic activity than ER membrane-associated ACAT1, revealing a mechanism by which macrophages increase cholesterol esterification capacity without upregulating ACAT1 protein. Subcellular fractionation, in vitro reconstituted ACAT enzyme assay, immunoblotting, cholesterol loading experiments Journal of lipid research High 20460577
2004 Human ACAT1 can be produced as a novel 56-kDa isoenzyme (in addition to the normal 50-kDa form) via interchromosomal trans-splicing of RNAs from chromosomes 1 and 7; the 56-kDa ACAT1 localizes to the ER and retains enzymatic activity, and uses GGC (glycine) as its translation initiation codon. Expression in CHO cells, mutagenesis, mass spectrometry, anti-peptide antibodies, immunolocalization The Journal of biological chemistry Medium 15319423
2014 ACAT1 inhibition (gene KO or K604 inhibitor) in microglia stimulates autophagosome formation and transcription factor EB (TFEB)-mediated lysosomal proteolysis, increasing phagocytic uptake and lysosomal degradation of oligomeric Aβ1-42; this autophagy induction is mTOR-independent and can be modulated by agents disrupting cholesterol biosynthesis. Acat1 gene KO in mouse, pharmacological ACAT1 inhibitor K604, autophagy assays, lysosomal proteolysis assays, in vitro and in vivo Aβ uptake/degradation experiments The Journal of neuroscience High 25339759
2010 ACAT1 gene ablation in triple-transgenic AD mice causes a 32% increase in 24-hydroxycholesterol content, a 65% decrease in HMG-CoA reductase protein, and a 28% decrease in sterol synthesis rate in the brain, and reduces full-length APP and its proteolytic fragments by >60%, ameliorating cognitive deficits; treating hippocampal neurons with 24-hydroxycholesterol recapitulates these reductions in APP and HMGR. Acat1 KO mouse cross with 3XTg-AD model, biochemical assays, sterol synthesis rate measurement, hippocampal neuron treatment experiments Proceedings of the National Academy of Sciences of the United States of America High 20133765
1996 A point mutation at codon 265 (Ser→Leu) of ACAT1 in SRD-4 hamster cells results in an inactive enzyme; complementation with wild-type ACAT1 cDNA restored cholesteryl ester synthesis but did not restore sterol-mediated SREBP cleavage inhibition, demonstrating that ACAT deficiency and the sterol-regulatory defect are caused by independent mutations and can be uncoupled. Mutagenesis characterization of SRD-4 cells, transfection with wild-type cDNA, enzyme activity and SREBP processing assays The Journal of biological chemistry High 8662991
2003 Acyl-CoA binding protein (ACBP) regulates microsomal ACAT activity: in the presence of exogenous cholesterol, ACBP stimulates ACAT more potently than SCP-2 or L-FABP in proportion to their fatty acyl-CoA binding affinities; in the absence of exogenous cholesterol, these proteins inhibit ACAT. ACBP co-localizes with ACAT2 and ER markers in cells. In vitro microsomal ACAT assay with recombinant lipid-binding proteins, immunolocalization Journal of lipid research Medium 12518025
2009 Leptin increases ACAT1 protein expression (~1.9-fold) and ACAT activity (~1.8-fold) in human monocyte-derived macrophages via JAK2 and PI3K signaling pathways, leading to increased cholesteryl ester accumulation and suppression of HDL-mediated cholesterol efflux; ACAT1 inhibitor K604 reversed the leptin-induced suppression of cholesterol efflux. JAK2/PI3K inhibitor treatment, ACAT activity assay, protein expression (Western blot), cholesterol efflux assay American journal of physiology. Endocrinology and metabolism Medium 19625677
2009 TNF-α, through NF-κB pathway activation at a unique NF-κB element in the human ACAT1 proximal promoter, specifically enhances ACAT1 (but not ACAT2) gene expression in differentiating human monocytes, increasing cholesteryl ester accumulation and promoting lipid-laden cell formation. NF-κB inhibitor treatment, promoter reporter assay, gene expression analysis, CE accumulation measurement Journal of lipid research Medium 19189937
2023 25-Hydroxycholesterol (25HC) activates ACAT in the ER to create an imbalance in accessible cholesterol distribution between ER and plasma membrane, triggering rapid internalization of accessible cholesterol from the PM; this is sustained by concurrent SREBP suppression. In ACAT-deficient cells, 25HC fails to suppress Zika virus, coronavirus, or Listeria infection, placing ACAT activation mechanistically upstream of oxysterol-mediated antimicrobial immunity. ACAT-deficient cell lines, viral/bacterial infection assays, cholesterol trafficking assays, epistasis with SREBP pathway eLife High 36695568
2023 Acute ACAT1/SOAT1 blockade increases cholesterol content at the mitochondria-associated ER membrane (MAM), leading to enrichment of ACAT1 itself at the MAM and strengthening ER-mitochondria connectivity by increasing contact site number and shortening inter-organelle distance, as shown by MAM proteomics, confocal microscopy, and electron microscopy. Biochemical fractionation, MAM proteomics, confocal microscopy, electron microscopy, pharmacological ACAT1 inhibition International journal of molecular sciences Medium 36982602
2022 Acat1/Soat1 knockout in mutant Npc1 mice prolongs lifespan by 34% and improves motor function, hepatosplenic pathology, and Purkinje neuron survival; in mutant NPC1 fibroblasts, ACAT1 blockade increases cholesterol at TGN-rich membranes and mitochondria, decreases cholesterol at late endosomes, and restores proper localization of syntaxin 6, golgin 97, cathepsin D, and ABCA1, placing ACAT1 at the intersection of cholesterol distribution among multiple organelles. Genetic Acat1 KO in Npc1 mouse model, fibroblast cholesterol fractionation, immunolocalization of organelle markers Proceedings of the National Academy of Sciences of the United States of America High 35507892
2019 Myeloid-specific Acat1 KO (Acat1-M/-M) mice are resistant to Western diet-induced obesity; mechanistically, Ly6Chi monocytes from Acat1-M/-M mice express reduced integrin-β1, impairing their interaction with inflamed endothelium and infiltration into white adipose tissue; ACAT1 inhibition in RAW264.7 macrophages also reduces LPS-induced inflammatory responses. Myeloid-specific Acat1 KO mouse, adoptive transfer experiment, flow cytometry, pharmacological ACAT1 inhibition, gene expression analysis American journal of physiology. Endocrinology and metabolism High 29533741
2013 Global Acat1 knockout mice show a significantly higher proportion of Lin-Sca-1+c-Kit+ hematopoietic stem/progenitor cells in proliferation, resulting in elevated myeloid progenitor numbers and leukocytosis, demonstrating that ACAT1 plays a role in restraining hematopoietic progenitor proliferation in bone marrow. Acat1 KO mouse model, flow cytometry of bone marrow populations, cell proliferation assays Arteriosclerosis, thrombosis, and vascular biology Medium 23846496
2007 RNAi-mediated knockdown of ACAT1 (~50% reduction in protein) reduced cholesteryl ester levels by 22% with a slight increase in ER free cholesterol, correlating with ~40% reduction in Aβ secretion from APP-expressing cells, demonstrating that even partial reduction of ACAT1 activity is sufficient to suppress amyloidogenic APP processing. ACAT1 siRNA knockdown, cholesteryl ester measurement, Aβ ELISA FEBS letters Medium 17412327
2025 ACAT1 acetylates malate enzyme 2 (ME2) at lysine 156, potentiating ME2 enzyme activity and facilitating lactate production from glutamine-derived malate; this occurs when decreased intracellular glucose levels (under chemotherapy) reduce glucose uptake, triggering ME2-K156 acetylation by ACAT1, which drives lactylation of homologous recombination proteins and chemoresistance in ovarian cancer. Co-IP, mass spectrometry identification of acetylation site, mutagenesis of K156, in vitro ME2 enzyme activity assay, in vivo tumor models Advanced science Medium 39951294
2023 ACAT1 acetylates METTL3 protein in triple-negative breast cancer cells; this acetylation stabilizes METTL3 by inhibiting ubiquitin-proteasome-mediated degradation, and the NR2F6/ACAT1/METTL3 axis suppresses TNBC cell migration and invasion. Co-IP, GST pulldown, IP-based acetylation detection, ubiquitination assays, functional migration/invasion assays Genes and immunity Medium 36890220
2001 ACAT1 deletion in macrophages reduces total cellular cholesterol efflux by 25% despite upregulation of ABCA1, while increasing efflux of lipoprotein-derived cholesterol by 32% and increasing accumulation of free cholesterol from acetylated LDL by 26%, accompanied by a 75% increase in intracellular vesicles, demonstrating ACAT1's role in routing cholesterol toward efflux pathways. Acat1-/- peritoneal macrophages, radiolabeled cholesterol efflux assay, ABCA1 expression analysis, electron microscopy Arteriosclerosis, thrombosis, and vascular biology Medium 15499044
1998 The adrenocortical lipid depletion (ald) phenotype in AKR inbred mice is caused by a deletion of the first coding exon and two missense mutations in the ACAT1 (Acact) gene; genetic non-complementation with Acact-/- mice and immunoblotting confirmed the ald allele encodes a truncated ACAT protein; despite structural differences, the mutant protein retained cholesterol esterification activity, suggesting the adrenal phenotype arises from altered susceptibility to post-translational modifying factors. Genetic mapping, complementation cross, immunoblotting, cDNA sequence analysis The Journal of biological chemistry Medium 9422770
2023 SCD1 inhibition reduces oleic acid and ACAT1-generated esterified cholesterol in CD8+ T cells, enhancing IFN-γ production and cytotoxic activity; restoration of cholesteryl oleate reverses the enhanced T cell function, establishing an SCD1-ACAT1 axis in which ACAT1-mediated cholesterol esterification suppresses CD8+ T cell effector functions. SCD1 inhibitor treatment, ACAT1 inhibitor treatment, cholesterol/esterified cholesterol measurement, T cell functional assays, in vivo tumor models Cancer science Medium 37879607
2018 NLRP3 inflammasome activation downstream of free cholesterol accumulation in ACAT1-deficient macrophages is the primary driver of cutaneous xanthomatosis in hyperlipidemic mice; loss of NLRP3 completely reversed the cutaneous xanthoma caused by bone marrow ACAT1 deficiency, while ACAT1-null macrophages showed enhanced CHOP and TNF-α expression upon cholesterol loading. Bone marrow transplantation with Acat1/Nlrp3 double KO, histology, cytokine analysis, LDLR-null mouse model Arteriosclerosis, thrombosis, and vascular biology High 30354239

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Effect of ACAT inhibition on the progression of coronary atherosclerosis. The New England journal of medicine 327 16554527
1998 ACAT-2, a second mammalian acyl-CoA:cholesterol acyltransferase. Its cloning, expression, and characterization. The Journal of biological chemistry 325 9756919
2014 Tyr phosphorylation of PDP1 toggles recruitment between ACAT1 and SIRT3 to regulate the pyruvate dehydrogenase complex. Molecular cell 253 24486017
2001 Increased atherosclerosis in LDL receptor-null mice lacking ACAT1 in macrophages. The Journal of clinical investigation 201 11160132
2000 Immunological quantitation and localization of ACAT-1 and ACAT-2 in human liver and small intestine. The Journal of biological chemistry 194 10846185
1991 Therapeutic potential of ACAT inhibitors as lipid lowering and anti-atherosclerotic agents. Trends in pharmacological sciences 185 1862535
2000 Absence of ACAT-1 attenuates atherosclerosis but causes dry eye and cutaneous xanthomatosis in mice with congenital hyperlipidemia. The Journal of biological chemistry 176 10777503
2010 ACAT1 gene ablation increases 24(S)-hydroxycholesterol content in the brain and ameliorates amyloid pathology in mice with AD. Proceedings of the National Academy of Sciences of the United States of America 169 20133765
2009 High ACAT1 expression in estrogen receptor negative basal-like breast cancer cells is associated with LDL-induced proliferation. Breast cancer research and treatment 142 19851860
1995 High affinity YY1 binding motifs: identification of two core types (ACAT and CCAT) and distribution of potential binding sites within the human beta globin cluster. Nucleic acids research 137 7501456
2000 Differential expression of ACAT1 and ACAT2 among cells within liver, intestine, kidney, and adrenal of nonhuman primates. Journal of lipid research 135 11108732
1988 Ca++ antagonists and ACAT inhibitors promote cholesterol efflux from macrophages by different mechanisms. I. Characterization of cellular lipid metabolism. Arteriosclerosis (Dallas, Tex.) 117 2829803
2003 Identification of ACAT1- and ACAT2-specific inhibitors using a novel, cell-based fluorescence assay: individual ACAT uniqueness. Journal of lipid research 114 14617738
2000 Localization of human acyl-coenzyme A: cholesterol acyltransferase-1 (ACAT-1) in macrophages and in various tissues. The American journal of pathology 110 10623671
2000 The ACAT inhibitor avasimibe reduces macrophages and matrix metalloproteinase expression in atherosclerotic lesions of hypercholesterolemic rabbits. Arteriosclerosis, thrombosis, and vascular biology 102 10634802
2020 Structural basis for catalysis and substrate specificity of human ACAT1. Nature 90 32433614
1994 ACAT inhibitors as antiatherosclerotic agents: compounds and mechanisms. Medicinal research reviews 90 8007738
2014 Inhibiting ACAT1/SOAT1 in microglia stimulates autophagy-mediated lysosomal proteolysis and increases Aβ1-42 clearance. The Journal of neuroscience : the official journal of the Society for Neuroscience 89 25339759
2019 The recent insights into the function of ACAT1: A possible anti-cancer therapeutic target. Life sciences 87 31228515
2005 Investigating the allosterism of acyl-CoA:cholesterol acyltransferase (ACAT) by using various sterols: in vitro and intact cell studies. The Biochemical journal 87 15992359
2006 A selective ACAT-1 inhibitor, K-604, suppresses fatty streak lesions in fat-fed hamsters without affecting plasma cholesterol levels. Atherosclerosis 86 16820149
2020 Structure of nevanimibe-bound tetrameric human ACAT1. Nature 80 32433613
1998 Immunodepletion experiments suggest that acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT-1) protein plays a major catalytic role in adult human liver, adrenal gland, macrophages, and kidney, but not in intestines. Journal of lipid research 80 9717734
2006 Sitosterol-containing lipoproteins trigger free sterol-induced caspase-independent death in ACAT-competent macrophages. The Journal of biological chemistry 74 16935859
2001 Differential modulation of ACAT1 and ACAT2 transcription and activity by long chain free fatty acids in cultured cells. Biochemistry 69 11294643
2005 Potential role of acyl-coenzyme A:cholesterol transferase (ACAT) Inhibitors as hypolipidemic and antiatherosclerosis drugs. Pharmaceutical research 62 16180116
2009 Leptin modulates ACAT1 expression and cholesterol efflux from human macrophages. American journal of physiology. Endocrinology and metabolism 58 19625677
2014 TLR4-mediated inflammation promotes foam cell formation of vascular smooth muscle cell by upregulating ACAT1 expression. Cell death & disease 57 25522268
2005 Reduced ABCA1-mediated cholesterol efflux and accelerated atherosclerosis in apolipoprotein E-deficient mice lacking macrophage-derived ACAT1. Circulation 57 15851589
2003 Pharmacology of the ACAT inhibitor avasimibe (CI-1011). Cardiovascular drug reviews 55 12595916
2009 TNF-alpha stimulates the ACAT1 expression in differentiating monocytes to promote the CE-laden cell formation. Journal of lipid research 54 19189937
2007 Esculeogenin A, a new tomato sapogenol, ameliorates hyperlipidemia and atherosclerosis in ApoE-deficient mice by inhibiting ACAT. Arteriosclerosis, thrombosis, and vascular biology 54 17872457
2003 ACBP and cholesterol differentially alter fatty acyl CoA utilization by microsomal ACAT. Journal of lipid research 54 12518025
2010 ACAT inhibition and amyloid beta reduction. Biochimica et biophysica acta 53 20398792
2004 ACAT1 deficiency disrupts cholesterol efflux and alters cellular morphology in macrophages. Arteriosclerosis, thrombosis, and vascular biology 50 15499044
1995 Tissue specific changes in acyl-CoA: cholesterol acyltransferase (ACAT) mRNA levels in rabbits. Journal of lipid research 50 7616126
1994 ACAT inhibition decreases LDL cholesterol in rabbits fed a cholesterol-free diet. Marked changes in LDL cholesterol without changes in LDL receptor mRNA abundance. Arteriosclerosis and thrombosis : a journal of vascular biology 50 8148358
1997 Characterization of thiL, encoding thiamin-monophosphate kinase, in Salmonella typhimurium. The Journal of biological chemistry 49 9188462
1996 Complementation of mutation in acyl-CoA:cholesterol acyltransferase (ACAT) fails to restore sterol regulation in ACAT-defective sterol-resistant hamster cells. The Journal of biological chemistry 49 8662991
2020 Assessment of acyl-CoA cholesterol acyltransferase (ACAT-1) role in ovarian cancer progression-An in vitro study. PloS one 46 31978092
2002 Up-regulation of acyl-coenzyme A:cholesterol acyltransferase (ACAT) in nephrotic syndrome. Kidney international 46 11967026
1998 HMG-CoA reductase and ACAT inhibitors act synergistically to lower plasma cholesterol and limit atherosclerotic lesion development in the cholesterol-fed rabbit. Atherosclerosis 45 9699888
2015 Mitochondrial proteomics with siRNA knockdown to reveal ACAT1 and MDH2 in the development of doxorubicin-resistant uterine cancer. Journal of cellular and molecular medicine 44 25639359
2007 Knockdown of ACAT-1 reduces amyloidogenic processing of APP. FEBS letters 44 17412327
2006 Human acyl-CoA:cholesterol acyltransferase (ACAT) and its potential as a target for pharmaceutical intervention against atherosclerosis. Acta biochimica et biophysica Sinica 43 16518538
2006 ACAT inhibitor pactimibe sulfate (CS-505) reduces and stabilizes atherosclerotic lesions by cholesterol-lowering and direct effects in apolipoprotein E-deficient mice. Atherosclerosis 43 16626720
1995 Terpendoles, novel ACAT inhibitors produced by Albophoma yamanashiensis. I. Production, isolation and biological properties. The Journal of antibiotics 40 7868384
2016 TLR4 siRNA inhibits proliferation and invasion in colorectal cancer cells by downregulating ACAT1 expression. Life sciences 39 27177773
2001 Preferential pharmacological inhibition of macrophage ACAT increases plaque formation in mouse and rabbit models of atherogenesis. Atherosclerosis 39 11254906
1982 thiK and thiL loci of Escherichia coli. Journal of bacteriology 38 6284709
2018 Insulin promotes progression of colon cancer by upregulation of ACAT1. Lipids in health and disease 36 29793481
2008 Androgen-mediated cholesterol metabolism in LNCaP and PC-3 cell lines is regulated through two different isoforms of acyl-coenzyme A:Cholesterol Acyltransferase (ACAT). The Prostate 35 18000807
2008 Identification of putative active site residues of ACAT enzymes. Journal of lipid research 34 18480028
2018 In vitro exploration of ACAT contributions to lipid droplet formation during adipogenesis. Journal of lipid research 33 29549095
2013 Homocysteine-mediated cholesterol efflux via ABCA1 and ACAT1 DNA methylation in THP-1 monocyte-derived foam cells. Acta biochimica et biophysica Sinica 32 23305686
2021 Acyl-Coenzyme A: Cholesterol Acyltransferase (ACAT) in Cholesterol Metabolism: From Its Discovery to Clinical Trials and the Genomics Era. Metabolites 31 34436484
2004 Quantitative analysis of the expression of ACAT genes in human tissues by real-time PCR. Journal of lipid research 31 14729857
2001 Preclinical safety evaluation of avasimibe in beagle dogs: an ACAT inhibitor with minimal adrenal effects. Toxicological sciences : an official journal of the Society of Toxicology 31 11158726
2023 Elevated serum β-hydroxybutyrate, a circulating ketone metabolite, accelerates colorectal cancer proliferation and metastasis via ACAT1. Oncogene 29 37185457
2004 ACAT inhibition reverses LCAT deficiency and improves plasma HDL in chronic renal failure. American journal of physiology. Renal physiology 29 15280162
2004 HMG-CoA reductase, cholesterol 7alpha-hydroxylase, LDL receptor, SR-B1, and ACAT in diet-induced syndrome X. Kidney international 29 15458444
1986 Chlorpromazine inhibits arterial ACAT and reduces arterial cholesterol and cholesteryl ester accumulation in cholesterol-fed rabbits. Arteriosclerosis (Dallas, Tex.) 29 3942557
2023 A concerted mechanism involving ACAT and SREBPs by which oxysterols deplete accessible cholesterol to restrict microbial infection. eLife 28 36695568
2023 Acute ACAT1/SOAT1 Blockade Increases MAM Cholesterol and Strengthens ER-Mitochondria Connectivity. International journal of molecular sciences 28 36982602
2019 Mutation update on ACAT1 variants associated with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency. Human mutation 27 31268215
2010 A selective ACAT-1 inhibitor, K-604, stimulates collagen production in cultured smooth muscle cells and alters plaque phenotype in apolipoprotein E-knockout mice. Atherosclerosis 27 20843517
2004 Human acyl-coenzyme A:cholesterol acyltransferase 1 (acat1) sequences located in two different chromosomes (7 and 1) are required to produce a novel ACAT1 isoenzyme with additional sequence at the N terminus. The Journal of biological chemistry 27 15319423
2001 Catalysis of ACAT may be completed within the plane of the membrane: a working hypothesis. Journal of lipid research 27 11734565
2023 SCD1 inhibition enhances the effector functions of CD8+ T cells via ACAT1-dependent reduction of esterified cholesterol. Cancer science 26 37879607
2020 Grape seed proanthocyanidins suppressed macrophage foam cell formation by miRNA-9 via targeting ACAT1 in THP-1 cells. Food & function 26 31967154
2003 Selective ACAT inhibitors as promising antihyperlipidemic, antiathero-sclerotic and anti-Alzheimer drugs. Mini reviews in medicinal chemistry 26 12871160
2024 Targeting ACAT1 in cancer: from threat to treatment. Frontiers in oncology 24 38720812
2019 Effect of inhibiting ACAT-1 expression on the growth and metastasis of Lewis lung carcinoma. Oncology letters 24 31423222
2003 HMG-CoA reductase, cholesterol 7alpha-hydroxylase, LCAT, ACAT, LDL receptor, and SRB-1 in hereditary analbuminemia. Kidney international 24 12787409
1997 Acyl-CoA binding protein (ACBP) regulates acyl-CoA:cholesterol acyltransferase (ACAT) in human mononuclear phagocytes. Biochimica et biophysica acta 24 9219899
2025 ACAT1-Mediated ME2 Acetylation Drives Chemoresistance in Ovarian Cancer by Linking Glutaminolysis to Lactate Production. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 23 39951294
2020 C. elegans ACAT regulates lipolysis and its related lifespan in fasting through modulation of the genes in lipolysis and insulin/IGF-1 signaling. BioFactors (Oxford, England) 23 32639091
2019 Myeloid Acat1/Soat1 KO attenuates pro-inflammatory responses in macrophages and protects against atherosclerosis in a model of advanced lesions. The Journal of biological chemistry 23 31495784
2018 Myeloid-specific Acat1 ablation attenuates inflammatory responses in macrophages, improves insulin sensitivity, and suppresses diet-induced obesity. American journal of physiology. Endocrinology and metabolism 23 29533741
2008 Novel N-terminal cleavage of APP precludes Abeta generation in ACAT-defective AC29 cells. Journal of molecular neuroscience : MN 23 18618086
2022 Acat1/Soat1 knockout extends the mutant Npc1 mouse lifespan and ameliorates functional deficiencies in multiple organelles of mutant cells. Proceedings of the National Academy of Sciences of the United States of America 22 35507892
2022 Targeting Sterol O-Acyltransferase/Acyl-CoA:Cholesterol Acyltransferase (ACAT): A Perspective on Small-Molecule Inhibitors and Their Therapeutic Potential. Journal of medicinal chemistry 22 36473091
2017 Quantitative Trait Locus Mapping of Macrophage Cholesterol Metabolism and CRISPR/Cas9 Editing Implicate an ACAT1 Truncation as a Causal Modifier Variant. Arteriosclerosis, thrombosis, and vascular biology 22 29097366
2016 5-Hydroxymethylcytosine in E-box motifs ACAT|GTG and ACAC|GTG increases DNA-binding of the B-HLH transcription factor TCF4. Integrative biology : quantitative biosciences from nano to macro 22 27485769
2011 Three Japanese Patients with Beta-Ketothiolase Deficiency Who Share a Mutation, c.431A>C (H144P) in ACAT1 : Subtle Abnormality in Urinary Organic Acid Analysis and Blood Acylcarnitine Analysis Using Tandem Mass Spectrometry. JIMD reports 22 23430882
2023 ACAT1-mediated METTL3 acetylation inhibits cell migration and invasion in triple negative breast cancer. Genes and immunity 21 36890220
2010 Cholesterol loading in macrophages stimulates formation of ER-derived vesicles with elevated ACAT1 activity. Journal of lipid research 20 20460577
1995 Studies on acyl-CoA: cholesterol acyltransferase (ACAT) inhibitory effects and enzyme selectivity of F-1394, a pantotheic acid derivative. Japanese journal of pharmacology 20 7630037
2020 The ThiL enzyme is a valid antibacterial target essential for both thiamine biosynthesis and salvage pathways in Pseudomonas aeruginosa. The Journal of biological chemistry 19 32404369
1998 Adrenocortical lipid depletion gene (ald) in AKR mice is associated with an acyl-CoA:cholesterol acyltransferase (ACAT) mutation. The Journal of biological chemistry 19 9422770
1997 Inhibitory effects of oren-gedoku-to and its components on cholesteryl ester synthesis in cultured human hepatocyte HepG2 cells: evidence from the cultured HepG2 cells and in vitro assay of ACAT. Planta medica 19 9140228
2023 Inhibition of ACAT as a Therapeutic Target for Alzheimer's Disease Is Independent of ApoE4 Lipidation. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics 18 37157042
2005 Polyacetylenic compounds, ACAT inhibitors from the roots of Panax ginseng. Journal of agricultural and food chemistry 18 15712998
2016 Exon 10 skipping in ACAT1 caused by a novel c.949G>A mutation located at an exonic splice enhancer site. Molecular medicine reports 17 27748876
2012 Sex-specific association of ACAT-1 rs1044925 SNP and serum lipid levels in the hypercholesterolemic subjects. Lipids in health and disease 16 22243772
1996 Lack of correlation between ACAT mRNA expression and cholesterol esterification in primary liver cells. Biochimica et biophysica acta 16 8555254
2020 Acidic extracellular pH promotes accumulation of free cholesterol in human monocyte-derived macrophages via inhibition of ACAT1 activity. Atherosclerosis 15 32942042
2018 Inflammasome Activation Aggravates Cutaneous Xanthomatosis and Atherosclerosis in ACAT1 (Acyl-CoA Cholesterol Acyltransferase 1) Deficiency in Bone Marrow. Arteriosclerosis, thrombosis, and vascular biology 15 30354239
2013 Acat1 gene ablation in mice increases hematopoietic progenitor cell proliferation in bone marrow and causes leukocytosis. Arteriosclerosis, thrombosis, and vascular biology 15 23846496
2004 Acyl-coenzyme A:cholesterol acyltransferase-2 (ACAT-2) is responsible for elevated intestinal ACAT activity in diabetic rats. Arteriosclerosis, thrombosis, and vascular biology 15 15242859