{"id":"aa5da90d-9d3e-5427-8eaa-1fd1b857f09a","stable_key":"b26c9d01-98fd-50d3-8f39-44db46961ee5:acetate-exogenous-acetate-sparing","predicate":"limits","statement":"Exogenous acetate uptake is controlled by expression of both ACSS2 and the mitochondrial ACSS1, and the mitochondrial and lipogenic demand for two-carbon acetyl units considerably exceeds the uptake of exogenous acetate, leaving it to only sparingly contribute to histone acetylation.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"negative","is_public":true,"mechanism_event_id":"2b185efa-3da5-5526-871d-ab8e8b21043e","mechanism_event_label":"Acetate taken in from outside is mostly burned or built into fat; very little of it reaches the histones.","subject":{"id":"05ebe667-4516-5bcd-9266-b9235a17c8f0","slug":"exogenous-acetate-uptake","display_name":"Uptake of acetate from outside the cell","entity_type_key":"cellular_process"},"object":{"id":"ec8d4882-1462-5107-8400-367298f439e1","slug":"histone-acetylation","display_name":"Core histone lysine acetylation","entity_type_key":"cellular_process"},"evidence_count":1,"mechanism_event":{"id":"2b185efa-3da5-5526-871d-ab8e8b21043e","stable_key":"b26c9d01-98fd-50d3-8f39-44db46961ee5:acetate-exogenous-acetate-sparing-event","event_type":"biochemical_relationship","label":"Acetate taken in from outside is mostly burned or built into fat; very little of it reaches the histones.","description":"Exogenous acetate uptake is controlled by expression of both ACSS2 and the mitochondrial ACSS1, and the mitochondrial and lipogenic demand for two-carbon acetyl units considerably exceeds the uptake of exogenous acetate, leaving it to only sparingly contribute to histone acetylation.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"64044850-0d45-5593-9a51-fa645679f99b","slug":"acss2","display_name":"Human acetyl-CoA synthetase 2 / ACSS2","entity_type_key":"protein"},"role":"uptake_enzyme","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"38c58a6d-e55c-5fac-b3b0-696e88823fbd","slug":"acss1","display_name":"Mitochondrial acetyl-CoA synthetase 1 / ACSS1","entity_type_key":"protein"},"role":"uptake_enzyme","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"e366e758-1fb0-5573-aed1-34f6df874ac7","slug":"acetate","display_name":"Acetate","entity_type_key":"small_molecule"},"role":"limiting_substrate","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""},{"entity":{"id":"61ff7226-64b4-5ea6-954e-d6b1192f155d","slug":"de-novo-lipogenesis","display_name":"De novo lipogenesis","entity_type_key":"cellular_process"},"role":"competing_demand","stoichiometry":null,"state_label":"","sequence_order":3,"notes":""},{"entity":{"id":"05ebe667-4516-5bcd-9266-b9235a17c8f0","slug":"exogenous-acetate-uptake","display_name":"Uptake of acetate from outside the cell","entity_type_key":"cellular_process"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":4,"notes":""},{"entity":{"id":"ec8d4882-1462-5107-8400-367298f439e1","slug":"histone-acetylation","display_name":"Core histone lysine acetylation","entity_type_key":"cellular_process"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":5,"notes":""}]},"contexts":[{"dimension":"evidence_span","value_text":"{\"source_cache\": \"artifacts/acetate-research/28099844.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"6df5e8ccde04ad8a222db774f6a8b1e8838ad6a1d918ff84b667d6dde57de188\", \"start_char\": 0, \"end_char\": 1134, \"text_sha256\": \"6df5e8ccde04ad8a222db774f6a8b1e8838ad6a1d918ff84b667d6dde57de188\"}","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Quantitative analysis of acetate metabolism in cultured cells under oxygen and serum limitation","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"Exogenous acetate with ACSS2 and ACSS1 manipulation under oxygen and serum limitation","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"The quantitative accounting here is the important part and it is a limiting result: demand for two-carbon units far exceeds what exogenous acetate supplies. Cultured cells at a given acetate concentration, which is not a fed human.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient_topic","value_text":"Acetic acid research collection; topical membership is not evidence of a direct clinical effect, and the ingested acid is recorded separately from the circulating acetate anion.","comparator":null,"unit":null,"notes":"","entity":{"slug":"acetic-acid","display_name":"Acetic acid","entity_type_key":"chemical_species"}},{"dimension":"organism","value_text":"Cultured cells","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"Acetate taken in from outside is mostly burned or built into fat; very little of it reaches the histones.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[acetate-p28099844] Acetate Recapturing by Nuclear Acetyl-CoA Synthetase 2 Prevents Loss of Histone Acetylation during Oxygen and Serum Limitation. (2017). https://pubmed.ncbi.nlm.nih.gov/28099844/ DOI: 10.1016/j.celrep.2016.12.055","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"Nucleus and cytosol","comparator":null,"unit":null,"notes":"","entity":null}],"evidence":[{"id":"af6d4097-c640-5ba2-a36c-f3b0dea53d65","evidence_kind":"source_excerpt","locator":"Lines 589-600","start_line":589,"end_line":600,"excerpt":"### acetate-exogenous-acetate-sparing\nExogenous acetate uptake is controlled by expression of both ACSS2 and the mitochondrial ACSS1, and the mitochondrial and lipogenic demand for two-carbon acetyl units considerably exceeds the uptake of exogenous acetate, leaving it to only sparingly contribute to histone acetylation.\nCondition category: normal\nnutrient_topic: Acetic acid research collection; topical membership is not evidence of a direct clinical effect, and the ingested acid is recorded separately from the circulating acetate anion.\nplain_language: Acetate taken in from outside is mostly burned or built into fat; very little of it reaches the histones.\norganism: Cultured cells\ntissue_or_cell_type: Nucleus and cytosol\nexperimental_model: Quantitative analysis of acetate metabolism in cultured cells under oxygen and serum limitation\nlimitations: The quantitative accounting here is the important part and it is a limiting result: demand for two-carbon units far exceeds what exogenous acetate supplies. Cultured cells at a given acetate concentration, which is not a fed human.\nexposure: Exogenous acetate with ACSS2 and ACSS1 manipulation under oxygen and serum limitation\nevidence_span: {\"source_cache\": \"artifacts/acetate-research/28099844.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"6df5e8ccde04ad8a222db774f6a8b1e8838ad6a1d918ff84b667d6dde57de188\", \"start_char\": 0, \"end_char\": 1134, \"text_sha256\": \"6df5e8ccde04ad8a222db774f6a8b1e8838ad6a1d918ff84b667d6dde57de188\"}\n[acetate-p28099844] Acetate Recapturing by Nuclear Acetyl-CoA Synthetase 2 Prevents Loss of Histone Acetylation during Oxygen and Serum Limitation. (2017). https://pubmed.ncbi.nlm.nih.gov/28099844/ DOI: 10.1016/j.celrep.2016.12.055","model_system":"Quantitative analysis of acetate metabolism in cultured cells under oxygen and serum limitation","directness":"author_interpretation","verification_status":"source_derived_draft","notes":"Exact curation-document quotation, not publisher quotation. Study references: [acetate-p28099844] Acetate Recapturing by Nuclear Acetyl-CoA Synthetase 2 Prevents Loss of Histone Acetylation during Oxygen and Serum Limitation. (2017). https://pubmed.ncbi.nlm.nih.gov/28099844/ DOI: 10.1016/j.celrep.2016.12.055","relationship":"supports","weight":1.0,"link_notes":"","source":{"id":"8356baaf-173c-5549-80cd-bbbb2007ffb5","stable_key":"import-b26c9d01-98fd-50d3-8f39-44db46961ee5","title":"Acetic acid: the ingested acid, the receptors acetate binds, the acetyl-CoA it becomes, and the acetyl groups that reach histones (2026-09-21)","document_type":"imported_text","citation_label":"AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text.","file_path":"","sha256":"1441d249b16db25c0d488407e5cc881222acffc2f16af88cb3197d9d5697bccc","revision_id":"9bfeb605-f589-5e99-84b9-e56968a3bc1f","review_status":"unverified_draft","notes":""}}],"relations":[],"conflicts":[{"id":"c2beddd7-ebce-5226-93f4-ce8edbd28098","title":"Does acetate taken in from outside the cell reach histones in a quantity that matters?","kind":"qualification","status":"open","why":"Quantitative accounting in cultured cells found that mitochondrial and lipogenic demand for two-carbon acetyl units considerably exceeds the uptake of exogenous acetate, leaving it to contribute only sparingly to histone acetylation; in that system the enzyme maintains histone acetylation mainly by recapturing acetate already released from histones. Against that, in vivo isotope labelling in mice placed acetyl groups derived from alcohol and from injected labelled acetate directly onto brain histones, and a single large oral dose of an acetate precursor in rats raised three specific brain histone marks. The conditions differ sharply: cultured cells at a fixed acetate concentration against whole animals given alcohol or a 6 g/kg precursor dose, which produce far higher blood acetate than a meal does. The rat study also found the marks rose because deacetylation slowed rather than because acetylation increased, which is a different mechanism again. Whether ordinary dietary acetate reaches histones in any meaningful quantity is not settled by these records.","resolution":"Unresolved; needs review.","created_at":"2026-09-22 01:55:55","record_type":"conflict","display_label":"Recorded conflict","record_url":"/conflicts/c2beddd7-ebce-5226-93f4-ce8edbd28098","sides":[{"conflict_id":"c2beddd7-ebce-5226-93f4-ce8edbd28098","ordinal":0,"label":"Acetate taken in from outside is mostly burned or built into fat; very little of it reaches the histones.","revision_id":"9bfeb605-f589-5e99-84b9-e56968a3bc1f","start_line":589,"end_line":600,"quote":"### acetate-exogenous-acetate-sparing\nExogenous acetate uptake is controlled by expression of both ACSS2 and the mitochondrial ACSS1, and the mitochondrial and lipogenic demand for two-carbon acetyl units considerably exceeds the uptake of exogenous acetate, leaving it to only sparingly contribute to histone acetylation.\nCondition category: normal\nnutrient_topic: Acetic acid research collection; topical membership is not evidence of a direct clinical effect, and the ingested acid is recorded separately from the circulating acetate anion.\nplain_language: Acetate taken in from outside is mostly burned or built into fat; very little of it reaches the histones.\norganism: Cultured cells\ntissue_or_cell_type: Nucleus and cytosol\nexperimental_model: Quantitative analysis of acetate metabolism in cultured cells under oxygen and serum limitation\nlimitations: The quantitative accounting here is the important part and it is a limiting result: demand for two-carbon units far exceeds what exogenous acetate supplies. Cultured cells at a given acetate concentration, which is not a fed human.\nexposure: Exogenous acetate with ACSS2 and ACSS1 manipulation under oxygen and serum limitation\nevidence_span: {\"source_cache\": \"artifacts/acetate-research/28099844.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"6df5e8ccde04ad8a222db774f6a8b1e8838ad6a1d918ff84b667d6dde57de188\", \"start_char\": 0, \"end_char\": 1134, \"text_sha256\": \"6df5e8ccde04ad8a222db774f6a8b1e8838ad6a1d918ff84b667d6dde57de188\"}\n[acetate-p28099844] Acetate Recapturing by Nuclear Acetyl-CoA Synthetase 2 Prevents Loss of Histone Acetylation during Oxygen and Serum Limitation. (2017). https://pubmed.ncbi.nlm.nih.gov/28099844/ DOI: 10.1016/j.celrep.2016.12.055","source_key":"import-b26c9d01-98fd-50d3-8f39-44db46961ee5","source_title":"Acetic acid: the ingested acid, the receptors acetate binds, the acetyl-CoA it becomes, and the acetyl groups that reach histones (2026-09-21)","claim_ids":["aa5da90d-9d3e-5427-8eaa-1fd1b857f09a"]},{"conflict_id":"c2beddd7-ebce-5226-93f4-ce8edbd28098","ordinal":1,"label":"Atoms from the drink end up on the proteins that package DNA in the brain.","revision_id":"9bfeb605-f589-5e99-84b9-e56968a3bc1f","start_line":615,"end_line":626,"quote":"### acetate-alcohol-to-brain-histones\nUsing in vivo stable-isotope labelling in mice, the metabolism of alcohol contributed to rapid acetylation of histones in the brain, in part through direct deposition of acetyl groups derived from alcohol onto histones in an ACSS2-dependent manner, and a similar direct deposition was observed when mice were injected with heavy-labelled acetate in vivo.\nCondition category: normal\nnutrient_topic: Acetic acid research collection; topical membership is not evidence of a direct clinical effect, and the ingested acid is recorded separately from the circulating acetate anion.\nplain_language: Atoms from the drink end up on the proteins that package DNA in the brain.\norganism: Mouse\ntissue_or_cell_type: Brain and gestating fetus\nexperimental_model: In vivo stable-isotope labelling in mice, with primary hippocampal neurons and behavioural testing\nlimitations: Isotope labelling traces the actual carbon atoms onto histones, which is stronger than correlating acetylation with exposure. A mouse study; the fetal result is a single reported exposure.\nexposure: Labelled alcohol or heavy-labelled acetate administered in vivo, with ACSS2 inhibition and deletion\nevidence_span: {\"source_cache\": \"artifacts/acetate-research/31645761.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"a7a812a410fd8be3bad8512ab46d4b8a7fd3329d1552ee30965b66860eeb2b2f\", \"start_char\": 0, \"end_char\": 1646, \"text_sha256\": \"a7a812a410fd8be3bad8512ab46d4b8a7fd3329d1552ee30965b66860eeb2b2f\"}\n[acetate-p31645761] Alcohol metabolism contributes to brain histone acetylation. (2019). https://pubmed.ncbi.nlm.nih.gov/31645761/ DOI: 10.1038/s41586-019-1700-7","source_key":"import-b26c9d01-98fd-50d3-8f39-44db46961ee5","source_title":"Acetic acid: the ingested acid, the receptors acetate binds, the acetyl-CoA it becomes, and the acetyl groups that reach histones (2026-09-21)","claim_ids":["9c663765-1b21-5c17-ba13-d55199602ba6"]},{"conflict_id":"c2beddd7-ebce-5226-93f4-ce8edbd28098","ordinal":2,"label":"Three specific marks on brain histones went up for a few hours; the rest, and the liver, did not move.","revision_id":"9bfeb605-f589-5e99-84b9-e56968a3bc1f","start_line":654,"end_line":665,"quote":"### acetate-acetate-brain-histones\nA single oral dose of glyceryl triacetate increased the acetylation state of brain histone H4 at lysine 8 at 2 and 4 hours, histone H4 at lysine 16 at 4 and 24 hours, and histone H3 at lysine 9 at 4 hours, with no changes in other forms of brain or liver H3 and H4 acetylation state at any time measured.\nCondition category: normal\nnutrient_topic: Acetic acid research collection; topical membership is not evidence of a direct clinical effect, and the ingested acid is recorded separately from the circulating acetate anion.\nplain_language: Three specific marks on brain histones went up for a few hours; the rest, and the liver, did not move.\norganism: Rat\ntissue_or_cell_type: Brain and liver\nexperimental_model: Time-course Western blot analysis of brain and liver histone acetylation in rats after a single oral dose\nlimitations: A large single dose of a precursor, not dietary acetate. The mechanism is loss of deacetylation rather than added acetylation, and only some marks moved.\nexposure: A single oral dose of 6 g/kg glyceryl triacetate, an acetate precursor\nevidence_span: {\"source_cache\": \"artifacts/acetate-research/21359531.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"a60e30b6fa78f5fc4d9da17279ec1ecc29dd20939df5771ba26996900102014b\", \"start_char\": 0, \"end_char\": 1456, \"text_sha256\": \"a60e30b6fa78f5fc4d9da17279ec1ecc29dd20939df5771ba26996900102014b\"}\n[acetate-p21359531] Acetate supplementation increases brain histone acetylation and inhibits histone deacetylase activity and expression. (2011). https://pubmed.ncbi.nlm.nih.gov/21359531/ DOI: 10.1007/s11010-011-0751-3","source_key":"import-b26c9d01-98fd-50d3-8f39-44db46961ee5","source_title":"Acetic acid: the ingested acid, the receptors acetate binds, the acetyl-CoA it becomes, and the acetyl groups that reach histones (2026-09-21)","claim_ids":["4916fe61-cf4b-5b4b-a548-9952388df2d3"]}]}],"corrections":[],"research":null}