{"gene":"GPAT3","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2010,"finding":"GPAT3 catalyzes the first step in de novo glycerolipid synthesis (acylation of glycerol-3-phosphate) and is the predominant GPAT isoform in adipocytes; shRNA-mediated knockdown of GPAT3 in 3T3-L1 adipocytes significantly decreased total GPAT activity, inhibited lipid accumulation, and blocked expression of adipogenic markers during differentiation, while GPAT4 knockdown had no such effect.","method":"shRNA knockdown in 3T3-L1 adipocytes, GPAT activity assay, overexpression in insect and mammalian cells","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal gain- and loss-of-function with defined enzymatic and cellular phenotypes, replicated across cell types","pmids":["20181984"],"is_preprint":false},{"year":2010,"finding":"GPAT3 (and GPAT4) are phosphorylated at Ser and Thr residues in response to insulin, leading to increased GPAT enzymatic activity that is sensitive to the PI3K inhibitor wortmannin, linking insulin signaling to microsomal GPAT activity.","method":"Phosphorylation assay after insulin stimulation, wortmannin inhibition, overexpression in mammalian cells","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, phosphorylation demonstrated but specific kinase not identified; wortmannin sensitivity places it downstream of PI3K","pmids":["20181984"],"is_preprint":false},{"year":2006,"finding":"GPAT3 (LPAAT-theta) localizes primarily to the endoplasmic reticulum and its overexpression induces mTOR-dependent phosphorylation of p70S6K at Thr389 and 4EBP1 at Ser65 in HEK293T cells.","method":"EGFP fusion protein subcellular localization in COS-7 cells, western blot of p70S6K and 4EBP1 phosphorylation upon overexpression in HEK293T cells","journal":"Journal of biochemistry and molecular biology","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single lab, localization by fluorescent fusion and signaling by overexpression only, no mutagenesis or pathway epistasis","pmids":["17002884"],"is_preprint":false},{"year":2014,"finding":"GPAT3 is the primary GPAT enzyme in white adipose tissue in vivo; Gpat3-/- mice show 80% reduction in total GPAT activity in white adipose tissue, altered energy expenditure, improved glucose tolerance under high-fat diet, and dysregulated cholesterol metabolism, establishing GPAT3 as a rate-limiting enzyme for glycerolipid synthesis in adipose.","method":"Gpat3 knockout mice, GPAT activity assays in multiple tissues, metabolic phenotyping under standard and high-fat diet conditions","journal":"American journal of physiology. Endocrinology and metabolism","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO with direct enzymatic activity measurement and multiple metabolic phenotypes","pmids":["24714397"],"is_preprint":false},{"year":2020,"finding":"GPAT3 physically associates with the lipodystrophy scaffold protein seipin via direct protein-protein interaction, and seipin can simultaneously bind both GPAT3 and AGPAT2; loss of GPAT3 in seipin-deficient preadipocytes exacerbates the failure of adipogenesis, indicating GPAT3 plays a modest positive role in adipocyte differentiation downstream of seipin.","method":"Co-immunoprecipitation, direct interaction assays, siRNA knockdown in cultured preadipocytes, assessment of adipogenic marker expression","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding assays and genetic epistasis in cell culture, single lab, two orthogonal methods","pmids":["32094408"],"is_preprint":false},{"year":2020,"finding":"GPAT3 deficiency in seipin-null (BSCL2) mice partially rescues white adipose tissue mass, nearly completely restores brown adipose tissue mass, and significantly improves liver steatosis and insulin sensitivity, establishing a functional in vivo link between seipin and GPAT3 in lipid homeostasis.","method":"Double knockout mouse model (Seipin-/-Gpat3-/-), metabolic phenotyping, histology, insulin tolerance tests","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo double-KO genetic epistasis with multiple defined phenotypic readouts","pmids":["31873720"],"is_preprint":false},{"year":2023,"finding":"GPAT3 upregulation in Kupffer cells increases lysophosphatidic acid (LPA) production, which activates the ERK signaling pathway to exacerbate inflammatory responses; GPAT3 loss-of-function reduced LPA levels, improved mitochondrial function, and decreased ERK-mediated inflammation both in vivo and in vitro.","method":"GPAT3 siRNA/KO in Kupffer cells, LPA measurement, ERK pathway western blot, LPS stimulation model in vivo and in vitro","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function with mechanistic lipid intermediate measurement and pathway readout, single lab","pmids":["36964139"],"is_preprint":false},{"year":2021,"finding":"Mycobacterium leprae infection induces GPAT3 expression in human THP-1 macrophages, and CRISPR/Cas9 knockout of GPAT3 dramatically reduces triacylglycerol accumulation, intracellular mycobacterial load, and bacterial viability, demonstrating that GPAT3-driven TAG synthesis is exploited by M. leprae for intracellular survival.","method":"CRISPR/Cas9 GPAT3 knockout in THP-1 cells, [14C] stearic acid tracing, HPTLC lipid analysis, bacterial viability assay","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR KO with radiolabeled lipid tracing and multiple functional readouts in a single rigorous study","pmids":["33770127"],"is_preprint":false},{"year":2024,"finding":"GPAT3 upregulation in sorafenib-resistant HCC cells is driven by STAT3 transcriptional activation (ChIP confirmed); GPAT3 overexpression increases triglyceride synthesis and activates the NF-κB/Bcl2 signaling pathway, leading to apoptosis resistance, while GPAT3 restoration resensitized resistant cells to sorafenib.","method":"ChIP assay (STAT3 binding to GPAT3 promoter), proteomics, gain- and loss-of-function studies, flow cytometry, western blot for NF-κB/Bcl2, in vivo xenograft","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP for upstream regulation plus gain/loss-of-function with pathway readout, single lab","pmids":["38948063"],"is_preprint":false},{"year":2024,"finding":"GPAT3 expression is directly controlled at the transcriptional level by the glucocorticoid receptor (GR); deletion of GPAT3 in CORT-treated cells activates the GSK3β/Nrf2 pathway, reducing hepatic fat accumulation and oxidative stress and increasing fatty acid oxidation gene expression.","method":"GPAT3 siRNA in AML12 cells and Gpat3-/- mice, GR binding to GPAT3 promoter, western blot for GSK3β/Nrf2, ROS measurement, mitochondrial membrane potential assay","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO/KD with mechanistic pathway analysis and promoter regulation, single lab","pmids":["38185063"],"is_preprint":false},{"year":2025,"finding":"ER stress induces GPAT3 gene expression through ATF4-dependent activation of AP-1 elements located in the GPAT3 promoter and second intron; CRISPR/Cas9 deletion of the intronic AP-1 region reduced GPAT3 expression and triglyceride content in both unstressed and ER-stressed hepatoma cells.","method":"CRISPR/Cas9 ATF4 disruption, luciferase reporter assays with mutational analysis, CRISPR deletion of intronic AP-1 region, transcriptome profiling, triglyceride measurement","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (reporter assays with mutagenesis, CRISPR deletion, transcriptomics) in a single study establishing the regulatory mechanism","pmids":["41392190"],"is_preprint":false}],"current_model":"GPAT3 is a microsomal acyl-CoA:glycerol-3-phosphate acyltransferase localized to the endoplasmic reticulum that catalyzes the rate-limiting first step in de novo glycerolipid/triglyceride synthesis; it is the predominant GPAT in white adipose tissue, is transcriptionally regulated by GR, ATF4/AP-1, and STAT3, is post-translationally activated by insulin-stimulated (PI3K-dependent) phosphorylation, physically associates with the scaffold protein seipin (which co-ordinates GPAT3 with AGPAT2), produces the lipid intermediate LPA to activate ERK signaling in macrophages, and drives NF-κB/Bcl2-mediated apoptosis resistance through triglyceride accumulation in cancer cells."},"narrative":{"mechanistic_narrative":"GPAT3 is an endoplasmic reticulum-resident acyl-CoA:glycerol-3-phosphate acyltransferase that catalyzes the first, rate-limiting acylation step of de novo glycerolipid and triglyceride synthesis, and it is the predominant GPAT isoform in adipocytes and white adipose tissue [PMID:20181984, PMID:24714397]. Knockdown or knockout abolishes most cellular and tissue GPAT activity, blocks adipogenic differentiation, and in vivo alters energy expenditure, glucose tolerance, and cholesterol handling, establishing GPAT3 as the principal driver of adipose glycerolipid storage [PMID:20181984, PMID:24714397]. Its activity is acutely tuned by insulin through PI3K-dependent Ser/Thr phosphorylation, and its expression is transcriptionally controlled by multiple stress- and metabolism-linked inputs: the glucocorticoid receptor, ATF4-driven AP-1 elements activated during ER stress, and STAT3 [PMID:20181984, PMID:38185063, PMID:41392190, PMID:38948063]. GPAT3 functions in coordination with the lipodystrophy scaffold seipin, with which it directly interacts and which can simultaneously engage AGPAT2; loss of GPAT3 in seipin-null mice partially rescues adipose mass, hepatic steatosis, and insulin sensitivity, defining a seipin-GPAT3 axis in lipid homeostasis [PMID:32094408, PMID:31873720]. Beyond lipid storage, GPAT3-generated lysophosphatidic acid activates ERK signaling to amplify Kupffer-cell inflammation, GPAT3-driven triacylglycerol accumulation is exploited by Mycobacterium leprae for intracellular survival in macrophages, and in sorafenib-resistant hepatocellular carcinoma GPAT3 promotes triglyceride synthesis and NF-κB/Bcl2-mediated apoptosis resistance [PMID:36964139, PMID:33770127, PMID:38948063].","teleology":[{"year":2006,"claim":"Established the subcellular site of GPAT3 action and an early link to growth signaling, framing whether this acyltransferase resides where de novo lipid synthesis occurs.","evidence":"EGFP-fusion localization in COS-7 cells and overexpression-driven p70S6K/4EBP1 phosphorylation readouts in HEK293T cells","pmids":["17002884"],"confidence":"Medium","gaps":["mTOR-pathway effect shown only by overexpression without mutagenesis or epistasis","no direct demonstration that catalytic activity drives the signaling effect"]},{"year":2010,"claim":"Defined GPAT3 as the catalytically dominant, rate-limiting GPAT isoform in adipocytes and showed insulin acutely regulates its activity, connecting hormonal signaling to glycerolipid synthesis.","evidence":"shRNA knockdown and overexpression in 3T3-L1 adipocytes with GPAT activity assays, plus insulin-stimulated phosphorylation with wortmannin inhibition","pmids":["20181984"],"confidence":"High","gaps":["specific kinase mediating insulin-driven phosphorylation not identified","phosphosite-to-activity causality (Medium-confidence arm) not resolved by mutagenesis"]},{"year":2014,"claim":"Confirmed in vivo that GPAT3 carries most adipose GPAT activity and shapes systemic metabolism, elevating the cell-culture findings to a whole-organism rate-limiting role.","evidence":"Gpat3-/- mice with tissue GPAT activity assays and metabolic phenotyping on standard and high-fat diets","pmids":["24714397"],"confidence":"High","gaps":["mechanism linking GPAT3 loss to altered cholesterol metabolism unresolved","tissue-specific contributions outside white adipose not dissected"]},{"year":2020,"claim":"Placed GPAT3 in a physical and genetic partnership with the lipodystrophy scaffold seipin, explaining how the acyltransferase is organized with AGPAT2 during adipocyte lipid synthesis.","evidence":"Co-immunoprecipitation and direct interaction assays plus siRNA epistasis in preadipocytes, and a Seipin-/-Gpat3-/- double-knockout mouse with metabolic phenotyping","pmids":["32094408","31873720"],"confidence":"High","gaps":["structural basis of the seipin-GPAT3-AGPAT2 assembly not determined","interaction and epistasis data derive from single labs"]},{"year":2023,"claim":"Showed GPAT3 acts beyond storage by generating LPA that drives ERK-dependent inflammation, identifying a signaling-lipid output of the enzyme in macrophage-lineage cells.","evidence":"siRNA/KO of GPAT3 in Kupffer cells with LPA measurement, ERK western blots, and LPS stimulation in vivo and in vitro","pmids":["36964139"],"confidence":"Medium","gaps":["direct causal link between GPAT3-derived LPA and ERK activation not isolated from other lipid changes","single-lab study"]},{"year":2021,"claim":"Demonstrated that pathogen-induced GPAT3 fuels TAG accumulation co-opted for intracellular bacterial survival, extending GPAT3 function into host-pathogen lipid metabolism.","evidence":"CRISPR/Cas9 GPAT3 knockout in THP-1 macrophages with [14C]stearic acid tracing, HPTLC, and bacterial viability assays after M. leprae infection","pmids":["33770127"],"confidence":"High","gaps":["transcriptional inducer of GPAT3 upon M. leprae infection not identified","whether TAG itself or downstream lipids support bacterial survival unresolved"]},{"year":2024,"claim":"Connected stress- and hormone-responsive transcription factors (GR and STAT3) to GPAT3 and linked GPAT3-driven triglyceride synthesis to hepatic oxidative stress and cancer apoptosis resistance.","evidence":"GR and STAT3 promoter-binding/ChIP, Gpat3-/- mice and siRNA with GSK3β/Nrf2 and NF-κB/Bcl2 pathway readouts, plus HCC xenograft sorafenib resistance assays","pmids":["38185063","38948063"],"confidence":"Medium","gaps":["whether GPAT3 catalytic product or protein scaffolding drives NF-κB/Bcl2 and GSK3β/Nrf2 effects not separated","single-lab findings for each disease context"]},{"year":2025,"claim":"Resolved how ER stress induces GPAT3 transcription, identifying an ATF4-dependent AP-1 regulatory architecture spanning promoter and intron that controls triglyceride output.","evidence":"CRISPR/Cas9 ATF4 disruption, luciferase reporters with mutagenesis, CRISPR deletion of an intronic AP-1 region, and transcriptome and triglyceride profiling in hepatoma cells","pmids":["41392190"],"confidence":"High","gaps":["interplay between ATF4/AP-1, GR, and STAT3 inputs at the GPAT3 locus not integrated","physiological stressors engaging this element in vivo not defined"]},{"year":null,"claim":"How GPAT3's catalytic acyltransferase activity is mechanistically partitioned between bulk lipid storage and the production of signaling lipids (LPA) across different cell types remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["no structural model of the catalytic site or of the seipin-GPAT3-AGPAT2 complex","kinase responsible for insulin-driven activation unidentified","whether disease phenotypes require catalysis versus scaffolding not dissected"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,3]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,3,7]}],"complexes":[],"partners":["BSCL2","AGPAT2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q53EU6","full_name":"Glycerol-3-phosphate acyltransferase 3","aliases":["1-acyl-sn-glycerol-3-phosphate O-acyltransferase 10","AGPAT 10","1-acyl-sn-glycerol-3-phosphate O-acyltransferase 9","1-AGP acyltransferase 9","1-AGPAT 9","Acyl-CoA:glycerol-3-phosphate acyltransferase 3","hGPAT3","Lung cancer metastasis-associated protein 1","Lysophosphatidic acid acyltransferase theta","LPAAT-theta","MAG-1"],"length_aa":434,"mass_kda":48.7,"function":"Converts glycerol-3-phosphate to 1-acyl-sn-glycerol-3-phosphate (lysophosphatidic acid or LPA) by incorporating an acyl moiety at the sn-1 position of the glycerol backbone (PubMed:17170135). Also converts LPA into 1,2-diacyl-sn-glycerol-3-phosphate (phosphatidic acid or PA) by incorporating an acyl moiety at the sn-2 position of the glycerol backbone (PubMed:19318427). Protects cells against lipotoxicity (PubMed:30846318)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q53EU6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/GPAT3","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000138678","cell_line_id":"CID000326","localizations":[{"compartment":"er","grade":3}],"interactors":[{"gene":"CHP1","stoichiometry":10.0},{"gene":"RAB11FIP2","stoichiometry":0.2},{"gene":"UBE3B","stoichiometry":0.2},{"gene":"EIF4G3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000326","total_profiled":1310},"omim":[{"mim_id":"610958","title":"1-@ACYLGLYCEROL-3-PHOSPHATE O-ACYLTRANSFERASE 9; AGPAT9","url":"https://www.omim.org/entry/610958"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"kidney","ntpm":82.6}],"url":"https://www.proteinatlas.org/search/GPAT3"},"hgnc":{"alias_symbol":["MGC11324","LPAAT-theta","MAG1","HMFN0839","AGPAT10"],"prev_symbol":["AGPAT9"]},"alphafold":{"accession":"Q53EU6","domains":[{"cath_id":"3.40.1130","chopping":"138-407","consensus_level":"medium","plddt":91.7607,"start":138,"end":407}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q53EU6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q53EU6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q53EU6-F1-predicted_aligned_error_v6.png","plddt_mean":85.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=GPAT3","jax_strain_url":"https://www.jax.org/strain/search?query=GPAT3"},"sequence":{"accession":"Q53EU6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q53EU6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q53EU6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q53EU6"}},"corpus_meta":[{"pmid":"20181984","id":"PMC_20181984","title":"GPAT3 and GPAT4 are regulated by insulin-stimulated phosphorylation and play distinct roles in adipogenesis.","date":"2010","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/20181984","citation_count":94,"is_preprint":false},{"pmid":"14998514","id":"PMC_14998514","title":"The Toxoplasma gondii bradyzoite antigens BAG1 and MAG1 induce early humoral and cell-mediated immune responses upon human infection.","date":"2004","source":"Microbes and infection","url":"https://pubmed.ncbi.nlm.nih.gov/14998514","citation_count":66,"is_preprint":false},{"pmid":"10656761","id":"PMC_10656761","title":"mag-1, a homolog of Drosophila mago nashi, regulates hermaphrodite germ-line sex determination in Caenorhabditis elegans.","date":"2000","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/10656761","citation_count":47,"is_preprint":false},{"pmid":"17202305","id":"PMC_17202305","title":"Use of MAG1 recombinant antigen for diagnosis of Toxoplasma gondii infection in humans.","date":"2007","source":"Clinical and vaccine immunology : CVI","url":"https://pubmed.ncbi.nlm.nih.gov/17202305","citation_count":46,"is_preprint":false},{"pmid":"24714397","id":"PMC_24714397","title":"Mice deleted for GPAT3 have reduced GPAT activity in white adipose tissue and altered energy and cholesterol homeostasis in diet-induced obesity.","date":"2014","source":"American journal of physiology. 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cancer : basic and clinical research","url":"https://pubmed.ncbi.nlm.nih.gov/20697529","citation_count":4,"is_preprint":false},{"pmid":"22985252","id":"PMC_22985252","title":"Metastasis-associated gene, mag-1 improves tumour microenvironmental adaptation and potentiates tumour metastasis.","date":"2012","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/22985252","citation_count":4,"is_preprint":false},{"pmid":"24575387","id":"PMC_24575387","title":"Growth Impairment of Small-Cell Cancer by Targeting Pro-Vasopressin with MAG-1 Antibody.","date":"2014","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/24575387","citation_count":4,"is_preprint":false},{"pmid":"26094316","id":"PMC_26094316","title":"Recombinant MAG1 Protein of Toxoplasma gondii as a Diagnostic Antigen.","date":"2015","source":"Polish journal of microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/26094316","citation_count":3,"is_preprint":false},{"pmid":"7941752","id":"PMC_7941752","title":"The MAG1* 3-methyladenine DNA glycosylase gene is closely linked to the SPT15 TATA-binding TFIID gene on chromosome V-R in Saccharomyces cerevisiae.","date":"1994","source":"Yeast (Chichester, England)","url":"https://pubmed.ncbi.nlm.nih.gov/7941752","citation_count":3,"is_preprint":false},{"pmid":"16280667","id":"PMC_16280667","title":"Immunohistochemical detection of NRSA on small cell lung cancer with a monoclonal antibody (MAG-1) that recognizes the carboxyl terminus of provasopressin.","date":"2005","source":"Applied immunohistochemistry & molecular morphology : AIMM","url":"https://pubmed.ncbi.nlm.nih.gov/16280667","citation_count":3,"is_preprint":false},{"pmid":"20716399","id":"PMC_20716399","title":"[Promotion of MAG-1 on Metastasis of Lung Cancer Cells in vitro and Its Expression in Lung Cancer Tissue of 24 Cases.].","date":"2009","source":"Zhongguo fei ai za zhi = Chinese journal of lung cancer","url":"https://pubmed.ncbi.nlm.nih.gov/20716399","citation_count":2,"is_preprint":false},{"pmid":"36600165","id":"PMC_36600165","title":"Protective efficacy of Toxoplasma gondii bivalent MAG1 and SAG1 DNA vaccine against acute toxoplasmosis in BALB/c mice.","date":"2023","source":"Parasitology research","url":"https://pubmed.ncbi.nlm.nih.gov/36600165","citation_count":1,"is_preprint":false},{"pmid":"39820567","id":"PMC_39820567","title":"Isolation and Characterization of GPAT3 Gene from Jojoba Plant and its Inferior Early Diagnosis of Sex.","date":"2025","source":"Pakistan journal of biological sciences : PJBS","url":"https://pubmed.ncbi.nlm.nih.gov/39820567","citation_count":0,"is_preprint":false},{"pmid":"41791621","id":"PMC_41791621","title":"Babaodan alleviates MAFLD through hepatic glycerophospholipid metabolism and PPARγ/RXRA/GPAT3 based on spatial metabolomics and proteomics analysis.","date":"2026","source":"Journal of ethnopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41791621","citation_count":0,"is_preprint":false},{"pmid":"41392190","id":"PMC_41392190","title":"AP-1 elements in the promoter and second intron mediate endoplasmic reticulum stress-induced expression of the GPAT3 gene.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/41392190","citation_count":0,"is_preprint":false},{"pmid":"41962784","id":"PMC_41962784","title":"GPAT3 facilitates AHPND-causing Vibrio parahaemolyticus pathogenesis by driving lipid droplets accumulation in shrimp.","date":"2026","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41962784","citation_count":0,"is_preprint":false},{"pmid":"41547406","id":"PMC_41547406","title":"Evaluation of recombinant Toxoplasma gondii matrix antigen MAG1 for toxoplasmosis screening in HIV/AIDS patients.","date":"2026","source":"Acta tropica","url":"https://pubmed.ncbi.nlm.nih.gov/41547406","citation_count":0,"is_preprint":false},{"pmid":"21310131","id":"PMC_21310131","title":"[Identification of novel metastasis associated genes MAG-1 and MAG-2].","date":"2003","source":"Zhongguo fei ai za zhi = Chinese journal of lung cancer","url":"https://pubmed.ncbi.nlm.nih.gov/21310131","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.11.08.622601","title":"<i>Toxoplasma gondii</i>  infection of neurons alters the production and content of extracellular vesicles altering astrocyte phenotype and contributing to the loss of GLT-1 in the infected brain","date":"2024-11-08","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.08.622601","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":25614,"output_tokens":2864,"usd":0.059901,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10210,"output_tokens":3211,"usd":0.065662,"stage2_stop_reason":"end_turn"},"total_usd":0.125563,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2010,\n      \"finding\": \"GPAT3 catalyzes the first step in de novo glycerolipid synthesis (acylation of glycerol-3-phosphate) and is the predominant GPAT isoform in adipocytes; shRNA-mediated knockdown of GPAT3 in 3T3-L1 adipocytes significantly decreased total GPAT activity, inhibited lipid accumulation, and blocked expression of adipogenic markers during differentiation, while GPAT4 knockdown had no such effect.\",\n      \"method\": \"shRNA knockdown in 3T3-L1 adipocytes, GPAT activity assay, overexpression in insect and mammalian cells\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal gain- and loss-of-function with defined enzymatic and cellular phenotypes, replicated across cell types\",\n      \"pmids\": [\"20181984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"GPAT3 (and GPAT4) are phosphorylated at Ser and Thr residues in response to insulin, leading to increased GPAT enzymatic activity that is sensitive to the PI3K inhibitor wortmannin, linking insulin signaling to microsomal GPAT activity.\",\n      \"method\": \"Phosphorylation assay after insulin stimulation, wortmannin inhibition, overexpression in mammalian cells\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, phosphorylation demonstrated but specific kinase not identified; wortmannin sensitivity places it downstream of PI3K\",\n      \"pmids\": [\"20181984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"GPAT3 (LPAAT-theta) localizes primarily to the endoplasmic reticulum and its overexpression induces mTOR-dependent phosphorylation of p70S6K at Thr389 and 4EBP1 at Ser65 in HEK293T cells.\",\n      \"method\": \"EGFP fusion protein subcellular localization in COS-7 cells, western blot of p70S6K and 4EBP1 phosphorylation upon overexpression in HEK293T cells\",\n      \"journal\": \"Journal of biochemistry and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, localization by fluorescent fusion and signaling by overexpression only, no mutagenesis or pathway epistasis\",\n      \"pmids\": [\"17002884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"GPAT3 is the primary GPAT enzyme in white adipose tissue in vivo; Gpat3-/- mice show 80% reduction in total GPAT activity in white adipose tissue, altered energy expenditure, improved glucose tolerance under high-fat diet, and dysregulated cholesterol metabolism, establishing GPAT3 as a rate-limiting enzyme for glycerolipid synthesis in adipose.\",\n      \"method\": \"Gpat3 knockout mice, GPAT activity assays in multiple tissues, metabolic phenotyping under standard and high-fat diet conditions\",\n      \"journal\": \"American journal of physiology. Endocrinology and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO with direct enzymatic activity measurement and multiple metabolic phenotypes\",\n      \"pmids\": [\"24714397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"GPAT3 physically associates with the lipodystrophy scaffold protein seipin via direct protein-protein interaction, and seipin can simultaneously bind both GPAT3 and AGPAT2; loss of GPAT3 in seipin-deficient preadipocytes exacerbates the failure of adipogenesis, indicating GPAT3 plays a modest positive role in adipocyte differentiation downstream of seipin.\",\n      \"method\": \"Co-immunoprecipitation, direct interaction assays, siRNA knockdown in cultured preadipocytes, assessment of adipogenic marker expression\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding assays and genetic epistasis in cell culture, single lab, two orthogonal methods\",\n      \"pmids\": [\"32094408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"GPAT3 deficiency in seipin-null (BSCL2) mice partially rescues white adipose tissue mass, nearly completely restores brown adipose tissue mass, and significantly improves liver steatosis and insulin sensitivity, establishing a functional in vivo link between seipin and GPAT3 in lipid homeostasis.\",\n      \"method\": \"Double knockout mouse model (Seipin-/-Gpat3-/-), metabolic phenotyping, histology, insulin tolerance tests\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo double-KO genetic epistasis with multiple defined phenotypic readouts\",\n      \"pmids\": [\"31873720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"GPAT3 upregulation in Kupffer cells increases lysophosphatidic acid (LPA) production, which activates the ERK signaling pathway to exacerbate inflammatory responses; GPAT3 loss-of-function reduced LPA levels, improved mitochondrial function, and decreased ERK-mediated inflammation both in vivo and in vitro.\",\n      \"method\": \"GPAT3 siRNA/KO in Kupffer cells, LPA measurement, ERK pathway western blot, LPS stimulation model in vivo and in vitro\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with mechanistic lipid intermediate measurement and pathway readout, single lab\",\n      \"pmids\": [\"36964139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Mycobacterium leprae infection induces GPAT3 expression in human THP-1 macrophages, and CRISPR/Cas9 knockout of GPAT3 dramatically reduces triacylglycerol accumulation, intracellular mycobacterial load, and bacterial viability, demonstrating that GPAT3-driven TAG synthesis is exploited by M. leprae for intracellular survival.\",\n      \"method\": \"CRISPR/Cas9 GPAT3 knockout in THP-1 cells, [14C] stearic acid tracing, HPTLC lipid analysis, bacterial viability assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR KO with radiolabeled lipid tracing and multiple functional readouts in a single rigorous study\",\n      \"pmids\": [\"33770127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GPAT3 upregulation in sorafenib-resistant HCC cells is driven by STAT3 transcriptional activation (ChIP confirmed); GPAT3 overexpression increases triglyceride synthesis and activates the NF-κB/Bcl2 signaling pathway, leading to apoptosis resistance, while GPAT3 restoration resensitized resistant cells to sorafenib.\",\n      \"method\": \"ChIP assay (STAT3 binding to GPAT3 promoter), proteomics, gain- and loss-of-function studies, flow cytometry, western blot for NF-κB/Bcl2, in vivo xenograft\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP for upstream regulation plus gain/loss-of-function with pathway readout, single lab\",\n      \"pmids\": [\"38948063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GPAT3 expression is directly controlled at the transcriptional level by the glucocorticoid receptor (GR); deletion of GPAT3 in CORT-treated cells activates the GSK3β/Nrf2 pathway, reducing hepatic fat accumulation and oxidative stress and increasing fatty acid oxidation gene expression.\",\n      \"method\": \"GPAT3 siRNA in AML12 cells and Gpat3-/- mice, GR binding to GPAT3 promoter, western blot for GSK3β/Nrf2, ROS measurement, mitochondrial membrane potential assay\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO/KD with mechanistic pathway analysis and promoter regulation, single lab\",\n      \"pmids\": [\"38185063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ER stress induces GPAT3 gene expression through ATF4-dependent activation of AP-1 elements located in the GPAT3 promoter and second intron; CRISPR/Cas9 deletion of the intronic AP-1 region reduced GPAT3 expression and triglyceride content in both unstressed and ER-stressed hepatoma cells.\",\n      \"method\": \"CRISPR/Cas9 ATF4 disruption, luciferase reporter assays with mutational analysis, CRISPR deletion of intronic AP-1 region, transcriptome profiling, triglyceride measurement\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (reporter assays with mutagenesis, CRISPR deletion, transcriptomics) in a single study establishing the regulatory mechanism\",\n      \"pmids\": [\"41392190\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GPAT3 is a microsomal acyl-CoA:glycerol-3-phosphate acyltransferase localized to the endoplasmic reticulum that catalyzes the rate-limiting first step in de novo glycerolipid/triglyceride synthesis; it is the predominant GPAT in white adipose tissue, is transcriptionally regulated by GR, ATF4/AP-1, and STAT3, is post-translationally activated by insulin-stimulated (PI3K-dependent) phosphorylation, physically associates with the scaffold protein seipin (which co-ordinates GPAT3 with AGPAT2), produces the lipid intermediate LPA to activate ERK signaling in macrophages, and drives NF-κB/Bcl2-mediated apoptosis resistance through triglyceride accumulation in cancer cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"GPAT3 is an endoplasmic reticulum-resident acyl-CoA:glycerol-3-phosphate acyltransferase that catalyzes the first, rate-limiting acylation step of de novo glycerolipid and triglyceride synthesis, and it is the predominant GPAT isoform in adipocytes and white adipose tissue [#0, #3]. Knockdown or knockout abolishes most cellular and tissue GPAT activity, blocks adipogenic differentiation, and in vivo alters energy expenditure, glucose tolerance, and cholesterol handling, establishing GPAT3 as the principal driver of adipose glycerolipid storage [#0, #3]. Its activity is acutely tuned by insulin through PI3K-dependent Ser/Thr phosphorylation, and its expression is transcriptionally controlled by multiple stress- and metabolism-linked inputs: the glucocorticoid receptor, ATF4-driven AP-1 elements activated during ER stress, and STAT3 [#1, #9, #10, #8]. GPAT3 functions in coordination with the lipodystrophy scaffold seipin, with which it directly interacts and which can simultaneously engage AGPAT2; loss of GPAT3 in seipin-null mice partially rescues adipose mass, hepatic steatosis, and insulin sensitivity, defining a seipin-GPAT3 axis in lipid homeostasis [#4, #5]. Beyond lipid storage, GPAT3-generated lysophosphatidic acid activates ERK signaling to amplify Kupffer-cell inflammation, GPAT3-driven triacylglycerol accumulation is exploited by Mycobacterium leprae for intracellular survival in macrophages, and in sorafenib-resistant hepatocellular carcinoma GPAT3 promotes triglyceride synthesis and NF-\\u03baB/Bcl2-mediated apoptosis resistance [#6, #7, #8].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established the subcellular site of GPAT3 action and an early link to growth signaling, framing whether this acyltransferase resides where de novo lipid synthesis occurs.\",\n      \"evidence\": \"EGFP-fusion localization in COS-7 cells and overexpression-driven p70S6K/4EBP1 phosphorylation readouts in HEK293T cells\",\n      \"pmids\": [\"17002884\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"mTOR-pathway effect shown only by overexpression without mutagenesis or epistasis\", \"no direct demonstration that catalytic activity drives the signaling effect\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined GPAT3 as the catalytically dominant, rate-limiting GPAT isoform in adipocytes and showed insulin acutely regulates its activity, connecting hormonal signaling to glycerolipid synthesis.\",\n      \"evidence\": \"shRNA knockdown and overexpression in 3T3-L1 adipocytes with GPAT activity assays, plus insulin-stimulated phosphorylation with wortmannin inhibition\",\n      \"pmids\": [\"20181984\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"specific kinase mediating insulin-driven phosphorylation not identified\", \"phosphosite-to-activity causality (Medium-confidence arm) not resolved by mutagenesis\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Confirmed in vivo that GPAT3 carries most adipose GPAT activity and shapes systemic metabolism, elevating the cell-culture findings to a whole-organism rate-limiting role.\",\n      \"evidence\": \"Gpat3-/- mice with tissue GPAT activity assays and metabolic phenotyping on standard and high-fat diets\",\n      \"pmids\": [\"24714397\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"mechanism linking GPAT3 loss to altered cholesterol metabolism unresolved\", \"tissue-specific contributions outside white adipose not dissected\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed GPAT3 in a physical and genetic partnership with the lipodystrophy scaffold seipin, explaining how the acyltransferase is organized with AGPAT2 during adipocyte lipid synthesis.\",\n      \"evidence\": \"Co-immunoprecipitation and direct interaction assays plus siRNA epistasis in preadipocytes, and a Seipin-/-Gpat3-/- double-knockout mouse with metabolic phenotyping\",\n      \"pmids\": [\"32094408\", \"31873720\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"structural basis of the seipin-GPAT3-AGPAT2 assembly not determined\", \"interaction and epistasis data derive from single labs\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed GPAT3 acts beyond storage by generating LPA that drives ERK-dependent inflammation, identifying a signaling-lipid output of the enzyme in macrophage-lineage cells.\",\n      \"evidence\": \"siRNA/KO of GPAT3 in Kupffer cells with LPA measurement, ERK western blots, and LPS stimulation in vivo and in vitro\",\n      \"pmids\": [\"36964139\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"direct causal link between GPAT3-derived LPA and ERK activation not isolated from other lipid changes\", \"single-lab study\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated that pathogen-induced GPAT3 fuels TAG accumulation co-opted for intracellular bacterial survival, extending GPAT3 function into host-pathogen lipid metabolism.\",\n      \"evidence\": \"CRISPR/Cas9 GPAT3 knockout in THP-1 macrophages with [14C]stearic acid tracing, HPTLC, and bacterial viability assays after M. leprae infection\",\n      \"pmids\": [\"33770127\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"transcriptional inducer of GPAT3 upon M. leprae infection not identified\", \"whether TAG itself or downstream lipids support bacterial survival unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected stress- and hormone-responsive transcription factors (GR and STAT3) to GPAT3 and linked GPAT3-driven triglyceride synthesis to hepatic oxidative stress and cancer apoptosis resistance.\",\n      \"evidence\": \"GR and STAT3 promoter-binding/ChIP, Gpat3-/- mice and siRNA with GSK3\\u03b2/Nrf2 and NF-\\u03baB/Bcl2 pathway readouts, plus HCC xenograft sorafenib resistance assays\",\n      \"pmids\": [\"38185063\", \"38948063\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"whether GPAT3 catalytic product or protein scaffolding drives NF-\\u03baB/Bcl2 and GSK3\\u03b2/Nrf2 effects not separated\", \"single-lab findings for each disease context\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved how ER stress induces GPAT3 transcription, identifying an ATF4-dependent AP-1 regulatory architecture spanning promoter and intron that controls triglyceride output.\",\n      \"evidence\": \"CRISPR/Cas9 ATF4 disruption, luciferase reporters with mutagenesis, CRISPR deletion of an intronic AP-1 region, and transcriptome and triglyceride profiling in hepatoma cells\",\n      \"pmids\": [\"41392190\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"interplay between ATF4/AP-1, GR, and STAT3 inputs at the GPAT3 locus not integrated\", \"physiological stressors engaging this element in vivo not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How GPAT3's catalytic acyltransferase activity is mechanistically partitioned between bulk lipid storage and the production of signaling lipids (LPA) across different cell types remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"no structural model of the catalytic site or of the seipin-GPAT3-AGPAT2 complex\", \"kinase responsible for insulin-driven activation unidentified\", \"whether disease phenotypes require catalysis versus scaffolding not dissected\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0016746\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 3, 7]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"BSCL2\",\n      \"AGPAT2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}