{"gene":"ABHD15","run_date":"2026-06-09T22:02:37","timeline":{"discoveries":[{"year":2018,"finding":"ABHD15 physically associates with and stabilizes phosphodiesterase 3B (PDE3B) in white adipose tissue; loss of ABHD15 decreases PDE3B protein expression, mechanistically explaining increased PKA activity, elevated HSL phosphorylation, and failure of insulin to suppress fatty acid release.","method":"In vitro co-association assay (ABHD15–PDE3B interaction), global and conditional Abhd15-KO mice with biochemical readouts (AKT phosphorylation, HSL phosphorylation, cAMP/PKA activity, FA release, glucose uptake, de novo lipogenesis)","journal":"Cell Reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal in vitro association data plus KO mouse model with multiple orthogonal biochemical readouts; replicated directionally in a second independent study (PMID:31105056)","pmids":["29768196"],"is_preprint":false},{"year":2019,"finding":"ABHD15 is required for insulin-mediated suppression of lipolysis in adipocytes via the PDE3B–cAMP–PKA axis; deletion of ABHD15 leaves PKA substrate Perilipin-1 phosphorylation elevated in response to insulin, confirming that ABHD15 acts upstream of PKA suppression. No effect on insulin-mediated glucose uptake was observed in adipocytes.","method":"ABHD15 knockdown and knockout adipocytes/fat explants; lipolysis assays, PKA substrate phosphorylation (Perilipin-1), glucose uptake, and whole-body fatty acid/lipid metabolism in ABHD15−/− mice","journal":"Molecular Metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined cellular phenotype, multiple orthogonal metabolic readouts, replicates and extends PMID:29768196 in an independent lab","pmids":["31105056"],"is_preprint":false},{"year":2013,"finding":"ABHD15 is a direct transcriptional target of PPARγ; stable knockdown of Abhd15 in 3T3-L1 cells causes a differentiation defect (reduced lipid accumulation, decreased adipocyte marker gene expression) and, in preconfluent cells, induces apoptosis (increased SubG1 fraction, caspase 3/7 activity, BAX protein, reduced BCL-2), identifying ABHD15 as an essential pro-survival and adipogenic factor.","method":"Stable shRNA knockdown in 3T3-L1 cells; lipid staining, RT-qPCR for marker genes, flow cytometry (SubG1), caspase 3/7 activity assay, western blot (BAX, BCL-2); PPARγ target gene validation","journal":"PLoS ONE","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean loss-of-function with multiple orthogonal cellular readouts in a single lab","pmids":["24236098"],"is_preprint":false},{"year":2020,"finding":"In hypoxic cardiomyocytes, ABHD15 overexpression promotes glucose uptake and glycolysis (via GLUT4 expression/translocation and rate-limiting glycolytic enzyme activation) and inhibits apoptosis; effects on viability and apoptosis were abolished by inhibitors of IR, Raf/ERK, AKT, or Bcl2 phosphorylation, suggesting ABHD15 acts through IR/Ras/Raf/ERK/MEK and IR/PI3K/AKT/Bcl2/Bad/caspase9 pathways.","method":"ABHD15 overexpression vector and siRNA knockdown in hypoxic cardiomyocytes; cell viability assay, glucose uptake, IR phosphorylation (p-IR), GLUT4 translocation, glycolytic enzyme activity, apoptosis assays, pathway inhibitor experiments","journal":"Nutrition, Metabolism, and Cardiovascular Diseases","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, overexpression/knockdown with inhibitor pharmacology but no direct binding or reconstitution data; pathway placement inferred from inhibitor rescue only","pmids":["33257193"],"is_preprint":false}],"current_model":"ABHD15 is a PPARγ-target α/β-hydrolase domain protein expressed in adipose tissue that stabilizes PDE3B protein, thereby enabling insulin-stimulated PDE3B activity to lower cAMP, suppress PKA, reduce HSL phosphorylation, and inhibit lipolysis; loss of ABHD15 destabilizes PDE3B, sustains PKA activity and fatty acid release, and ultimately causes insulin resistance, while ABHD15 also plays a pro-survival, pro-adipogenic role by suppressing apoptosis downstream of PPARγ-driven differentiation."},"narrative":{"mechanistic_narrative":"ABHD15 is a PPARγ-induced α/β-hydrolase domain protein that functions in adipose tissue as a positive regulator of insulin's anti-lipolytic action and as a pro-survival, pro-adipogenic factor [PMID:29768196, PMID:24236098]. Mechanistically, ABHD15 physically associates with and stabilizes phosphodiesterase 3B (PDE3B); loss of ABHD15 lowers PDE3B protein, leaving PKA activity elevated, increasing phosphorylation of HSL and Perilipin-1, and preventing insulin from suppressing fatty acid release — establishing ABHD15 as a required component upstream of insulin-mediated PKA suppression in the PDE3B–cAMP–PKA axis, with no role in insulin-stimulated glucose uptake in adipocytes [PMID:29768196, PMID:31105056]. As a direct transcriptional target of PPARγ, ABHD15 is required for adipocyte differentiation, and its loss in preadipocytes triggers apoptosis (increased BAX, reduced BCL-2, elevated caspase 3/7) [PMID:24236098]. Beyond these adipocyte roles, no biochemical detail of the ABHD15–PDE3B interaction interface or any catalytic hydrolase substrate has been characterized in the available corpus.","teleology":[{"year":2013,"claim":"Established ABHD15 as a downstream effector of the master adipogenic regulator PPARγ and as a survival factor, answering whether ABHD15 has a functional role in fat-cell development.","evidence":"Stable shRNA knockdown in 3T3-L1 cells with lipid staining, marker qPCR, apoptosis readouts, and PPARγ target validation","pmids":["24236098"],"confidence":"Medium","gaps":["Molecular mechanism linking ABHD15 to apoptosis suppression not defined","No connection yet made to PDE3B or lipolysis","Single-lab cell-line data only"]},{"year":2018,"claim":"Identified the molecular partner and mechanism — ABHD15 binds and stabilizes PDE3B — explaining how its loss elevates PKA activity and disrupts insulin suppression of fatty acid release.","evidence":"In vitro ABHD15–PDE3B co-association assay plus global and conditional Abhd15-KO mice with cAMP/PKA, HSL phosphorylation, and FA-release readouts","pmids":["29768196"],"confidence":"High","gaps":["Interaction interface and stoichiometry not mapped","Whether ABHD15 has intrinsic hydrolase activity toward a substrate unresolved","Mechanism by which ABHD15 protects PDE3B from degradation unknown"]},{"year":2019,"claim":"Placed ABHD15 causally upstream of PKA suppression by showing PKA substrate phosphorylation stays elevated without it, confirming its requirement for insulin's anti-lipolytic action while excluding a glucose-uptake role in adipocytes.","evidence":"ABHD15 knockdown/knockout adipocytes and fat explants with lipolysis assays, Perilipin-1 phosphorylation, glucose uptake, and whole-body lipid metabolism in ABHD15−/− mice","pmids":["31105056"],"confidence":"High","gaps":["Does not address tissues outside adipose","Contribution of ABHD15 to systemic insulin resistance not fully resolved at molecular level"]},{"year":2020,"claim":"Extended ABHD15 function to cardiomyocytes under hypoxia, where overexpression promotes glucose uptake/glycolysis and inhibits apoptosis through insulin-receptor signaling branches.","evidence":"ABHD15 overexpression and siRNA in hypoxic cardiomyocytes with viability, glucose uptake, GLUT4 translocation, and inhibitor rescue experiments","pmids":["33257193"],"confidence":"Low","gaps":["Pathway placement inferred from inhibitor pharmacology only, with no direct binding or reconstitution data","Single-lab study not independently confirmed","Contradicts adipocyte finding of no glucose-uptake role — cell-type basis unexplained"]},{"year":null,"claim":"Whether ABHD15 possesses intrinsic enzymatic (hydrolase) activity and what its physiological substrate or catalytic role is remains unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No catalytic substrate identified","No structural model of ABHD15 or its complex with PDE3B","Function outside adipose tissue and heart uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0]}],"localization":[],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1]}],"complexes":[],"partners":["PDE3B"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6UXT9","full_name":"Protein ABHD15","aliases":["Alpha/beta hydrolase domain-containing protein 15","Abhydrolase domain-containing protein 15"],"length_aa":468,"mass_kda":51.8,"function":"May regulate adipocyte lipolysis and liver lipid accumulation","subcellular_location":"Secreted","url":"https://www.uniprot.org/uniprotkb/Q6UXT9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ABHD15","classification":"Not Classified","n_dependent_lines":69,"n_total_lines":1208,"dependency_fraction":0.057119205298013245},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ABHD15","total_profiled":1310},"omim":[{"mim_id":"619894","title":"ABHYDROLASE DOMAIN-CONTAINING PROTEIN 15; ABHD15","url":"https://www.omim.org/entry/619894"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ABHD15"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q6UXT9","domains":[{"cath_id":"3.40.50.1820","chopping":"64-145_156-267_345-421","consensus_level":"high","plddt":89.5344,"start":64,"end":421},{"cath_id":"-","chopping":"268-341","consensus_level":"medium","plddt":91.3234,"start":268,"end":341}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6UXT9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6UXT9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6UXT9-F1-predicted_aligned_error_v6.png","plddt_mean":79.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ABHD15","jax_strain_url":"https://www.jax.org/strain/search?query=ABHD15"},"sequence":{"accession":"Q6UXT9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6UXT9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6UXT9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6UXT9"}},"corpus_meta":[{"pmid":"29768196","id":"PMC_29768196","title":"Loss of ABHD15 Impairs the Anti-lipolytic Action of Insulin by Altering PDE3B Stability and Contributes to Insulin Resistance.","date":"2018","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/29768196","citation_count":41,"is_preprint":false},{"pmid":"31105056","id":"PMC_31105056","title":"ABHD15 regulates adipose tissue lipolysis and hepatic lipid accumulation.","date":"2019","source":"Molecular metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/31105056","citation_count":27,"is_preprint":false},{"pmid":"24236098","id":"PMC_24236098","title":"α/β-hydrolase domain containing protein 15 (ABHD15)--an adipogenic protein protecting from apoptosis.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24236098","citation_count":7,"is_preprint":false},{"pmid":"33257193","id":"PMC_33257193","title":"ABHD15 promotes cell viability, glycolysis, and inhibits apoptosis in cardiomyocytes under hypoxia.","date":"2020","source":"Nutrition, metabolism, and cardiovascular diseases : NMCD","url":"https://pubmed.ncbi.nlm.nih.gov/33257193","citation_count":0,"is_preprint":false},{"pmid":"42058679","id":"PMC_42058679","title":"Molecular mechanisms underlying psoriasis and depression: an integrated analysis using mendelian randomization, transcriptomics, and single-cell sequencing.","date":"2026","source":"Frontiers in molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/42058679","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4830,"output_tokens":1343,"usd":0.017317,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8081,"output_tokens":1914,"usd":0.044128,"stage2_stop_reason":"end_turn"},"total_usd":0.061445,"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\": 2018,\n      \"finding\": \"ABHD15 physically associates with and stabilizes phosphodiesterase 3B (PDE3B) in white adipose tissue; loss of ABHD15 decreases PDE3B protein expression, mechanistically explaining increased PKA activity, elevated HSL phosphorylation, and failure of insulin to suppress fatty acid release.\",\n      \"method\": \"In vitro co-association assay (ABHD15–PDE3B interaction), global and conditional Abhd15-KO mice with biochemical readouts (AKT phosphorylation, HSL phosphorylation, cAMP/PKA activity, FA release, glucose uptake, de novo lipogenesis)\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal in vitro association data plus KO mouse model with multiple orthogonal biochemical readouts; replicated directionally in a second independent study (PMID:31105056)\",\n      \"pmids\": [\"29768196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ABHD15 is required for insulin-mediated suppression of lipolysis in adipocytes via the PDE3B–cAMP–PKA axis; deletion of ABHD15 leaves PKA substrate Perilipin-1 phosphorylation elevated in response to insulin, confirming that ABHD15 acts upstream of PKA suppression. No effect on insulin-mediated glucose uptake was observed in adipocytes.\",\n      \"method\": \"ABHD15 knockdown and knockout adipocytes/fat explants; lipolysis assays, PKA substrate phosphorylation (Perilipin-1), glucose uptake, and whole-body fatty acid/lipid metabolism in ABHD15−/− mice\",\n      \"journal\": \"Molecular Metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined cellular phenotype, multiple orthogonal metabolic readouts, replicates and extends PMID:29768196 in an independent lab\",\n      \"pmids\": [\"31105056\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ABHD15 is a direct transcriptional target of PPARγ; stable knockdown of Abhd15 in 3T3-L1 cells causes a differentiation defect (reduced lipid accumulation, decreased adipocyte marker gene expression) and, in preconfluent cells, induces apoptosis (increased SubG1 fraction, caspase 3/7 activity, BAX protein, reduced BCL-2), identifying ABHD15 as an essential pro-survival and adipogenic factor.\",\n      \"method\": \"Stable shRNA knockdown in 3T3-L1 cells; lipid staining, RT-qPCR for marker genes, flow cytometry (SubG1), caspase 3/7 activity assay, western blot (BAX, BCL-2); PPARγ target gene validation\",\n      \"journal\": \"PLoS ONE\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean loss-of-function with multiple orthogonal cellular readouts in a single lab\",\n      \"pmids\": [\"24236098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In hypoxic cardiomyocytes, ABHD15 overexpression promotes glucose uptake and glycolysis (via GLUT4 expression/translocation and rate-limiting glycolytic enzyme activation) and inhibits apoptosis; effects on viability and apoptosis were abolished by inhibitors of IR, Raf/ERK, AKT, or Bcl2 phosphorylation, suggesting ABHD15 acts through IR/Ras/Raf/ERK/MEK and IR/PI3K/AKT/Bcl2/Bad/caspase9 pathways.\",\n      \"method\": \"ABHD15 overexpression vector and siRNA knockdown in hypoxic cardiomyocytes; cell viability assay, glucose uptake, IR phosphorylation (p-IR), GLUT4 translocation, glycolytic enzyme activity, apoptosis assays, pathway inhibitor experiments\",\n      \"journal\": \"Nutrition, Metabolism, and Cardiovascular Diseases\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, overexpression/knockdown with inhibitor pharmacology but no direct binding or reconstitution data; pathway placement inferred from inhibitor rescue only\",\n      \"pmids\": [\"33257193\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ABHD15 is a PPARγ-target α/β-hydrolase domain protein expressed in adipose tissue that stabilizes PDE3B protein, thereby enabling insulin-stimulated PDE3B activity to lower cAMP, suppress PKA, reduce HSL phosphorylation, and inhibit lipolysis; loss of ABHD15 destabilizes PDE3B, sustains PKA activity and fatty acid release, and ultimately causes insulin resistance, while ABHD15 also plays a pro-survival, pro-adipogenic role by suppressing apoptosis downstream of PPARγ-driven differentiation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ABHD15 is a PPARγ-induced α/β-hydrolase domain protein that functions in adipose tissue as a positive regulator of insulin's anti-lipolytic action and as a pro-survival, pro-adipogenic factor [#0, #2]. Mechanistically, ABHD15 physically associates with and stabilizes phosphodiesterase 3B (PDE3B); loss of ABHD15 lowers PDE3B protein, leaving PKA activity elevated, increasing phosphorylation of HSL and Perilipin-1, and preventing insulin from suppressing fatty acid release — establishing ABHD15 as a required component upstream of insulin-mediated PKA suppression in the PDE3B–cAMP–PKA axis, with no role in insulin-stimulated glucose uptake in adipocytes [#0, #1]. As a direct transcriptional target of PPARγ, ABHD15 is required for adipocyte differentiation, and its loss in preadipocytes triggers apoptosis (increased BAX, reduced BCL-2, elevated caspase 3/7) [#2]. Beyond these adipocyte roles, no biochemical detail of the ABHD15–PDE3B interaction interface or any catalytic hydrolase substrate has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established ABHD15 as a downstream effector of the master adipogenic regulator PPARγ and as a survival factor, answering whether ABHD15 has a functional role in fat-cell development.\",\n      \"evidence\": \"Stable shRNA knockdown in 3T3-L1 cells with lipid staining, marker qPCR, apoptosis readouts, and PPARγ target validation\",\n      \"pmids\": [\"24236098\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism linking ABHD15 to apoptosis suppression not defined\", \"No connection yet made to PDE3B or lipolysis\", \"Single-lab cell-line data only\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified the molecular partner and mechanism — ABHD15 binds and stabilizes PDE3B — explaining how its loss elevates PKA activity and disrupts insulin suppression of fatty acid release.\",\n      \"evidence\": \"In vitro ABHD15–PDE3B co-association assay plus global and conditional Abhd15-KO mice with cAMP/PKA, HSL phosphorylation, and FA-release readouts\",\n      \"pmids\": [\"29768196\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interaction interface and stoichiometry not mapped\", \"Whether ABHD15 has intrinsic hydrolase activity toward a substrate unresolved\", \"Mechanism by which ABHD15 protects PDE3B from degradation unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Placed ABHD15 causally upstream of PKA suppression by showing PKA substrate phosphorylation stays elevated without it, confirming its requirement for insulin's anti-lipolytic action while excluding a glucose-uptake role in adipocytes.\",\n      \"evidence\": \"ABHD15 knockdown/knockout adipocytes and fat explants with lipolysis assays, Perilipin-1 phosphorylation, glucose uptake, and whole-body lipid metabolism in ABHD15−/− mice\",\n      \"pmids\": [\"31105056\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address tissues outside adipose\", \"Contribution of ABHD15 to systemic insulin resistance not fully resolved at molecular level\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended ABHD15 function to cardiomyocytes under hypoxia, where overexpression promotes glucose uptake/glycolysis and inhibits apoptosis through insulin-receptor signaling branches.\",\n      \"evidence\": \"ABHD15 overexpression and siRNA in hypoxic cardiomyocytes with viability, glucose uptake, GLUT4 translocation, and inhibitor rescue experiments\",\n      \"pmids\": [\"33257193\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Pathway placement inferred from inhibitor pharmacology only, with no direct binding or reconstitution data\", \"Single-lab study not independently confirmed\", \"Contradicts adipocyte finding of no glucose-uptake role — cell-type basis unexplained\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Whether ABHD15 possesses intrinsic enzymatic (hydrolase) activity and what its physiological substrate or catalytic role is remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No catalytic substrate identified\", \"No structural model of ABHD15 or its complex with PDE3B\", \"Function outside adipose tissue and heart uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PDE3B\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":3,"faith_total":3,"faith_pct":100.0}}