Affinage

ACAT1

Sterol O-acyltransferase 1 · UniProt P35610

Length
550 aa
Mass
64.7 kDa
Annotated
2026-06-09
100 papers in source corpus 38 papers cited in narrative 37 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ACAT1 is a cholesterol-esterifying enzyme that maintains intracellular cholesterol homeostasis and, through this lipid-handling role, governs membrane sterol pools in macrophages, neurons, and adipocytes (PMID:32433614, PMID:9857049, PMID:39481851). In the ER membrane it assembles as a dimer-of-dimers tetramer in which each protomer presents converging cytosolic and transmembrane tunnels that admit acyl-CoA and cholesterol, respectively, to a shared catalytic site; long-chain unsaturated acyl-CoA (preferentially oleoyl-CoA) is conjugated to free cholesterol, and the enzyme behaves allosterically with sigmoidal kinetics toward its cholesterol substrate (PMID:32433614, PMID:32433613, PMID:9857049). Catalysis depends on a cytosolic-facing active-site serine (Ser269) and on histidines H386 and H460, and substrate recognition is stereospecific for the 3β-hydroxyl steroid configuration (PMID:11071899, PMID:16647063, PMID:20964445). ACAT1 accounts for the dominant fraction of cholesterol-esterifying activity in human liver, adrenal, macrophage, and kidney tissue, and is enriched at mitochondria-associated ER membranes, where its inhibition raises local cholesterol and strengthens ER–mitochondria contacts (PMID:9717734, PMID:36982602). In macrophages, ACAT1 controls the balance between cholesterol esterification and efflux and is transcriptionally driven by TNF-α through an NF-κB element in its promoter; myeloid ACAT1 ablation attenuates atherosclerotic lesion formation, adipose inflammation, and TLR4-dependent inflammatory signaling (PMID:15499044, PMID:19189937, PMID:31495784, PMID:36982689). In neurons, ACAT1 activity controls plasma-membrane and ER free-cholesterol pools and thereby modulates APP processing and amyloid-β generation, placing cholesterol esterification upstream of amyloidogenesis (PMID:20133765, PMID:26474739). Beyond its esterase function, mitochondrial ACAT1 acts as a protein acetyltransferase that acetylates PDHA1 (K321) and PDP1 (K202) to inhibit the pyruvate dehydrogenase complex and promote the Warburg effect, opposed by the deacetylase SIRT3 (PMID:24486017). The human enzyme is unusual in arising from a chimeric mRNA assembled by interchromosomal trans-splicing, which additionally yields a 56-kDa ER-localized isoform via IRES-dependent translation from a GGC start codon (PMID:10196189, PMID:15319423).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1998 High

    Established that ACAT1 is the dominant cholesterol-esterifying enzyme in most human tissues and that it behaves as an allosteric enzyme regulated by its cholesterol substrate, defining its homeostatic role.

    Evidence Immunodepletion-activity assays across human tissues and purified-enzyme kinetics in micelles and reconstituted vesicles

    PMID:9717734 PMID:9857049

    Open questions at the time
    • Structural basis of allostery not yet resolved
    • Tissue partitioning relative to ACAT2 not fully defined
  2. 2000 High

    Resolved the membrane topology and identified the catalytically essential cytosolic-facing Ser269, and distinguished ACAT1 from ACAT2 as non-interacting isoenzymes with tissue-specific dominance.

    Evidence Glycosylation reporter and FLAG accessibility assays with active-site mutagenesis; immunodepletion and immunohistochemistry of human liver and intestine

    PMID:10846185 PMID:11071899

    Open questions at the time
    • Later cryo-EM revised the transmembrane segment count
    • Mechanism coupling Ser269 to the histidine residues not yet established
  3. 2006 High

    Defined H386 and H460 as catalytic rather than structural residues, refining the active-site chemistry of cholesterol esterification.

    Evidence Histidine site-directed mutagenesis with baculovirus expression, activity and substrate-binding assays, and oxysterol substrate rescue

    PMID:16647063

    Open questions at the time
    • Precise catalytic mechanism (general base vs. nucleophile roles) not fully resolved
  4. 2010 High

    Provided direct binding evidence for stereospecific substrate recognition, showing acyl-CoA and cholesterol binding induce conformational change.

    Evidence Difference intrinsic fluorescence spectroscopy on purified human ACAT1 with cholesterol vs. epicholesterol

    PMID:20964445

    Open questions at the time
    • Binding stoichiometry per tetramer not determined
    • Order of substrate addition not established
  5. 2020 High

    Cryo-EM structures resolved the tetrameric architecture and the converging substrate tunnels, giving a physical model for catalysis, acyl-chain preference, and inhibitor binding.

    Evidence Cryo-EM of human ACAT1 alone and with the inhibitor nevanimibe, plus structure-guided mutagenesis

    PMID:32433613 PMID:32433614

    Open questions at the time
    • Conformational basis of the allosteric cholesterol response not captured
    • Dynamics of substrate entry not directly visualized
  6. 1999 High

    Demonstrated the human ACAT1 transcript arises by interchromosomal trans-splicing, a novel origin for a metabolic enzyme mRNA.

    Evidence Genomic cloning, gene mapping, and RNase protection assays

    PMID:10196189

    Open questions at the time
    • Trans-splicing machinery not identified
    • Physiological significance of the chimeric origin unclear
  7. 2008 Medium

    Showed the chimeric mRNA produces an enzymatically active 56-kDa ER isoform via IRES-dependent initiation from a GGC codon flanked by required stem-loops.

    Evidence Expression, mutagenesis, MS and localization for the isoform; deletion/point mutation of stem-loops in mono- and bicistronic reporters

    PMID:15319423 PMID:18542101

    Open questions at the time
    • IRES trans-acting factors not identified
    • Functional role distinct from the canonical isoform unresolved
  8. 2004 Medium

    Defined the macrophage cholesterol balance role, showing ACAT1 deficiency reroutes lipoprotein-derived cholesterol toward efflux while reducing net efflux despite ABCA1 upregulation.

    Evidence Radiolabeled cholesterol efflux and esterification assays in ACAT1−/− peritoneal macrophages with ABCA1 and SREBP1a readouts

    PMID:15499044 PMID:16144700

    Open questions at the time
    • Mechanism linking esterification to SREBP suppression not fully dissected
    • In vivo efflux consequences not measured here
  9. 2010 Medium

    Mapped the dynamic subcellular redistribution of ACAT1 upon cholesterol loading into more active ER-derived and late-endosomal/lysosomal compartments, linking localization to esterification capacity.

    Evidence Immunoelectron microscopy, subcellular fractionation, immunoadsorption, and reconstituted ACAT activity assays in cholesterol-loaded macrophages

    PMID:10623671 PMID:20460577 PMID:20523008

    Open questions at the time
    • Trigger and machinery for ER vesiculation unknown
    • Basis for higher specific activity in vesicles unexplained
  10. 2014 High

    Identified a moonlighting acetyltransferase function for mitochondrial ACAT1 toward the pyruvate dehydrogenase complex, mechanistically linking it to the Warburg effect.

    Evidence MS, Co-IP, in vitro acetyltransferase assays, mutagenesis, and siRNA knockdown with tumor growth readout in cancer cells

    PMID:24486017

    Open questions at the time
    • Structural basis for acetyltransferase versus esterase activity not defined
    • Relationship between mitochondrial and ER pools unclear
  11. 2014 High

    Connected ACAT1 inhibition to enhanced microglial autophagy-lysosomal clearance of amyloid-β through an mTOR-independent, TFEB-mediated route.

    Evidence Acat1 KO and K604 inhibitor in primary microglia with autophagosome, TFEB reporter, lysosomal degradation, and phagocytosis assays

    PMID:25339759

    Open questions at the time
    • Signal coupling cholesterol esterification to TFEB activation unknown
  12. 2010 High

    Placed cholesterol esterification upstream of APP processing in vivo, showing ACAT1 ablation lowers amyloidogenic processing via oxysterol-mediated control of sterol synthesis.

    Evidence Acat1 KO in 3xTg-AD mice with 24(S)-hydroxycholesterol, HMGR, and amyloid measurements plus neuronal oxysterol treatment; complemented by RNAi and PM free-cholesterol studies

    PMID:17412327 PMID:20133765 PMID:26474739

    Open questions at the time
    • Direct molecular link between cholesterol pools and secretase activity not established
    • Relative contribution of PM vs ER cholesterol not quantified
  13. 2019 High

    Demonstrated that myeloid ACAT1 drives atherosclerotic and metabolic inflammation, with KO reducing lesion burden, monocyte infiltration, and inflammatory responses.

    Evidence Myeloid-specific Acat1 KO in ApoE-KO and Western-diet mouse models with lesion analysis, adoptive transfer, and macrophage inflammatory assays

    PMID:23846496 PMID:29533741 PMID:31495784

    Open questions at the time
    • Mechanism linking esterification to integrin-β1 expression and HSPC proliferation incomplete
  14. 2009 Medium

    Defined transcriptional and hormonal control of ACAT1, identifying an NF-κB promoter element driving TNF-α induction and a leptin–JAK2–PI3K axis raising ACAT1 activity in macrophages.

    Evidence Promoter reporter mutagenesis with NF-κB inhibitors; leptin treatment with JAK2/PI3K inhibitors and efflux assays

    PMID:19189937 PMID:19625677

    Open questions at the time
    • Integration of these inputs with post-translational regulation unknown
  15. 2023 Medium

    Showed ACAT1 protein levels are set by ubiquitin-dependent degradation and by enrichment at MAM, where its activity tunes ER–mitochondria contact and inflammatory TLR4 trafficking.

    Evidence Orthogonal ubiquitin transfer (UBE3A) with mouse liver validation; MAM proteomics and EM; myeloid Acat1 KO with TLR4 endocytosis assays

    PMID:36920305 PMID:36982602 PMID:36982689

    Open questions at the time
    • UBE3A ubiquitination site on ACAT1 not mapped
    • How MAM cholesterol regulates contact-site machinery unresolved
  16. 2024 Medium

    Extended ACAT1's esterase role to adipogenesis, showing catalytic activity is required for SREBP2-driven cholesterol uptake and PPARγ transcription.

    Evidence ACAT1 KO with WT versus catalytic-dead rescue and cholesterol replenishment in preadipocytes

    PMID:39481851

    Open questions at the time
    • Link between cholesterol pools and PPARγ transcription mechanistic detail lacking
  17. 2025 Medium

    Expanded the acetyltransferase repertoire to metabolic and tumor-microenvironment substrates and described succinylation-based regulation, though several of these axes rest on single-lab evidence.

    Evidence Co-IP/mutagenesis for ME2-K156 and METTL3 acetylation; in vivo CRISPR screen for hypersuccinylation/ROS; SIRT5 desuccinylation assays in lung cancer models

    PMID:36890220 PMID:39524872 PMID:39951294 PMID:40166933

    Open questions at the time
    • Direct acetylation of METTL3 not biochemically demonstrated
    • SIRT5 succinylation site on ACAT1 not mapped
    • Several substrates await independent replication

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single protein partitions between ER cholesterol-esterase and mitochondrial protein-acetyltransferase activities, and what structural or localization switch governs this dual function, remains unresolved.
  • No structure of the acetyltransferase-active form
  • Determinants of ER versus mitochondrial targeting unknown
  • Substrate selection rules for acetylation not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 5 GO:0008289 lipid binding 2 GO:0140096 catalytic activity, acting on a protein 2 GO:0098772 molecular function regulator activity 1
Localization
GO:0005783 endoplasmic reticulum 3 GO:0005739 mitochondrion 2 GO:0031410 cytoplasmic vesicle 2 GO:0005764 lysosome 1
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-168256 Immune System 3 R-HSA-392499 Metabolism of proteins 2
Partners
ME2METTL3PDHA1PDP1SIRT3SIRT5UBE3A

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2020 Cryo-EM structure of human ACAT1 revealed it forms a dimer-of-dimers tetramer; each protomer has nine transmembrane segments enclosing a cytosolic tunnel and a transmembrane tunnel that converge at the predicted catalytic site. Structure-guided mutagenesis showed acyl-CoA enters through the cytosolic tunnel and cholesterol likely enters from the side through the transmembrane tunnel, rationalizing ACAT1's preference for unsaturated acyl chains. Cryo-EM structure determination plus structure-guided mutagenesis and biochemical analyses Nature High 32433614
2020 Cryo-EM structure of human ACAT1 in complex with the clinical-stage inhibitor nevanimibe confirmed a tetrameric (dimer-of-dimers) holoenzyme; each monomer has nine transmembrane helices with TM4–TM9 forming a cavity that accommodates nevanimibe and an endogenous acyl-CoA; this cavity contains the catalytically essential histidine residue. The structure provides a physical model for cholesterol esterification and inhibitor binding. Cryo-EM structure determination with bound inhibitor, biochemical analyses Nature High 32433613
1998 Recombinant human ACAT1 purified to homogeneity exhibits allosteric (sigmoidal) kinetics with respect to cholesterol substrate whether assayed in mixed micelles or reconstituted vesicles, while the oleoyl-CoA saturation curves are hyperbolic, supporting the hypothesis that ACAT1 is an allosteric enzyme regulated by cholesterol. Protein purification (~7000-fold), in vitro enzyme kinetics in mixed micelles and reconstituted vesicles The Journal of biological chemistry High 9857049
2000 ACAT1 topology study using glycosylation reporters and FLAG epitope tags showed ACAT1 spans the ER membrane five times with its N-terminus in the cytosol and C-terminus in the ER lumen. The putative active-site serine (Ser269 in ACAT1) is positioned on the cytosolic face; mutation of Ser269 inactivated ACAT1, demonstrating its catalytic essentiality. Glycosylation reporter constructs, FLAG epitope accessibility assays, in vitro microsomal assembly, immunofluorescence microscopy, site-directed mutagenesis Molecular biology of the cell High 11071899
2006 Histidine residues H386 and H460 in ACAT1 are essential for catalytic activity; H386A and H460A substitutions abolished enzymatic activity without altering substrate-binding affinity, indicating these residues are catalytic rather than structural. Partial restoration of H386A activity with 25-hydroxycholesterol (but not cholesterol) as substrate further defined the catalytic role. Site-directed mutagenesis of histidine residues, baculovirus expression, enzyme activity assays, substrate-binding affinity measurements FEBS letters High 16647063
2010 Purified human ACAT1 binds oleoyl-CoA with Kd ~1.9 μM, inducing significant intrinsic fluorescence changes indicating structural rearrangement; cholesterol binding produces larger fluorescence changes than its diastereomer epicholesterol, demonstrating stereospecificity (3β-OH on steroid ring A) in substrate recognition by ACAT1. Protein purification from H293 cells, difference intrinsic fluorescence spectroscopy Biochemistry High 20964445
2014 Mitochondrial ACAT1 was identified as an acetyltransferase for PDHA1 (K321) and PDP1 (K202) in the pyruvate dehydrogenase complex; K321 acetylation of PDHA1 recruits PDK1 to inhibit PDC activity, and K202 acetylation of PDP1 dissociates its substrate PDHA1, both promoting the Warburg effect. SIRT3 acts as the opposing deacetylase. Y381 phosphorylation of PDP1 dissociates SIRT3 and recruits ACAT1 to the PDC. Mass spectrometry, Co-IP, in vitro acetyltransferase assays, site-directed mutagenesis, siRNA knockdown with tumor growth readout, EGF stimulation in cancer cells Molecular cell High 24486017
2000 In human macrophages, ACAT1 localizes to the tubular rough ER under normal conditions; upon cholesterol loading, ~30–40% of total ACAT1 immunoreactivity shifts into small ER-derived vesicles that are also enriched in the ER marker GRP78, suggesting cholesterol overload activates an ER vesiculation process. Immunoelectron microscopy, immunoblot, immunofluorescence microscopy, subcellular fractionation The American journal of pathology High 10623671
2010 Cholesterol loading of macrophages causes ACAT1 to redistribute from high-density ER membranes to lower-density ER-derived vesicles positive for both ER and trans-Golgi network markers; these vesicles exhibit ~3-fold higher ACAT1-specific enzymatic activity than ER membranes, and reconstitution assays showed this is not due to increased cholesterol content in the vesicles. Subcellular fractionation, in vitro ACAT enzyme activity assays on isolated membranes, reconstituted ACAT assay Journal of lipid research High 20460577
1999 The human ACAT1 4.3-kb mRNA is produced from sequences on two different chromosomes (exons 1–16 and P1 promoter on chromosome 1; exon Xa and P7 promoter on chromosome 7), requiring a novel interchromosomal trans-splicing mechanism of two discontinuous precursor RNAs. Genomic cloning, gene mapping, RNase protection assays The Journal of biological chemistry High 10196189
2004 The chimeric 4.3-kb human ACAT1 mRNA (derived from chromosomes 1 and 7 via trans-splicing) produces a 56-kDa ACAT1 isoform using a GGC (glycine) start codon upstream of the normal AUG; this 56-kDa isoform localizes to the ER and is enzymatically active. Both chromosomal sequences are required for its production. Expression in CHO cells, site-directed mutagenesis, mass spectrometry, immunoblot with isoform-specific antibodies, subcellular localization, enzyme activity assay The Journal of biological chemistry High 15319423
2008 Production of the 56-kDa ACAT1 isoform from the chimeric mRNA requires two specific RNA secondary structures (stem-loops at nt 1255–1268 from chromosome 7 and nt 1286–1342 from chromosome 1) flanking the GGC start codon; translation initiation from GGC is mediated by an IRES mechanism requiring an upstream AU-constituted structure and downstream GC-rich structure. Deletion and point mutation analyses of stem-loop sequences, monocistronic and bicistronic vector experiments with stable hairpin, western blot Cell research Medium 18542101
1998 Immunodepletion experiments demonstrated that ACAT1 protein accounts for ~90% of ACAT activity in adult human liver, ~98% in adrenal gland, ~91% in macrophages, and ~80% in kidney, but only ~19% in intestines, establishing tissue-specific catalytic roles. Immunodepletion with anti-ACAT1 antibodies followed by residual activity measurement in solubilized tissue homogenates Journal of lipid research High 9717734
2000 In adult human liver, ACAT1 (not ACAT2) accounts for 85–90% of total ACAT activity as measured by immunodepletion. ACAT1 and ACAT2 do not form hetero-oligomeric complexes. In intestinal enterocytes, ACAT2 (not ACAT1) is the dominant isoenzyme, concentrated at villus apices. Specific polyclonal antibody immunodepletion, immunohistochemistry of human intestine and liver, activity assays in HepG2 and Caco-2 cells The Journal of biological chemistry High 10846185
2003 Purified ACAT1 expressed in insect cells exists preferentially as oligomers (dimer to tetramer); ACAT1 esterifies cholesterol more rapidly than ACAT2, which more efficiently esterifies cholic acid derivatives, demonstrating distinct substrate specificities. Pyripyropene A selectively inhibits ACAT2 (IC50 = 0.64 μM) but not ACAT1. Baculovirus-insect cell expression, protein purification, enzyme kinetics, inhibitor screening Biochemical and biophysical research communications Medium 13679053
2003 ACAT1 selectively esterifies oleic acid over polyunsaturated fatty acids in intact cells and microsomes (THP-1 macrophages), while ACAT2-expressing cells show broader unsaturated fatty acid utilization; K-604 competitively inhibits ACAT1 with respect to oleoyl-CoA (Ki = 0.378 μM), establishing the oleoyl-CoA binding site as part of the active site. NBD-cholesterol fluorescence assay, specific inhibitor kinetics in AC29 cells stably transfected with ACAT1 or ACAT2, microsomal activity assays Journal of lipid research Medium 14617738 16820149
2014 Pharmacological blockade (K604) or genetic knockout of ACAT1 in microglia stimulates autophagosome formation and TFEB-mediated lysosomal proteolysis in an mTOR-independent manner, increasing phagocytic uptake and lysosomal degradation of oligomeric Aβ1-42. The effect can be modulated by agents that disrupt cholesterol biosynthesis. Acat1 KO mouse primary microglia, specific ACAT1 inhibitor K604, autophagosome formation assays, TFEB reporter assays, lysosomal degradation assays, phagocytosis assays, mTOR signaling analysis The Journal of neuroscience High 25339759
2023 Acute ACAT1/SOAT1 blockade increases cholesterol content at the mitochondria-associated ER membrane (MAM), where ACAT1 is enriched; this increases the number of ER-mitochondria contact sites and shortens the distance between these organelles, strengthening ER-mitochondria connectivity. Biochemical fractionation (MAM isolation), MAM proteomics, confocal and electron microscopy of ER-mitochondria contact sites International journal of molecular sciences Medium 36982602
2023 ACAT1/SOAT1 blockade in microglia alters the intracellular fate of TLR4 by increasing TLR4 endocytosis and enhancing its trafficking to lysosomes for degradation, thereby suppressing LPS-induced pro-inflammatory signaling. Myeloid-specific Acat1 KO mice showed markedly attenuated LPS-induced neuroinflammation in hippocampus and cortex. Myeloid-specific Acat1 KO mice, pharmacological ACAT1 inhibitor K604, TLR4 localization by microscopy, endocytosis assays, cytokine measurements International journal of molecular sciences High 36982689
2018 Myeloid-specific Acat1 knockout reduces Ly6Chi monocyte integrin-β1 expression, impairing monocyte adhesion to inflamed endothelium and infiltration into adipose tissue; this attenuates Western diet-induced obesity and adipose tissue inflammation. ACAT1 inhibition in RAW264.7 macrophages also reduces LPS-induced inflammatory responses. Myeloid-specific Acat1 KO mouse model, adoptive transfer, flow cytometry, integrin-β1 expression analysis, small-molecule ACAT1 inhibitor in cell culture American journal of physiology. Endocrinology and metabolism High 29533741
2010 In cholesterol-loaded macrophages, approximately 20% of total ACAT1 co-localizes with the late endosome/lysosome marker LAMP2, and ACAT1-positive membranes isolated by immunoadsorption contain LAMP2; cholesterol-loaded macrophages can re-esterify LDL-derived cholesterol even when cholesterol egress from late endosomes is blocked by U18666A, suggesting ACAT1-positive LE/LS facilitate direct esterification of lipoprotein-derived free cholesterol. Confocal fluorescence microscopy, immunoelectron microscopy, subcellular fractionation, immunoadsorption, cholesterol esterification assay with pharmacological block Journal of atherosclerosis and thrombosis Medium 20523008
2005 ACAT1 deficiency in peritoneal macrophages increases de novo cholesterol synthesis by 134% and upregulates SREBP1a mRNA 6-fold, indicating that ACAT1 normally suppresses the SREBP-driven cholesterol/fatty acid synthesis program; total cellular cholesterol efflux increases proportionally but esterification of new cholesterol is reduced by 93%. Radiotracer cholesterol synthesis and efflux assays in ACAT1−/− peritoneal macrophages, qPCR for SREBP1a Atherosclerosis Medium 16144700
2004 ACAT1 deficiency in macrophages reduces overall cellular cholesterol efflux by 25% despite upregulated ABCA1 expression, while efflux of lipoprotein-derived (acLDL) cholesterol is increased by 32%; ACAT1-deficient macrophages accumulate 26% more free cholesterol from acLDL and show a 75% increase in intracellular vesicles. ACAT1−/− peritoneal macrophages, radiolabeled cholesterol efflux assays, ABCA1 expression analysis, vesicle quantification Arteriosclerosis, thrombosis, and vascular biology Medium 15499044
2023 ACAT1 acetylates ME2 (malate enzyme 2) at lysine 156, potentiating ME2 enzyme activity and promoting conversion of glutamine-derived malate to pyruvate and subsequently lactate; this ME2-derived lactate facilitates lactylation of homologous recombination repair proteins, contributing to chemoresistance in ovarian cancer. Glucose deprivation triggers this ACAT1-ME2 axis. Co-IP, site-directed mutagenesis of ME2-K156, in vitro ME2 enzyme activity assays, metabolomics, in vitro and in vivo cancer models Advanced science Medium 39951294
2023 ACAT1 acetylates METTL3, and this interaction (demonstrated by Co-IP and GST pulldown) stabilizes METTL3 protein by inhibiting ubiquitin-proteasome-mediated degradation; ACAT1-mediated METTL3 stabilization suppresses TNBC cell migration and invasion. NR2F6 transcriptionally activates ACAT1 to regulate this axis. Co-IP, GST pulldown, IP for ubiquitination, qPCR, western blot, migration/invasion assays Genes and immunity Low 36890220
2023 ACAT1 loss in lung tumor cells leads to mitochondrial protein hypersuccinylation and enhanced mitochondrial oxidative metabolism; this increases ROS, which impedes tertiary lymphoid structure (TLS) formation. ACAT1 knockdown reduced ROS and promoted B-cell aggregation and TLS construction, sensitizing tumors to anti-PD1 therapy. In vivo CRISPR screening in orthotopic lung tumor model, succinylation proteomics, ROS measurements, B-cell aggregation assays, NAC treatment, NSCLC tissue microarray (305 patients) The Journal of clinical investigation Medium 40166933
2024 SIRT5 acts as a desuccinylase of ACAT1, removing succinyl groups from ACAT1 and enhancing its enzymatic activity; SIRT5-mediated ACAT1 activation then activates the NRF2 pathway and inhibits secretion of CCL5 and CXCL10 chemokines that recruit CD8+ T cells, contributing to an immunosuppressive tumor microenvironment in EGFR-mutant LUAD. Desuccinylation assay, ACAT1 activity measurements, chemokine secretion assays, T-cell recruitment assays Heliyon Low 39524872
2023 ACAT1 inhibition suppresses fatty acid oxidation and acetyl-CoA production while increasing free fatty acids in glioblastoma cells; this restores mitochondrial function and negatively regulates the choline metabolic pathway, which is required for GBM cell differentiation into astrocytes. Chlorogenic acid inhibits ACAT1 phosphorylation to achieve this effect. ACAT1 KD in GBM cells, Seahorse metabolic assays, metabolomics, in vitro and in vivo differentiation assays International journal of biological sciences Low 39494339
2023 UBE3A ubiquitin ligase ubiquitinates ACAT1 (identified by orthogonal ubiquitin transfer), promoting its degradation; on a high-fat diet, reduced hepatic UBE3A expression is associated with increased ACAT1 protein and ketone body accumulation; forced UBE3A expression in mouse liver decreases ACAT1 protein content. Orthogonal ubiquitin transfer platform, overexpression in HEK293 cells, mouse liver forced expression, western blot, metabolite measurements Biochemistry Medium 36920305
2024 ACAT1-deficient preadipocytes show inhibited SREBP2-mediated cholesterol uptake, reduced intracellular and plasma membrane cholesterol, and impaired PPARγ transcription and adipogenesis; rescue with catalytically functional but not catalytic-dead ACAT1 restores cholesterol levels and PPARγ transcription, demonstrating that ACAT1 enzymatic activity is required for normal adipogenesis. ACAT1 KO, overexpression of WT vs. catalytic-dead ACAT1, cholesterol measurements, PPARγ transcription analysis, cholesterol replenishment rescue experiments Journal of lipid research Medium 39481851
2019 Myeloid-specific Acat1 KO in the ApoE-KO mouse model for advanced atherosclerosis significantly reduced lesion cholesterol crystal content, lesion size, and macrophage content without increasing apoptotic cell death; cell culture studies showed that ACAT1 inhibition in macrophages reduces pro-inflammatory responses to cholesterol loading by acetyl-LDL. Myeloid-specific Acat1 KO in ApoE-KO mice, lesion analysis (cholesterol crystal quantification, macrophage immunostaining), macrophage cell culture inflammatory response assays The Journal of biological chemistry High 31495784
2013 Global Acat1 knockout causes a higher proportion of Lin−Sca-1+c-Kit+ hematopoietic stem/progenitor cells to proliferate, resulting in increased myeloid progenitor cell numbers and leukocytosis in normal mice and elevated monocytosis in Apoe−/− mice during atherosclerosis, demonstrating that ACAT1 plays a role in regulating hematopoiesis. Acat1−/− mouse bone marrow analysis, flow cytometry of Lin−Sca-1+c-Kit+ population, myeloid progenitor cell quantification Arteriosclerosis, thrombosis, and vascular biology Medium 23846496
2010 ACAT1 gene ablation in a 3xTg-AD mouse model increases 24(S)-hydroxycholesterol content by 32% in the brain at 4 months, decreases HMG-CoA reductase protein by 65%, reduces sterol synthesis rate by 28%, and decreases full-length hAPP and its proteolytic fragments by >60%; treating hippocampal neurons with 24(S)-hydroxycholesterol recapitulates reductions in hAPP and HMGR, placing cholesterol esterification upstream of APP processing. Acat1 KO in 3xTg-AD mice, 24(S)-hydroxycholesterol measurement, HMGR activity assay, neuronal cell treatment with oxysterol, amyloid quantification Proceedings of the National Academy of Sciences High 20133765
2007 ACAT1 RNAi (~50% protein reduction) decreases cholesteryl ester levels by 22%, causes slight increase in ER free cholesterol, and reduces Aβ secretion by 40%, demonstrating that ACAT1 activity influences amyloidogenic APP processing. RNAi knockdown, cholesteryl ester quantification, Aβ ELISA FEBS letters Medium 17412327
2015 ACAT1 inhibition in SK-N-SH neuronal cells increases free cholesterol at the plasma membrane (PM-FC), and this increased PM-FC reduces APP α-processing; the effect on PM-FC and α-processing is independent of total cellular cholesterol and persists even when the NPC-dependent cholesterol trafficking pathway is blocked, identifying an ACAT1-dependent pathway for shuttling PM-FC to the intracellular pool. ACAT1 siRNA and pharmacological inhibitor, free cholesterol measurement by filipin staining, APP α-processing assay, NPC pathway blockade Acta biochimica et biophysica Sinica Medium 26474739
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, promoting cholesteryl ester accumulation and suppressing HDL-mediated cholesterol efflux; the efflux suppression is reversed by the ACAT1 inhibitor K604. Leptin treatment of differentiating monocytes, JAK2 and PI3K inhibitors, ACAT activity assay, western blot, cholesterol efflux assay American journal of physiology. Endocrinology and metabolism Medium 19625677
2009 TNF-α, through NF-κB, specifically enhances ACAT1 (but not ACAT2) gene expression in differentiating human monocytes; a functional NF-κB element in the human ACAT1 proximal promoter is required for this effect; increased ACAT1 promotes cholesteryl ester accumulation and lipid-laden cell formation. TNF-α treatment, NF-κB inhibitors, promoter reporter assays, mutational analysis of NF-κB binding site, cholesteryl ester accumulation assay Journal of lipid research Medium 19189937

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 Tyr phosphorylation of PDP1 toggles recruitment between ACAT1 and SIRT3 to regulate the pyruvate dehydrogenase complex. Molecular cell 255 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 195 10846185
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 170 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
2000 Differential expression of ACAT1 and ACAT2 among cells within liver, intestine, kidney, and adrenal of nonhuman primates. Journal of lipid research 135 11108732
1998 Expression of ACAT-1 protein in human atherosclerotic lesions and cultured human monocytes-macrophages. Arteriosclerosis, thrombosis, and vascular biology 124 9763528
2003 Identification of ACAT1- and ACAT2-specific inhibitors using a novel, cell-based fluorescence assay: individual ACAT uniqueness. Journal of lipid research 115 14617738
1998 Recombinant acyl-CoA:cholesterol acyltransferase-1 (ACAT-1) purified to essential homogeneity utilizes cholesterol in mixed micelles or in vesicles in a highly cooperative manner. The Journal of biological chemistry 112 9857049
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
1999 Human acyl-CoA:cholesterol acyltransferase-1 (ACAT-1) gene organization and evidence that the 4.3-kilobase ACAT-1 mRNA is produced from two different chromosomes. The Journal of biological chemistry 106 10196189
2000 ACAT1 and ACAT2 membrane topology segregates a serine residue essential for activity to opposite sides of the endoplasmic reticulum membrane. Molecular biology of the cell 94 11071899
2020 Structural basis for catalysis and substrate specificity of human ACAT1. Nature 93 32433614
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 90 25339759
2019 The recent insights into the function of ACAT1: A possible anti-cancer therapeutic target. Life sciences 88 31228515
2006 A selective ACAT-1 inhibitor, K-604, suppresses fatty streak lesions in fat-fed hamsters without affecting plasma cholesterol levels. Atherosclerosis 87 16820149
2020 Structure of nevanimibe-bound tetrameric human ACAT1. Nature 81 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
2013 Acat1 knockdown gene therapy decreases amyloid-β in a mouse model of Alzheimer's disease. Molecular therapy : the journal of the American Society of Gene Therapy 74 23774792
2001 Differential modulation of ACAT1 and ACAT2 transcription and activity by long chain free fatty acids in cultured cells. Biochemistry 69 11294643
2014 TLR4-mediated inflammation promotes foam cell formation of vascular smooth muscle cell by upregulating ACAT1 expression. Cell death & disease 59 25522268
2009 Leptin modulates ACAT1 expression and cholesterol efflux from human macrophages. American journal of physiology. Endocrinology and metabolism 58 19625677
2005 Reduced ABCA1-mediated cholesterol efflux and accelerated atherosclerosis in apolipoprotein E-deficient mice lacking macrophage-derived ACAT1. Circulation 57 15851589
2009 TNF-alpha stimulates the ACAT1 expression in differentiating monocytes to promote the CE-laden cell formation. Journal of lipid research 54 19189937
2004 ACAT1 deficiency disrupts cholesterol efflux and alters cellular morphology in macrophages. Arteriosclerosis, thrombosis, and vascular biology 50 15499044
1997 Characterization of thiL, encoding thiamin-monophosphate kinase, in Salmonella typhimurium. The Journal of biological chemistry 49 9188462
2020 Assessment of acyl-CoA cholesterol acyltransferase (ACAT-1) role in ovarian cancer progression-An in vitro study. PloS one 46 31978092
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 45 25639359
2007 Knockdown of ACAT-1 reduces amyloidogenic processing of APP. FEBS letters 44 17412327
2008 Differential effects of PARP inhibition on vascular cell survival and ACAT-1 expression favouring atherosclerotic plaque stability. Cardiovascular research 43 18245064
2016 TLR4 siRNA inhibits proliferation and invasion in colorectal cancer cells by downregulating ACAT1 expression. Life sciences 39 27177773
1982 thiK and thiL loci of Escherichia coli. Journal of bacteriology 39 6284709
2018 Insulin promotes progression of colon cancer by upregulation of ACAT1. Lipids in health and disease 38 29793481
2003 Mass-production of human ACAT-1 and ACAT-2 to screen isoform-specific inhibitor: a different substrate specificity and inhibitory regulation. Biochemical and biophysical research communications 34 13679053
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
2023 Elevated serum β-hydroxybutyrate, a circulating ketone metabolite, accelerates colorectal cancer proliferation and metastasis via ACAT1. Oncogene 30 37185457
2023 Acute ACAT1/SOAT1 Blockade Increases MAM Cholesterol and Strengthens ER-Mitochondria Connectivity. International journal of molecular sciences 29 36982602
2023 SCD1 inhibition enhances the effector functions of CD8+ T cells via ACAT1-dependent reduction of esterified cholesterol. Cancer science 29 37879607
2020 A Dipeptidyl Peptidase-4 Inhibitor Inhibits Foam Cell Formation of Macrophages in Type 1 Diabetes via Suppression of CD36 and ACAT-1 Expression. International journal of molecular sciences 29 32646003
2019 Mutation update on ACAT1 variants associated with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency. Human mutation 29 31268215
2020 Grape seed proanthocyanidins suppressed macrophage foam cell formation by miRNA-9 via targeting ACAT1 in THP-1 cells. Food & function 28 31967154
2025 ACAT1-Mediated ME2 Acetylation Drives Chemoresistance in Ovarian Cancer by Linking Glutaminolysis to Lactate Production. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 27 39951294
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
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
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
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
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
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
2005 ACAT1 deficiency increases cholesterol synthesis in mouse peritoneal macrophages. Atherosclerosis 20 16144700
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
2003 Single base substitutions at the initiator codon in the mitochondrial acetoacetyl-CoA thiolase (ACAT1/T2) gene result in production of varying amounts of wild-type T2 polypeptide. Human mutation 19 12754704
2020 Acidic extracellular pH promotes accumulation of free cholesterol in human monocyte-derived macrophages via inhibition of ACAT1 activity. Atherosclerosis 18 32942042
2010 Purification of recombinant acyl-coenzyme A:cholesterol acyltransferase 1 (ACAT1) from H293 cells and binding studies between the enzyme and substrates using difference intrinsic fluorescence spectroscopy. Biochemistry 18 20964445
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
2021 PPARα/γ signaling pathways are involved in Chlamydia pneumoniae-induced foam cell formation via upregulation of SR-A1 and ACAT1 and downregulation of ABCA1/G1. Microbial pathogenesis 15 34767930
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
2008 RNA secondary structures located in the interchromosomal region of human ACAT1 chimeric mRNA are required to produce the 56-kDa isoform. Cell research 15 18542101
2023 ACAT1 deficiency in myeloid cells promotes glioblastoma progression by enhancing the accumulation of myeloid-derived suppressor cells. Acta pharmaceutica Sinica. B 14 38045043
2010 Neuronal cholesterol esterification by ACAT1 in Alzheimer's disease. IUBMB life 14 20101629
2024 Modulating Cholesterol Metabolism via ACAT1 Knockdown Enhances Anti-B-Cell Lymphoma Activities of CD19-Specific Chimeric Antigen Receptor T Cells by Improving the Cell Activation and Proliferation. Cells 13 38534399
2023 Effects of UBE3A on Cell and Liver Metabolism through the Ubiquitination of PDHA1 and ACAT1. Biochemistry 13 36920305
2016 miR-467b regulates the cholesterol ester formation via targeting ACAT1 gene in RAW 264.7 macrophages. Biochimie 13 27678191
2013 Production of ACAT1 56-kDa isoform in human cells via trans-splicing involving the ampicillin resistance gene. Cell research 13 23835473
2025 ACAT1 regulates tertiary lymphoid structures and correlates with immunotherapy response in non-small cell lung cancer. The Journal of clinical investigation 12 40166933
2023 Role of acyl-coenzyme A: cholesterol transferase 1 (ACAT1) in retinal neovascularization. Journal of neuroinflammation 12 36691048
2023 ACAT1/SOAT1 Blockade Suppresses LPS-Mediated Neuroinflammation by Modulating the Fate of Toll-like Receptor 4 in Microglia. International journal of molecular sciences 12 36982689
2018 MiR-21 regulates the ACAT1 gene in MCF-7 cells. Life sciences 12 30092298
2017 Clinical and molecular analysis of 6 Chinese patients with isoleucine metabolism defects: identification of 3 novel mutations in the HSD17B10 and ACAT1 gene. Metabolic brain disease 12 28875337
2015 ACAT1 regulates the dynamics of free cholesterols in plasma membrane which leads to the APP-α-processing alteration. Acta biochimica et biophysica Sinica 11 26474739
2006 A critical role for the histidine residues in the catalytic function of acyl-CoA:cholesterol acyltransferase catalysis: evidence for catalytic difference between ACAT1 and ACAT2. FEBS letters 11 16647063
2004 A stable upstream stem-loop structure enhances selection of the first 5'-ORF-AUG as a main start codon for translation initiation of human ACAT1 mRNA. Acta biochimica et biophysica Sinica 11 15253151
2023 Chlorogenic Acid Induced Neuroblastoma Cells Differentiation via the ACAT1-TPK1-PDH Pathway. Pharmaceuticals (Basel, Switzerland) 10 37375824
2019 ACAT1 as a Therapeutic Target and its Genetic Relationship with Alzheimer's Disease. Current Alzheimer research 10 31441726
2017 ACAT-1 gene polymorphism is associated with increased susceptibility to coronary artery disease in Chinese Han population: a case-control study. Oncotarget 10 29179498
2010 Association of ACAT1-positive vesicles with late endosomes/ lysosomes in cholesterol-rich human macrophages. Journal of atherosclerosis and thrombosis 10 20523008
2023 Stealth Liposomes Encapsulating a Potent ACAT1/SOAT1 Inhibitor F12511: Pharmacokinetic, Biodistribution, and Toxicity Studies in Wild-Type Mice and Efficacy Studies in Triple Transgenic Alzheimer's Disease Mice. International journal of molecular sciences 9 37446191
2020 Relationship Between Genetic Variants of ACAT1 and APOE with the Susceptibility to Dementia (SADEM Study). Molecular neurobiology 9 33057949
2016 Ruminal expression of the NQO1, RGS5, and ACAT1 genes may be indicators of feed efficiency in beef steers. Animal genetics 9 27611366
2009 The optional long 5'-untranslated region of human ACAT1 mRNAs impairs the production of ACAT1 protein by promoting its mRNA decay. Acta biochimica et biophysica Sinica 9 19129948
2024 Silencing lncRNA-DARS-AS1 suppresses nonsmall cell lung cancer progression by stimulating miR-302a-3p to inhibit ACAT1 expression. Molecular carcinogenesis 8 38289172
2024 SIRT5 participates in the suppressive tumor immune microenvironment of EGFR-mutant LUAD by regulating the succinylation of ACAT1. Heliyon 8 39524872
2009 Study of the insulin signaling pathways in the regulation of ACAT1 expression in cultured macrophages. Cell biology international 8 19269342
2022 Epigenetic inactivation of ACAT1 promotes epithelial-mesenchymal transition of clear cell renal cell carcinoma. Genes & genomics 7 34985712
2016 [Analysis of clinical phenotype and ACAT1 gene mutation in a family affected with beta-ketothiolase deficiency]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 7 27264805
2013 Development of MLPA for human ACAT1 gene and identification of a heterozygous Alu-mediated deletion of exons 3 and 4 in a patient with mitochondrial acetoacetyl-CoA thiolase (T2) deficiency. Molecular genetics and metabolism 7 23920042
2009 Docosahexaenoic acid is a substrate for ACAT1 and inhibits cholesteryl ester formation from oleic acid in MCF-10A cells. Prostaglandins, leukotrienes, and essential fatty acids 7 19217763
2024 ACAT1/SOAT1 maintains adipogenic ability in preadipocytes by regulating cholesterol homeostasis. Journal of lipid research 6 39481851
2020 Downregulation of Acat1 by miR-21 may participate in liver fibrosis upon chronic DDT exposure. Toxicology mechanisms and methods 6 32508177
2018 Loss of ACAT1 Attenuates Atherosclerosis Aggravated by Loss of NCEH1 in Bone Marrow-Derived Cells. Journal of atherosclerosis and thrombosis 6 30282838
2017 Single-nucleotide substitution T to A in the polypyrimidine stretch at the splice acceptor site of intron 9 causes exon 10 skipping in the ACAT1 gene. Molecular genetics & genomic medicine 6 28361105
2024 ACAT1 Induces the Differentiation of Glioblastoma Cells by Rewiring Choline Metabolism. International journal of biological sciences 5 39494339
2024 Inhibiting the Cholesterol Storage Enzyme ACAT1/SOAT1 in Aging Apolipoprotein E4 Mice Alters Their Brains' Inflammatory Profiles. International journal of molecular sciences 5 39769453

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