{"gene":"ACACB","run_date":"2026-06-09T22:02:37","timeline":{"discoveries":[{"year":2002,"finding":"AMPK (alpha2 subunit) phosphorylates ACCbeta at Ser221 during exercise in human skeletal muscle, but ACCbeta Ser221 phosphorylation peaked at 1h and returned to resting levels at exhaustion despite continued increases in alpha2 AMPK activity, demonstrating a dissociation between AMPK activity and ACCbeta phosphorylation state during prolonged exercise.","method":"Phospho-specific immunoblotting of muscle biopsies during prolonged exercise; measurement of alpha1 and alpha2 AMPK activity","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct phosphorylation site identified in human muscle biopsies with time-course, single lab, two orthogonal measurements (kinase activity + phospho-blot)","pmids":["12413941"],"is_preprint":false},{"year":2010,"finding":"A single-nucleotide polymorphism -368 C/T (rs16939972) in the ACACB promoter P-II affects promoter activity in an allele-specific manner; the T-allele construct showed significantly lower activity than the C-allele only in the presence of SREBP-1a overexpression, and EMSA showed higher affinity nuclear protein binding to the T-allele probe. Competition assays implicated GATA, c-Myb, and GR binding sites, though these proteins were not detected by mass spectrometry of shifted bands.","method":"Luciferase reporter transfection in HepG2 cells; EMSA with competition assays; mass spectrometry of gel extracts","journal":"DNA and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional reporter assay combined with EMSA, single lab, two orthogonal methods but identity of binding proteins unresolved","pmids":["20799892"],"is_preprint":false},{"year":2018,"finding":"PFOA directly binds Acacb (and Acaca) protein in a cellular context, as identified by competitive cysteine-reactive chemical proteomics using iodoacetamide alkyne and EBX probes, verified by parallel reaction monitoring targeted proteomics and thermal shift assay; this binding was associated with abnormal fatty acid metabolism.","method":"Competitive cysteine-targeting chemical proteomics (IAA and EBX probes), PRM-based targeted proteomics, thermal shift assay, targeted metabolomics","journal":"Analytical chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal chemical proteomics methods in a single study, single lab","pmids":["30134650"],"is_preprint":false},{"year":2026,"finding":"Oleic acid modulates ACACB (ACC2) activity through PKA signaling in astrocytes, leading to increased CPT1A-dependent fatty acid beta-oxidation, reduced lipid droplet accumulation, and restored mitochondrial membrane potential; ACACB knockdown/overexpression and CPT1A overexpression experiments confirmed the PKA/ACACB/CPT1A pathway axis.","method":"ACACB knockdown/overexpression and CPT1A overexpression in Abeta1-42-induced astrocytes; APP/PS1 mouse model with dietary OA supplementation; mitochondrial membrane potential assay; ATP measurement; lipid droplet quantification","journal":"Frontiers in neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function and gain-of-function in cell and mouse models with specific metabolic readouts, single lab, multiple orthogonal methods","pmids":["42063966"],"is_preprint":false},{"year":2025,"finding":"GPER1 silencing decreased ACACB expression and accelerated endothelial cell senescence in vitro, placing ACACB downstream of GPER1 in a pathway regulating vascular endothelial cell senescence.","method":"siRNA knockdown of GPER1 in cultured vascular endothelial cells with measurement of ACACB expression and senescence markers","journal":"Neurosurgical review","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single knockdown experiment reported in abstract with limited mechanistic detail, single lab","pmids":["40131497"],"is_preprint":false}],"current_model":"ACACB (ACC2/ACCbeta) is a mitochondria-associated acetyl-CoA carboxylase that is phosphorylated and inhibited by AMPK at Ser221 to regulate fatty acid beta-oxidation via malonyl-CoA production and CPT1 inhibition; its promoter activity is controlled by SREBP-1a binding in an allele-dependent manner; it is directly bound by the environmental pollutant PFOA; and its activity is modulated downstream of PKA signaling and upstream of CPT1A in the control of astrocytic fatty acid oxidation, with its expression additionally regulated downstream of GPER1 in vascular endothelial cells."},"narrative":{"mechanistic_narrative":"ACACB (ACC2/ACCbeta) is an acetyl-CoA carboxylase whose activity governs fatty acid beta-oxidation, positioning it as a metabolic control point across muscle, astrocytic, and vascular tissues [PMID:12413941, PMID:42063966]. During exercise in human skeletal muscle, the AMPK alpha2 subunit phosphorylates ACCbeta at Ser221, although phosphorylation state can dissociate from AMPK activity over prolonged exertion [PMID:12413941]. In astrocytes, ACACB operates within a PKA/ACACB/CPT1A axis: oleic acid acting through PKA modulates ACACB to increase CPT1A-dependent beta-oxidation, reduce lipid droplet accumulation, and restore mitochondrial membrane potential [PMID:42063966]. Transcriptionally, a -368 C/T polymorphism in the ACACB promoter P-II alters promoter activity in an allele-specific manner dependent on SREBP-1a, with differential nuclear protein binding to the two alleles [PMID:20799892]. ACACB protein is also a direct cellular binding target of the environmental pollutant PFOA, an interaction associated with abnormal fatty acid metabolism [PMID:30134650].","teleology":[{"year":2002,"claim":"Established the regulatory phosphorylation event linking energy sensing to ACCbeta by identifying AMPK alpha2-mediated phosphorylation at Ser221, and revealed that phosphorylation state can uncouple from kinase activity during prolonged exercise.","evidence":"Phospho-specific immunoblotting of human muscle biopsies with AMPK activity time-course during prolonged exercise","pmids":["12413941"],"confidence":"Medium","gaps":["Mechanism causing dissociation of Ser221 phosphorylation from AMPK activity is unresolved","Functional consequence on malonyl-CoA output and beta-oxidation not directly measured here"]},{"year":2010,"claim":"Addressed how ACACB transcription is regulated by showing a promoter polymorphism alters activity in an SREBP-1a-dependent, allele-specific manner with differential nuclear protein binding.","evidence":"Luciferase reporter assays in HepG2 cells, EMSA competition, and mass spectrometry of shifted bands","pmids":["20799892"],"confidence":"Medium","gaps":["Identity of the allele-specific binding proteins (GATA, c-Myb, GR implicated) not confirmed by mass spectrometry","Whether SREBP-1a binds the promoter directly or acts indirectly is unresolved"]},{"year":2018,"claim":"Identified ACACB protein as a direct cellular target of an environmental contaminant, providing a molecular basis for PFOA-associated lipid metabolism disruption.","evidence":"Competitive cysteine-reactive chemical proteomics (IAA/EBX probes), PRM targeted proteomics, and thermal shift assay with targeted metabolomics","pmids":["30134650"],"confidence":"Medium","gaps":["Functional effect of PFOA binding on carboxylase catalytic activity not quantified","Specific cysteine residue(s) engaged not pinpointed"]},{"year":2025,"claim":"Placed ACACB downstream of GPER1 in a pathway influencing vascular endothelial cell senescence.","evidence":"siRNA knockdown of GPER1 in cultured endothelial cells with ACACB expression and senescence marker readouts","pmids":["40131497"],"confidence":"Low","gaps":["Single knockdown experiment reported in abstract with limited mechanistic detail","Whether ACACB regulation is direct or how it mediates senescence is unknown"]},{"year":2026,"claim":"Defined a PKA/ACACB/CPT1A signaling axis in astrocytes, connecting ACACB activity to beta-oxidation, lipid droplet clearance, and mitochondrial function.","evidence":"ACACB knockdown/overexpression and CPT1A overexpression in Abeta1-42-induced astrocytes plus APP/PS1 mouse model with mitochondrial and lipid readouts","pmids":["42063966"],"confidence":"Medium","gaps":["Direct PKA phosphorylation of ACACB not demonstrated biochemically","Relationship to AMPK/Ser221 regulation not addressed"]},{"year":null,"claim":"How the multiple regulatory inputs (AMPK phosphorylation, PKA signaling, SREBP-1a transcriptional control, PFOA binding) are integrated to set ACACB catalytic output and malonyl-CoA levels in vivo remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of ACACB regulation in the corpus","Quantitative coupling between phosphorylation state and carboxylase activity not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,3]}],"localization":[],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,2,3]}],"complexes":[],"partners":["AMPK","SREBP-1A","CPT1A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O00763","full_name":"Acetyl-CoA carboxylase 2","aliases":["ACC-beta"],"length_aa":2458,"mass_kda":276.5,"function":"Mitochondrial enzyme that catalyzes the carboxylation of acetyl-CoA to malonyl-CoA and plays a central role in fatty acid metabolism (PubMed:16854592, PubMed:19236960, PubMed:19900410, PubMed:20457939, PubMed:20952656, PubMed:26976583). Catalyzes a 2 steps reaction starting with the ATP-dependent carboxylation of the biotin carried by the biotin carboxyl carrier (BCC) domain followed by the transfer of the carboxyl group from carboxylated biotin to acetyl-CoA (PubMed:19236960, PubMed:20457939, PubMed:20952656, PubMed:26976583). Through the production of malonyl-CoA that allosterically inhibits carnitine palmitoyltransferase 1 at the mitochondria, negatively regulates fatty acid oxidation (By similarity). Together with its cytosolic isozyme ACACA, which is involved in de novo fatty acid biosynthesis, promotes lipid storage (By similarity)","subcellular_location":"Mitochondrion","url":"https://www.uniprot.org/uniprotkb/O00763/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ACACB","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ACACB","total_profiled":1310},"omim":[{"mim_id":"610762","title":"HIGH DENSITY LIPOPROTEIN CHOLESTEROL LEVEL QUANTITATIVE TRAIT LOCUS 6; HDLCQ6","url":"https://www.omim.org/entry/610762"},{"mim_id":"603328","title":"MUSASHI RNA BINDING PROTEIN 1; MSI1","url":"https://www.omim.org/entry/603328"},{"mim_id":"601557","title":"ACETYL-CoA CARBOXYLASE-BETA; ACACB","url":"https://www.omim.org/entry/601557"},{"mim_id":"301139","title":"ZINC FINGER PROTEIN 92; ZFP92","url":"https://www.omim.org/entry/301139"},{"mim_id":"300961","title":"MID1-INTERACTING PROTEIN 1; MID1IP1","url":"https://www.omim.org/entry/300961"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"adipose tissue","ntpm":171.9},{"tissue":"skeletal muscle","ntpm":160.4}],"url":"https://www.proteinatlas.org/search/ACACB"},"hgnc":{"alias_symbol":["HACC275","ACC2","ACCB","ACC-beta","ACCbeta","ACACbeta"],"prev_symbol":[]},"alphafold":{"accession":"O00763","domains":[{"cath_id":"3.30.1490.20","chopping":"434-495","consensus_level":"medium","plddt":84.274,"start":434,"end":495},{"cath_id":"3.30.470.20","chopping":"651-749_759-768","consensus_level":"medium","plddt":83.044,"start":651,"end":768},{"cath_id":"2.40.50.100","chopping":"893-970","consensus_level":"medium","plddt":81.8358,"start":893,"end":970},{"cath_id":"-","chopping":"993-1230","consensus_level":"medium","plddt":85.461,"start":993,"end":1230},{"cath_id":"-","chopping":"1253-1334_1364-1390_1419-1498","consensus_level":"medium","plddt":81.2699,"start":1253,"end":1498},{"cath_id":"2.40.460.10","chopping":"1839-1884_1897-1902","consensus_level":"medium","plddt":86.3498,"start":1839,"end":1902},{"cath_id":"3.90.226.10","chopping":"2026-2225","consensus_level":"medium","plddt":92.6222,"start":2026,"end":2225},{"cath_id":"-","chopping":"2229-2302","consensus_level":"medium","plddt":89.8489,"start":2229,"end":2302},{"cath_id":"-","chopping":"2328-2451","consensus_level":"medium","plddt":81.3939,"start":2328,"end":2451},{"cath_id":"3.30.700","chopping":"770-800_813-891_973-988","consensus_level":"medium","plddt":84.9166,"start":770,"end":988}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O00763","model_url":"https://alphafold.ebi.ac.uk/files/AF-O00763-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O00763-F1-predicted_aligned_error_v6.png","plddt_mean":78.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ACACB","jax_strain_url":"https://www.jax.org/strain/search?query=ACACB"},"sequence":{"accession":"O00763","fasta_url":"https://rest.uniprot.org/uniprotkb/O00763.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O00763/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O00763"}},"corpus_meta":[{"pmid":"12413941","id":"PMC_12413941","title":"Dissociation of AMPK activity and ACCbeta phosphorylation in human muscle during prolonged exercise.","date":"2002","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/12413941","citation_count":106,"is_preprint":false},{"pmid":"21908218","id":"PMC_21908218","title":"Association of ACACB polymorphisms with obesity and diabetes.","date":"2011","source":"Molecular genetics and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/21908218","citation_count":40,"is_preprint":false},{"pmid":"23081748","id":"PMC_23081748","title":"ACACβ gene (rs2268388) and AGTR1 gene (rs5186) polymorphism and the risk of nephropathy in Asian Indian patients with type 2 diabetes.","date":"2012","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23081748","citation_count":35,"is_preprint":false},{"pmid":"20519229","id":"PMC_20519229","title":"The acetyl-coenzyme A carboxylase beta (ACACB) gene is associated with nephropathy in Chinese patients with type 2 diabetes.","date":"2010","source":"Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association","url":"https://pubmed.ncbi.nlm.nih.gov/20519229","citation_count":34,"is_preprint":false},{"pmid":"17056747","id":"PMC_17056747","title":"Coordinate expression of the acetyl coenzyme A carboxylase genes, accB and accC, is necessary for normal regulation of biotin synthesis in Escherichia coli.","date":"2006","source":"Journal of bacteriology","url":"https://pubmed.ncbi.nlm.nih.gov/17056747","citation_count":33,"is_preprint":false},{"pmid":"30134650","id":"PMC_30134650","title":"Integrative Chemical Proteomics-Metabolomics Approach Reveals Acaca/Acacb as Direct Molecular Targets of PFOA.","date":"2018","source":"Analytical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30134650","citation_count":24,"is_preprint":false},{"pmid":"29521460","id":"PMC_29521460","title":"Genetic association of the ACACB gene with milk yield and composition traits in dairy cattle.","date":"2018","source":"Animal genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29521460","citation_count":17,"is_preprint":false},{"pmid":"36111743","id":"PMC_36111743","title":"ACACB is a novel metabolism-related biomarker in the prediction of response to cetuximab therapy inmetastatic colorectal cancer.","date":"2022","source":"Acta biochimica et biophysica Sinica","url":"https://pubmed.ncbi.nlm.nih.gov/36111743","citation_count":12,"is_preprint":false},{"pmid":"20799892","id":"PMC_20799892","title":"Functional single-nucleotide polymorphism in acetyl-CoA carboxylase ACACB gene promoter.","date":"2010","source":"DNA and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/20799892","citation_count":7,"is_preprint":false},{"pmid":"26030797","id":"PMC_26030797","title":"The ACACB gene rs2268388 polymorphism is associated with nephropathy in Caucasian patients with diabetes: a meta-analysis.","date":"2015","source":"Renal failure","url":"https://pubmed.ncbi.nlm.nih.gov/26030797","citation_count":6,"is_preprint":false},{"pmid":"20602615","id":"PMC_20602615","title":"Physiogenomic analysis of statin-treated patients: domain-specific counter effects within the ACACB gene on low-density lipoprotein cholesterol?","date":"2010","source":"Pharmacogenomics","url":"https://pubmed.ncbi.nlm.nih.gov/20602615","citation_count":6,"is_preprint":false},{"pmid":"35344865","id":"PMC_35344865","title":"Crystal structure of Acetyl-CoA carboxylase (AccB) from Streptomyces antibioticus and insights into the substrate-binding through in silico mutagenesis and biophysical investigations.","date":"2022","source":"Computers in biology and medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35344865","citation_count":4,"is_preprint":false},{"pmid":"38287712","id":"PMC_38287712","title":"Improving the substrate binding of acetyl-CoA carboxylase (AccB) from Streptomyces antibioticus through computational enzyme engineering.","date":"2024","source":"Biotechnology and applied biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38287712","citation_count":3,"is_preprint":false},{"pmid":"40131497","id":"PMC_40131497","title":"GPER1/ACACB are potential target genes associated with intracranial aneurysm and vascular endothelial cell senescence.","date":"2025","source":"Neurosurgical review","url":"https://pubmed.ncbi.nlm.nih.gov/40131497","citation_count":1,"is_preprint":false},{"pmid":"42063966","id":"PMC_42063966","title":"Oleic acid improves pathological changes in Aβ1-42-induced astrocytes and Alzheimer's disease mouse models through PKA/ACACB/CPT1A.","date":"2026","source":"Frontiers in neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/42063966","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9930,"output_tokens":1399,"usd":0.025388,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8113,"output_tokens":2049,"usd":0.045895,"stage2_stop_reason":"end_turn"},"total_usd":0.071283,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"AMPK (alpha2 subunit) phosphorylates ACCbeta at Ser221 during exercise in human skeletal muscle, but ACCbeta Ser221 phosphorylation peaked at 1h and returned to resting levels at exhaustion despite continued increases in alpha2 AMPK activity, demonstrating a dissociation between AMPK activity and ACCbeta phosphorylation state during prolonged exercise.\",\n      \"method\": \"Phospho-specific immunoblotting of muscle biopsies during prolonged exercise; measurement of alpha1 and alpha2 AMPK activity\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct phosphorylation site identified in human muscle biopsies with time-course, single lab, two orthogonal measurements (kinase activity + phospho-blot)\",\n      \"pmids\": [\"12413941\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"A single-nucleotide polymorphism -368 C/T (rs16939972) in the ACACB promoter P-II affects promoter activity in an allele-specific manner; the T-allele construct showed significantly lower activity than the C-allele only in the presence of SREBP-1a overexpression, and EMSA showed higher affinity nuclear protein binding to the T-allele probe. Competition assays implicated GATA, c-Myb, and GR binding sites, though these proteins were not detected by mass spectrometry of shifted bands.\",\n      \"method\": \"Luciferase reporter transfection in HepG2 cells; EMSA with competition assays; mass spectrometry of gel extracts\",\n      \"journal\": \"DNA and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional reporter assay combined with EMSA, single lab, two orthogonal methods but identity of binding proteins unresolved\",\n      \"pmids\": [\"20799892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PFOA directly binds Acacb (and Acaca) protein in a cellular context, as identified by competitive cysteine-reactive chemical proteomics using iodoacetamide alkyne and EBX probes, verified by parallel reaction monitoring targeted proteomics and thermal shift assay; this binding was associated with abnormal fatty acid metabolism.\",\n      \"method\": \"Competitive cysteine-targeting chemical proteomics (IAA and EBX probes), PRM-based targeted proteomics, thermal shift assay, targeted metabolomics\",\n      \"journal\": \"Analytical chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal chemical proteomics methods in a single study, single lab\",\n      \"pmids\": [\"30134650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Oleic acid modulates ACACB (ACC2) activity through PKA signaling in astrocytes, leading to increased CPT1A-dependent fatty acid beta-oxidation, reduced lipid droplet accumulation, and restored mitochondrial membrane potential; ACACB knockdown/overexpression and CPT1A overexpression experiments confirmed the PKA/ACACB/CPT1A pathway axis.\",\n      \"method\": \"ACACB knockdown/overexpression and CPT1A overexpression in Abeta1-42-induced astrocytes; APP/PS1 mouse model with dietary OA supplementation; mitochondrial membrane potential assay; ATP measurement; lipid droplet quantification\",\n      \"journal\": \"Frontiers in neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function and gain-of-function in cell and mouse models with specific metabolic readouts, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"42063966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GPER1 silencing decreased ACACB expression and accelerated endothelial cell senescence in vitro, placing ACACB downstream of GPER1 in a pathway regulating vascular endothelial cell senescence.\",\n      \"method\": \"siRNA knockdown of GPER1 in cultured vascular endothelial cells with measurement of ACACB expression and senescence markers\",\n      \"journal\": \"Neurosurgical review\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single knockdown experiment reported in abstract with limited mechanistic detail, single lab\",\n      \"pmids\": [\"40131497\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ACACB (ACC2/ACCbeta) is a mitochondria-associated acetyl-CoA carboxylase that is phosphorylated and inhibited by AMPK at Ser221 to regulate fatty acid beta-oxidation via malonyl-CoA production and CPT1 inhibition; its promoter activity is controlled by SREBP-1a binding in an allele-dependent manner; it is directly bound by the environmental pollutant PFOA; and its activity is modulated downstream of PKA signaling and upstream of CPT1A in the control of astrocytic fatty acid oxidation, with its expression additionally regulated downstream of GPER1 in vascular endothelial cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ACACB (ACC2/ACCbeta) is an acetyl-CoA carboxylase whose activity governs fatty acid beta-oxidation, positioning it as a metabolic control point across muscle, astrocytic, and vascular tissues [#0, #3]. During exercise in human skeletal muscle, the AMPK alpha2 subunit phosphorylates ACCbeta at Ser221, although phosphorylation state can dissociate from AMPK activity over prolonged exertion [#0]. In astrocytes, ACACB operates within a PKA/ACACB/CPT1A axis: oleic acid acting through PKA modulates ACACB to increase CPT1A-dependent beta-oxidation, reduce lipid droplet accumulation, and restore mitochondrial membrane potential [#3]. Transcriptionally, a -368 C/T polymorphism in the ACACB promoter P-II alters promoter activity in an allele-specific manner dependent on SREBP-1a, with differential nuclear protein binding to the two alleles [#1]. ACACB protein is also a direct cellular binding target of the environmental pollutant PFOA, an interaction associated with abnormal fatty acid metabolism [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established the regulatory phosphorylation event linking energy sensing to ACCbeta by identifying AMPK alpha2-mediated phosphorylation at Ser221, and revealed that phosphorylation state can uncouple from kinase activity during prolonged exercise.\",\n      \"evidence\": \"Phospho-specific immunoblotting of human muscle biopsies with AMPK activity time-course during prolonged exercise\",\n      \"pmids\": [\"12413941\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism causing dissociation of Ser221 phosphorylation from AMPK activity is unresolved\",\n        \"Functional consequence on malonyl-CoA output and beta-oxidation not directly measured here\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Addressed how ACACB transcription is regulated by showing a promoter polymorphism alters activity in an SREBP-1a-dependent, allele-specific manner with differential nuclear protein binding.\",\n      \"evidence\": \"Luciferase reporter assays in HepG2 cells, EMSA competition, and mass spectrometry of shifted bands\",\n      \"pmids\": [\"20799892\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Identity of the allele-specific binding proteins (GATA, c-Myb, GR implicated) not confirmed by mass spectrometry\",\n        \"Whether SREBP-1a binds the promoter directly or acts indirectly is unresolved\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified ACACB protein as a direct cellular target of an environmental contaminant, providing a molecular basis for PFOA-associated lipid metabolism disruption.\",\n      \"evidence\": \"Competitive cysteine-reactive chemical proteomics (IAA/EBX probes), PRM targeted proteomics, and thermal shift assay with targeted metabolomics\",\n      \"pmids\": [\"30134650\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional effect of PFOA binding on carboxylase catalytic activity not quantified\",\n        \"Specific cysteine residue(s) engaged not pinpointed\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed ACACB downstream of GPER1 in a pathway influencing vascular endothelial cell senescence.\",\n      \"evidence\": \"siRNA knockdown of GPER1 in cultured endothelial cells with ACACB expression and senescence marker readouts\",\n      \"pmids\": [\"40131497\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Single knockdown experiment reported in abstract with limited mechanistic detail\",\n        \"Whether ACACB regulation is direct or how it mediates senescence is unknown\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Defined a PKA/ACACB/CPT1A signaling axis in astrocytes, connecting ACACB activity to beta-oxidation, lipid droplet clearance, and mitochondrial function.\",\n      \"evidence\": \"ACACB knockdown/overexpression and CPT1A overexpression in Abeta1-42-induced astrocytes plus APP/PS1 mouse model with mitochondrial and lipid readouts\",\n      \"pmids\": [\"42063966\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct PKA phosphorylation of ACACB not demonstrated biochemically\",\n        \"Relationship to AMPK/Ser221 regulation not addressed\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the multiple regulatory inputs (AMPK phosphorylation, PKA signaling, SREBP-1a transcriptional control, PFOA binding) are integrated to set ACACB catalytic output and malonyl-CoA levels in vivo remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of ACACB regulation in the corpus\",\n        \"Quantitative coupling between phosphorylation state and carboxylase activity not established\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 2, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"AMPK\", \"SREBP-1a\", \"CPT1A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}