ACOT12

ACOT12 is the principal cytoplasmic acetyl-CoA thioesterase that hydrolyzes acetyl-CoA to acetate and coenzyme A, thereby governing intracellular acetyl-CoA pools that feed into de novo lipogenesis, cholesterol biosynthesis, histone acetylation, and peroxisome turnover. Its catalytic activity is allosterically inhibited by phosphatidic acid through a mechanism requiring the C-terminal START domain, and its expression is transcriptionally downregulated by insulin and positively regulated by PPARα (PMID:23709691, PMID:34987154). In hepatocytes, loss of ACOT12 elevates acetyl-CoA, driving histone acetylation–dependent induction of TWIST2 and Slug to promote epithelial–mesenchymal transition and metastasis in hepatocellular carcinoma and cholangiocarcinoma (PMID:30661930, PMID:35399720); in cartilage, ACOT12 deficiency causes acetyl-CoA accumulation that stimulates lipogenesis, MMP activation, FOXM1-driven chondrocyte senescence, and cartilage degradation consistent with osteoarthritis (PMID:34987154, PMID:37908734). In the kidney, ACOT12 supports ACBD5-dependent pexophagy independently of PPARα, and its loss leads to peroxisome accumulation, lipid deposition, and renal fibrosis (PMID:39939783).

1. 2013 High

   Establishing ACOT12 as the dominant hepatic acetyl-CoA thioesterase and defining its allosteric regulation resolved how acetyl-CoA hydrolysis is controlled in the cytoplasm.

   Evidence In vitro activity assays with phospholipid panels, START-domain deletion mutagenesis, lipid-binding assays, and insulin-treated rat hepatocytes

   PMID:23709691

   Open questions at the time

   • Structural basis for START-domain-mediated allosteric inhibition by phosphatidic acid unresolved
   • Upstream signaling pathway linking insulin to ACOT12 transcription not mapped
   • Contribution of other ACOT family members to acetyl-CoA hydrolysis in non-hepatic tissues unknown
2. 2019 High

   Demonstrating that ACOT12 loss raises acetyl-CoA to drive histone acetylation and TWIST2-mediated EMT in hepatocellular carcinoma revealed a metabolite–epigenetic axis linking acetyl-CoA homeostasis to metastasis.

   Evidence Gain- and loss-of-function in HCC cells and xenograft models, acetyl-CoA quantification, histone acetylation assays, TWIST2 epistasis

   PMID:30661930

   Open questions at the time

   • Specific histone marks and genomic loci altered by ACOT12 loss not mapped genome-wide
   • Whether ACOT12 re-expression fully reverses EMT in established tumors not tested
3. 2021 Medium

   Acot12-knockout mice developed NAFLD with elevated de novo lipogenesis and cholesterol biosynthesis, and BioID identified VPS33A as a proximity interactor, linking ACOT12 to vesicle-mediated cholesterol trafficking.

   Evidence Acot12−/− mice, acetyl-CoA and lipid quantification, BioID proximity proteomics in hepatocytes

   PMID:34285335

   Open questions at the time

   • VPS33A interaction not confirmed by reciprocal co-immunoprecipitation or functional validation
   • Whether cholesterol trafficking defect is a direct consequence of ACOT12–VPS33A interaction or secondary to acetyl-CoA accumulation unclear
4. 2022 High

   Placing ACOT12 downstream of PPARα in cartilage and showing that its loss causes acetyl-CoA-driven lipogenesis, MMP activation, and chondrocyte apoptosis established ACOT12 as a joint-protective enzyme relevant to osteoarthritis.

   Evidence Acot12−/− and Ppara−/− mice, acetyl-CoA chitosan delivery, rescue with ACOT12 in human OA chondrocytes, immunohistochemistry

   PMID:34987154

   Open questions at the time

   • Direct PPARα binding site on the Acot12 promoter not characterized
   • Whether other acyl-CoA thioesterases compensate partially in cartilage unknown
5. 2022 Medium

   Extending the ACOT12–EMT axis to cholangiocarcinoma via Slug induction broadened the tumor-suppressive role of ACOT12 beyond HCC.

   Evidence In vitro and in vivo ICC models with ACOT12 manipulation, Slug and EMT marker quantification

   PMID:35399720

   Open questions at the time

   • Whether Slug induction depends on the same histone acetylation mechanism as TWIST2 in HCC not tested
   • Single-lab finding without independent replication
6. 2023 Medium

   Double knockout of Acot12 and Nudt7 revealed that combined acetyl-CoA accumulation upregulates FOXM1 to drive chondrocyte senescence, identifying an additional transcription factor axis in cartilage degeneration.

   Evidence Acot12/Nudt7 dKO mice, microarray, FOXM1 overexpression and siFoxM1 nanoparticle rescue, acetyl-CoA scavenging with ACBP

   PMID:37908734

   Open questions at the time

   • Individual contributions of ACOT12 vs. NUDT7 to the FOXM1–senescence axis not fully deconvolved
   • Mechanism by which acetyl-CoA upregulates FOXM1 expression not defined
7. 2025 Medium

   ACOT12 loss impairs ACBD5-dependent pexophagy in the kidney independently of PPARα, establishing a non-hepatic, non-cartilage role for ACOT12 in organelle quality control and renal fibrosis.

   Evidence Acot12−/− and Acot12−/−Ppara−/− mice with UUO renal injury, ACBD5 quantification, pexophagy markers, ACOT12 rescue

   PMID:39939783

   Open questions at the time

   • Mechanism linking ACOT12 to ACBD5 protein levels (transcriptional, translational, or degradative) not determined
   • Whether the pexophagy defect is cell-autonomous in tubular epithelial cells not formally shown
   • Single lab; awaits independent replication

• Major open questions include the structural basis of START-domain-mediated allosteric regulation, whether ACOT12's non-enzymatic interactions (VPS33A, ACBD5) are direct or metabolite-mediated, and the relative contribution of acetyl-CoA-dependent histone acetylation versus other downstream metabolic pathways across tissues.
• No crystal structure of ACOT12 with or without phosphatidic acid available
• Quantitative contribution of ACOT12 vs. other acetyl-CoA consuming/producing enzymes to nuclear acetyl-CoA pools unknown
• Whether ACOT12 has thioesterase activity toward substrates other than acetyl-CoA in vivo not systematically tested