Affinage

ACACA

Acetyl-CoA carboxylase 1 · UniProt Q13085

Length
2346 aa
Mass
265.6 kDa
Annotated
2026-06-09
36 papers in source corpus 12 papers cited in narrative 13 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ACACA (ACC1/ACCα) catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the committed step of de novo fatty acid synthesis, and its activity governs cellular lipid homeostasis, mitochondrial function, and the balance between fatty acid synthesis and oxidation (PMID:34552920, PMID:33391420, PMID:38395901). Its hepatic transcription is induced through cooperative binding of SREBP-1 and the thyroid hormone receptor at the ACACA promoter, an effect potentiated by T3 and insulin and suppressed by cAMP and medium-chain fatty acids acting through a defined cis-element (-101 to -71 bp) (PMID:12576518); the gene's 5' end lies in a CpG island containing a bidirectional promoter shared with the divergently transcribed TADA2L gene (PMID:15607423). ACACA is additionally controlled post-transcriptionally and post-translationally: the RNA-binding protein ZXDB recruits EIF4A3 to the ACACA 5'UTR to enhance its translation (PMID:41873808), the transcription factor IRX1 together with nuclear NME1 represses its transcription (PMID:42225620), and the environmental pollutant PFOA binds ACACA at reactive cysteines (PMID:30134650). Functionally, ACACA activity sustains mitochondrial ATP production, mtDNA levels, and redox balance while restraining the AMPK–PPARα–CPT1A fatty acid oxidation axis (PMID:33391420, PMID:38395901); loss of ACACA elsewhere drives pathological phenotypes including a senescent SASP state in fibroblasts that recruits myeloid-derived suppressor cells to seed an immunosuppressive pre-metastatic niche (PMID:36607556) and, in androgen-receptor-independent prostate cancer, activation of the cPLA2–arachidonic acid–NF-κB inflammatory axis that promotes metastasis (PMID:40713618). Biallelic loss-of-function mutations in ACACA reduce enzyme activity and cause a neurodevelopmental syndrome with global developmental delay, microcephaly, and hypotonia, with a cell-motility defect partially rescued by palmitate (PMID:34552920).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 2002 Medium

    Established how hormonal and nutritional signals converge on the ACACA promoter, identifying SREBP-1/TR cooperativity as the activating axis and a discrete cis-element mediating cAMP/medium-chain-fatty-acid repression.

    Evidence Reporter/transfection assays and SREBP-1 protein time-courses in hepatocytes under T3, insulin, cAMP, and hexanoate

    PMID:12576518

    Open questions at the time
    • Limited to hepatocytes; tissue generality untested
    • Does not address post-transcriptional regulation
    • Endogenous chromatin occupancy of SREBP-1/TR not directly mapped
  2. 2005 Medium

    Defined the genomic architecture of ACACA transcription, showing it shares a bidirectional CpG-island promoter with TADA2L and that asymmetric expression is set by Pol II clearance/elongation rather than promoter sequence alone.

    Evidence Cross-species 5' boundary delineation, Pol II ChIP in mouse brain vs. liver, transcript quantification

    PMID:15607423

    Open questions at the time
    • Mechanism controlling differential Pol II elongation unresolved
    • Functional consequence of TADA2L co-regulation for ACACA unclear
  3. 2018 High

    Showed that ACACA is a direct molecular target of an environmental pollutant, providing a chemical basis for PFOA-induced fatty acid metabolism abnormalities.

    Evidence Cysteine-reactive chemical proteomics with PRM and thermal shift validation

    PMID:30134650

    Open questions at the time
    • Specific reactive cysteine residues and effect on catalytic activity not fully resolved
    • Physiological relevance of binding stoichiometry untested
  4. 2021 High

    Linked ACACA loss-of-function to a human Mendelian neurodevelopmental syndrome and demonstrated that its lipid output supports cell motility, establishing a causal genotype-phenotype connection.

    Evidence Whole-exome sequencing, patient-cell enzyme assays, lipidomics, RNAi recapitulation, and palmitate rescue

    PMID:34552920

    Open questions at the time
    • Mechanism connecting reduced fatty acid synthesis to neurodevelopment not defined
    • How palmitate restores motility molecularly unresolved
  5. 2021 Medium

    Connected ACACA activity to mitochondrial bioenergetics and redox state in cancer cells, beyond its canonical biosynthetic role.

    Evidence siRNA knockdown in prostate cancer cells with mito-ATP, mtDNA, MitoTracker, NAD+/NADH, ROS readouts and xenografts

    PMID:33391420

    Open questions at the time
    • Causal link between malonyl-CoA output and mtDNA maintenance unclear
    • Direct vs. indirect effect on mitochondria not separated
  6. 2023 High

    Revealed a non-cell-autonomous role: ACACA downregulation in fibroblasts induces senescence/SASP via reduced protein acetylation and lipid synthesis, recruiting MDSCs to build an immunosuppressive pre-metastatic niche.

    Evidence Transcriptomics, lipidomics, fibroblast–tumor co-culture, and an ACACA knock-in mouse rescuing lung metastasis

    PMID:36607556

    Open questions at the time
    • Source of acetyl-CoA limitation driving hypoacetylation not pinpointed
    • Which acetylated targets mediate the SASP unknown
  7. 2024 Medium

    Demonstrated reciprocal control of fatty acid oxidation: ACACA inhibition relieves the AMPK–PPARα–CPT1A axis to enhance oxidation and rescue lipid-overload mitochondrial dysfunction.

    Evidence siRNA plus CMS-121 inhibitor in a lipid-accumulation model with mitochondrial and AMPK/PPARα/CPT1A readouts and a high-fat-diet model

    PMID:38395901

    Open questions at the time
    • Whether AMPK activation is via malonyl-CoA depletion not directly proven
    • Tissue specificity of the response untested
  8. 2024 Medium

    Placed ACACA downstream of IL-17A/mTORC2 signaling in driving lipid-synthesis-dependent senescence and fibrosis in smooth muscle.

    Evidence PCR array, siRNA, metabolomics, and an in vivo neurogenic ED rat model with IL-17A antagonist

    PMID:39256772

    Open questions at the time
    • Direct mechanism linking mTORC2 to ACACA regulation undefined
    • Generalizability beyond cavernosum smooth muscle unknown
  9. 2024 Low

    Proposed AKR1B10 as a regulator of ACACA activity in hepatocytes relevant to NASH lipogenesis.

    Evidence Molecular docking, immunofluorescence co-localization, and ELISA-based malonyl-CoA assays in cell and rat NASH models

    PMID:38937844

    Open questions at the time
    • Co-localization and docking without direct co-IP validation of physical interaction
    • Mechanism by which AKR1B10 modulates ACACA activity unproven
  10. 2025 Medium

    Established epistasis placing ACACA upstream of the cPLA2–arachidonic acid–NF-κB axis, explaining how ACACA loss paradoxically promotes prostate cancer metastasis.

    Evidence shRNA/TOFA inhibition with transcriptomics, metabolomics, scRNA-seq, tail-vein metastasis, and rescue by cPLA2/NF-κB blockade

    PMID:40713618

    Open questions at the time
    • How reduced malonyl-CoA liberates arachidonic acid for cPLA2 not mechanistically defined
    • Restricted to AR-independent prostate cancer context
  11. 2026 Medium

    Identified post-transcriptional activation of ACACA: ZXDB recruits EIF4A3 to the 5'UTR to boost translation, coupling ACACA to macrophage inflammatory and glycolytic reprogramming.

    Evidence Co-IP with domain mapping, 5'UTR-dependent translation assay, and macrophage-specific Zxdb knockout in a sepsis-AKI model

    PMID:41873808

    Open questions at the time
    • Direct binding of ZXDB/EIF4A3 to the ACACA 5'UTR vs. indirect effect not fully separated
    • Whether translational control operates in non-macrophage cells unknown
  12. 2026 Medium

    Defined a transcriptional repression module in which IRX1 and nuclear NME1 downregulate ACACA to restrain de novo lipogenesis and breast cancer progression.

    Evidence Reciprocal co-IP, subcellular fractionation, reporter/ChIP for ACACA, and xenograft assays

    PMID:42225620

    Open questions at the time
    • Direct binding of IRX1/NME1 to the ACACA promoter region not finely mapped
    • Role of NME1 nucleotide-kinase activity in repression unclear

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the diverse upstream regulators (SREBP-1/TR, ZXDB/EIF4A3, IRX1/NME1, AKR1B10) are integrated to set ACACA output in a given tissue, and how malonyl-CoA depletion mechanistically rewires mitochondrial bioenergetics and eicosanoid signaling, remain unresolved.
  • No unified model integrating transcriptional, translational, and post-translational control
  • Structural basis of regulator binding and PFOA modification not determined
  • Causal chain from malonyl-CoA levels to downstream phenotypes incompletely defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 2 GO:0016874 ligase activity 1
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-1430728 Metabolism 3
Partners
AKR1B10EIF4A3IRX1SREBP-1THRAZXDB

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 SREBP-1 directly interacts with the thyroid hormone receptor (TR) on the ACCalpha (ACACA) gene promoter to enhance T3-induced transcription. Treatment with T3 or insulin increases mature SREBP-1 abundance, while cAMP or hexanoate suppresses this increase; inhibition of ACCalpha transcription by cAMP or hexanoate is mediated by sequences between -101 and -71 bp of the ACACA promoter. Transfection/reporter assays, time-course studies of SREBP-1 protein abundance in hepatocytes, pharmacological treatments (T3, insulin, cAMP, hexanoate) Journal of lipid research Medium 12576518
2005 The 5' end of ACACA is located within a CpG island that harbors a bidirectional promoter shared with the divergently oriented TADA2L gene; RNA polymerase II concentration within the intergenic region reflects tissue-specific abundance of both transcripts, but regulation of Pol II clearance from the promoter and elongation rate appear to be determinants of the asymmetric expression of ACACA and TADA2L transcripts. 5' boundary delineation across four species, RNA Pol II ChIP in mouse brain vs. liver, transcript quantification Genomics Medium 15607423
2018 ACACA (and ACACB) are direct binding targets of the environmental pollutant PFOA, identified by cysteine-reactive chemical proteomics probes; binding was verified by thermal shift assay and targeted proteomics (PRM), providing a mechanistic explanation for PFOA-induced abnormal fatty acid metabolism. Cysteine-targeting chemical proteomics (IAA and EBX probes), quantitative proteomics, parallel reaction monitoring (PRM), thermal shift assay, targeted metabolomics Analytical chemistry High 30134650
2021 Biallelic loss-of-function mutations in ACACA reduce ACC1 protein level and enzyme activity in patient-derived cells, causing disrupted lipid homeostasis (altered lipidomic profile), impaired cell motility, and a neurodevelopmental syndrome (global developmental delay, microcephaly, hypotonia). Cell motility deficit was recapitulated by RNAi-mediated ACC1 knockdown in fibroblasts and was partially rescued by palmitate supplementation. Whole-exome sequencing, ACC1 enzyme activity assay in patient lymphocytes, lipidomics, cell proliferation/apoptosis/migration assays, siRNA knockdown, palmitate rescue Frontiers in cell and developmental biology High 34552920
2021 ACACA knockdown in prostate cancer cells (DU145 and PC3) reduces proliferation, decreases mitochondrial ATP production, lowers mitochondrial DNA levels and MitoTracker staining, and elevates NAD+/NADH ratio and ROS levels, linking ACACA activity to mitochondrial function. siRNA knockdown, cell cycle and proliferation assays, mito-ATP measurement, mitochondrial staining (MitoTracker), mtDNA quantification, NAD+/NADH and ROS assays, xenograft tumor model Journal of Cancer Medium 33391420
2023 Downregulation of ACACA in lung fibroblasts reduces acetylation of protein lysine residues and fatty acid synthesis, triggers a senescent and inflammatory phenotypic shift (SASP), and enables CXCL1-mediated recruitment of granulocytic myeloid-derived suppressor cells into the lung, thereby promoting formation of an immunosuppressive pre-metastatic niche. ACACA knock-in prevented lung metastasis in the MMTV-PyVT mouse model. Transcriptomics (microarray), lipidomics (LC-MS/MS), co-culture of lung fibroblasts with breast cancer cells, immunoblot, IHC, qRT-PCR, senescence assays (SA-β-Gal), ACACA knock-in mouse model Cellular oncology High 36607556
2024 Inhibition of ACACA in a lipid accumulation cell model reduces intracellular TG and TC, alleviates mitochondrial dysfunction (preserving MMP, ATP production, reducing ROS), and enhances fatty acid oxidation via activation of the AMPK–PPARα–CPT1A pathway. siRNA knockdown, CMS-121 pharmacological inhibitor, lipid quantification, mitochondrial function assays (MMP, ATP, ROS, MRC complex expression), AMPK/PPARα/CPT1A western blotting, high-fat diet mouse model Journal of translational medicine Medium 38395901
2024 IL-17A activates the mTORC2–ACACA signaling pathway in corpus cavernosum smooth muscle cells (CSMCs), upregulating lipid synthesis and senescence transition, leading to increased secretion of fibro-matrix proteins and fibrosis; blockade of this signaling improved erectile function in a neurogenic ED rat model. PCR array, western blotting, immunofluorescence, IHC, non-target metabolomics, siRNA, SA-β-Gal staining, in vivo rat neurogenic ED model with IL-17A antagonist BMC medicine Medium 39256772
2024 AKR1B10 co-localizes with and regulates ACCα (ACACA) activity in hepatocytes; nicotinate-curcumin inhibits AKR1B10 binding to AKR1B10, reducing ACACA expression and activity, decreasing Malonyl-CoA levels, and thereby suppressing triglyceride and free fatty acid synthesis in NASH. Molecular docking, western blotting, immunofluorescence co-localization, ELISA (Acetyl-CoA and Malonyl-CoA activity), Ox-LDL-induced HepG2 cell model, rat NASH model Lipids in health and disease Low 38937844
2025 ACACA depletion in androgen receptor-independent prostate cancer cells (via shRNA or TOFA inhibitor) elevates arachidonic acid and eicosanoid levels, increases cPLA2 expression, and activates NF-κB signaling, thereby enhancing cell migration and metastasis. Inhibiting cPLA2 or NF-κB reversed these pro-metastatic effects, placing ACACA upstream of the cPLA2–AA–NF-κB axis. shRNA knockdown, TOFA pharmacological inhibition, transcriptomics, metabolomics, single-cell RNA sequencing, qPCR, western blotting, immunofluorescence, wound healing and transwell assays, mouse tail vein metastasis model, targeted cPLA2/NF-κB inhibition Cell communication and signaling Medium 40713618
2026 ZXDB (RNA-binding protein) directly interacts with EIF4A3 via its aa151–300 region and recruits EIF4A3 to the ACACA 5'UTR to enhance ACACA translation; macrophage-specific Zxdb deletion reduces ACACA expression, attenuates pro-inflammatory cytokine secretion and glycolytic reprogramming, and alleviates sepsis-induced acute kidney injury in mice. Co-IP (ZXDB–EIF4A3 interaction with domain mapping), 5'UTR-dependent translation assay, macrophage-specific Zxdb knockout mouse model, SI-AKI model, qPCR, western blotting FASEB journal Medium 41873808
2026 IRX1 transcription factor interacts with NME1 and promotes NME1 nuclear localization; nuclear NME1 then facilitates IRX1-mediated transcriptional downregulation of ACACA, thereby suppressing de novo fatty acid synthesis and breast cancer progression. IRX1 promoter hypermethylation causes its loss in breast cancer. Co-IP (IRX1–NME1), subcellular fractionation/localization, reporter/ChIP assays for ACACA transcription, in vitro and in vivo (xenograft) tumor growth assays, siRNA/overexpression Cell death & disease Medium 42225620
2025 CRISPRi screening identified ACACA as a key mediator of 1-deoxy-sphingolipid (1-deoxySL)-induced cellular toxicity; genetic knockdown validated that ACACA (involved in very long-chain fatty acid biosynthesis) modulates 1-deoxySL-induced cytotoxicity, mitochondrial toxicity, and neuronal toxicity. CRISPRi genome-wide screen, genetic knockdown validation, cytotoxicity assays, stable isotope-resolved lipidomics (LC-MS/MS) bioRxiv (preprint)preprint Low

Source papers

Stage 0 corpus · 36 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 MicroRNA-195 inhibits proliferation, invasion and metastasis in breast cancer cells by targeting FASN, HMGCR, ACACA and CYP27B1. Scientific reports 158 26632252
2024 ACACA reduces lipid accumulation through dual regulation of lipid metabolism and mitochondrial function via AMPK- PPARα- CPT1A axis. Journal of translational medicine 90 38395901
2002 SREBP-1 integrates the actions of thyroid hormone, insulin, cAMP, and medium-chain fatty acids on ACCalpha transcription in hepatocytes. Journal of lipid research 76 12576518
2013 The ACACA and SREBF1 genes are promising markers for pig carcass and performance traits, but not for fatty acid content in the longissimus dorsi muscle and adipose tissue. Meat science 34 23657179
2012 The SNPs in the ACACA gene are effective on fatty acid composition in Holstein milk. Molecular biology reports 33 22718502
2020 Evaluation of SCD, ACACA and FASN Mutations: Effects on Pork Quality and Other Production Traits in Pigs Selected Based on RNA-Seq Results. Animals : an open access journal from MDPI 31 31940936
2023 Involvement of ACACA (acetyl-CoA carboxylase α) in the lung pre-metastatic niche formation in breast cancer by senescence phenotypic conversion in fibroblasts. Cellular oncology (Dordrecht, Netherlands) 30 36607556
2020 Circular RNA circ‑ACACA regulates proliferation, migration and glycolysis in non‑small‑cell lung carcinoma via miR‑1183 and PI3K/PKB pathway. International journal of molecular medicine 30 32236577
2021 Down-regulation of ACACA suppresses the malignant progression of Prostate Cancer through inhibiting mitochondrial potential. Journal of Cancer 25 33391420
2018 Integrative Chemical Proteomics-Metabolomics Approach Reveals Acaca/Acacb as Direct Molecular Targets of PFOA. Analytical chemistry 24 30134650
2005 Asymmetric expression of transcripts derived from the shared promoter between the divergently oriented ACACA and TADA2L genes. Genomics 24 15607423
2010 Epistatic effect between ACACA and FABP2 gene on abdominal fat traits in broilers. Journal of genetics and genomics = Yi chuan xue bao 23 20816383
2021 circ-ACACA promotes proliferation, invasion, migration and glycolysis of cervical cancer cells by targeting the miR-582-5p/ERO1A signaling axis. Oncology letters 20 34584570
2013 The ACACA gene is a potential candidate gene for fat content in sheep milk. Animal genetics 19 23488977
2015 Feeding a High Concentrate Diet Down-Regulates Expression of ACACA, LPL and SCD and Modifies Milk Composition in Lactating Goats. PloS one 17 26086219
2023 Circular RNA ACACA negatively regulated p53-modulated mevalonate pathway to promote colorectal tumorigenesis via regulating miR-193a/b-3p/HDAC3 axis. Molecular carcinogenesis 13 36920044
2020 Impact of SNPs in ACACA, SCD1, and DGAT1 Genes on Fatty Acid Profile in Bovine Milk with Regard to Lactation Phases. Animals : an open access journal from MDPI 13 32521715
1998 Mapping of FASN and ACACA on two chicken microchromosomes disrupts the human 17q syntenic group well conserved in mammals. Mammalian genome : official journal of the International Mammalian Genome Society 12 9530626
2020 ssc-miR-451 Regulates Porcine Primary Adipocyte Differentiation by Targeting ACACA. Animals : an open access journal from MDPI 10 33081100
2024 Nicotinate-curcumin improves NASH by inhibiting the AKR1B10/ACCα-mediated triglyceride synthesis. Lipids in health and disease 9 38937844
2023 ND630 controls ACACA and lipid reprogramming in prostate cancer by regulating the expression of circKIF18B_003. Journal of translational medicine 9 38049827
2021 Nano-selenium alleviating the lipid metabolism disorder of LMH cells induced by potassium dichromate via down-regulating ACACA and FASN. Environmental science and pollution research international 9 34302249
2021 Biallelic Mutations in ACACA Cause a Disruption in Lipid Homeostasis That Is Associated With Global Developmental Delay, Microcephaly, and Dysmorphic Facial Features. Frontiers in cell and developmental biology 9 34552920
2019 Analysis of allele-specific expression of seven candidate genes involved in lipid metabolism in pig skeletal muscle and fat tissues reveals allelic imbalance of ACACA, LEP, SCD, and TNF. Journal of applied genetics 8 30684136
2024 IL-17A exacerbates corpus cavernosum fibrosis and neurogenic erectile dysfunction by inducing CSMC senescence via the mTORC2-ACACA pathway. BMC medicine 6 39256772
2017 Full-length sequencing and identification of novel polymorphisms in the ACACA gene of Valle del Belice sheep breed. Journal of genetics 5 28947707
2024 Omega-3 fatty acids mitigate histological changes and modulate the expression of ACACA, PFK1 and ET-1 genes in broiler chickens under environmental stress: a pulmonary artery, cardiomyocyte and liver study. Poultry science 4 39476610
2023 The third patient of ACACA-related acetyl-CoA carboxylase deficiency with seizure and literature review. European journal of medical genetics 4 36709796
2022 Potential Involvement of NSD1, KRT24 and ACACA in the Genetic Predisposition to Colorectal Cancer. Cancers 3 35158968
2025 ACACA depletion activates the cPLA2-arachidonic acid-NF-κB axis to drive inflammatory reprogramming in androgen receptor-independent prostate cancer. Cell communication and signaling : CCS 2 40713618
2023 Identification of Genetic Polymorphisms of PI, PIII, and Exon 53 in the Acetyl-CoA Carboxylase-α (ACACα) Gene and Their Association with Milk Composition Traits of Najdi Sheep. Animals : an open access journal from MDPI 1 37106880
2026 ACACA modulates R-loop homeostasis to enhance lipid metabolism and microenvironmental interactions in ccRCC. NPJ precision oncology 0 41620551
2026 Methylation analysis of PHOSPHO1 and ACACA gene promoters in whole blood samples: insights into metabolic syndrome and associated factors. Journal of diabetes and metabolic disorders 0 41664674
2026 Integrated Multiomic Analysis Provides New Insights into the Adipogenic Differentiation of Porcine Adipocytes and Reveals the Regulatory Role of ACACA in Adipogenesis. Journal of agricultural and food chemistry 0 41729978
2026 ZXDB Drives Macrophage Inflammatory Programming in Sepsis-Induced Acute Kidney Injury by Recruiting EIF4A3 to Enhance ACACA Translation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 0 41873808
2026 IRX1 suppresses breast cancer progression by inhibiting fatty acid de novo synthesis through downregulating ACACA expression. Cell death & disease 0 42225620

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