{"gene":"GPAT3","run_date":"2026-04-28T18:06:53","timeline":{"discoveries":[{"year":2010,"finding":"GPAT3 catalyzes the first step in de novo glycerolipid synthesis (acylation of glycerol-3-phosphate) and is the major GPAT isoform in adipocytes; shRNA-mediated knockdown of GPAT3 in 3T3-L1 adipocytes significantly decreased GPAT activity, inhibited lipid accumulation, and blocked expression of adipogenic markers during differentiation.","method":"shRNA knockdown in 3T3-L1 adipocytes with GPAT activity assay, lipid accumulation measurement, and adipogenic marker expression analysis; overexpression in insect and mammalian cells","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (KD phenotype, activity assay, OE) in a single study with clear mechanistic readouts","pmids":["20181984"],"is_preprint":false},{"year":2010,"finding":"GPAT3 is phosphorylated at Ser and Thr residues in response to insulin stimulation, leading to increased GPAT enzymatic activity; this phosphorylation is sensitive to the PI3K inhibitor wortmannin, placing GPAT3 downstream of insulin/PI3K signaling.","method":"Insulin stimulation of cells expressing GPAT3 with phosphorylation detection (Ser/Thr), GPAT activity assay, wortmannin inhibition","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 2 — phosphorylation event linked to functional activity change with pharmacological inhibitor confirmation","pmids":["20181984"],"is_preprint":false},{"year":2014,"finding":"GPAT3 is the predominant GPAT isoform in white adipose tissue; Gpat3-/- mice showed 80% reduction in total GPAT activity in white adipose tissue, with no impact on liver total GPAT activity but a 30% reduction in N-ethylmaleimide-sensitive hepatic GPAT activity.","method":"Gpat3 knockout mice with tissue-specific GPAT activity assays (total and NEM-sensitive fractions)","journal":"American journal of physiology. Endocrinology and metabolism","confidence":"High","confidence_rationale":"Tier 2 — clean KO with direct enzyme activity measurement in multiple tissues","pmids":["24714397"],"is_preprint":false},{"year":2014,"finding":"GPAT3 deficiency in mice fed a high-fat diet leads to decreased body weight gain, reduced adiposity, and increased energy expenditure, with lowered fed glucose levels and improved glucose tolerance, establishing GPAT3 as a regulator of energy, glucose, and lipid homeostasis in vivo.","method":"Gpat3-/- mice on high-fat diet with metabolic phenotyping (body weight, adiposity, energy expenditure, glucose tolerance tests)","journal":"American journal of physiology. Endocrinology and metabolism","confidence":"High","confidence_rationale":"Tier 2 — KO with multiple defined metabolic phenotypic readouts","pmids":["24714397"],"is_preprint":false},{"year":2020,"finding":"Seipin directly interacts with GPAT3 and can simultaneously bind both GPAT3 and AGPAT2, forming a multi-enzyme complex; seipin acts as a scaffold that associates with GPAT3 via direct protein-protein interaction.","method":"Co-immunoprecipitation and direct interaction assays demonstrating seipin-GPAT3 and simultaneous seipin-GPAT3-AGPAT2 association","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 3 — direct binding shown by pulldown/Co-IP but single lab study","pmids":["32094408"],"is_preprint":false},{"year":2020,"finding":"Inhibition of GPAT3 expression impairs induction of early markers of adipocyte differentiation in cultured cells; loss of GPAT3 in seipin-deficient preadipocytes exacerbates failure of adipogenesis, indicating GPAT3 plays a positive modulatory role in adipogenesis downstream of seipin.","method":"siRNA/shRNA knockdown of GPAT3 in cultured preadipocytes with differentiation marker assays; genetic interaction with seipin-deficient cells","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2–3 — epistasis between seipin and GPAT3 in adipogenesis with cellular phenotype, single lab","pmids":["32094408"],"is_preprint":false},{"year":2020,"finding":"In vivo genetic interaction: Seipin-/-Gpat3-/- double-knockout mice showed partial recovery of white adipose tissue mass and near-complete restoration of brown adipose tissue mass compared to Seipin-/- single knockouts, with significant improvement in liver steatosis and insulin sensitivity, establishing a functional link between seipin and GPAT3 in vivo.","method":"Double-knockout mouse model (Seipin-/-Gpat3-/-) with tissue mass, histology, and metabolic phenotyping compared to single knockouts","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis in vivo with multiple orthogonal phenotypic readouts, independently confirming seipin-GPAT3 interaction","pmids":["31873720"],"is_preprint":false},{"year":2006,"finding":"GPAT3 (identified as LPAAT-theta) localizes primarily to the endoplasmic reticulum and overexpression activates mTOR-dependent p70S6K phosphorylation on Thr389 and 4EBP1 phosphorylation on Ser65 in HEK293T cells.","method":"EGFP fusion protein subcellular localization imaging; overexpression with western blot for mTOR pathway phosphorylation","journal":"Journal of biochemistry and molecular biology","confidence":"Medium","confidence_rationale":"Tier 3 — localization by fusion protein imaging and OE signaling assay, single lab","pmids":["17002884"],"is_preprint":false},{"year":2023,"finding":"GPAT3 promotes Kupffer cell inflammatory activation by synthesizing the lipid intermediate lysophosphatidic acid (LPA), which activates the ERK signaling pathway; loss of GPAT3 function reduced LPA production, improved mitochondrial function, and decreased inflammatory cytokine production both in vivo and in vitro.","method":"GPAT3 KO/knockdown in Kupffer cells with LPA measurement, ERK phosphorylation assay, mitochondrial function assays, in vivo LPS model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with defined substrate (LPA) and pathway (ERK) readouts in both in vitro and in vivo settings","pmids":["36964139"],"is_preprint":false},{"year":2021,"finding":"Mycobacterium leprae infection induces GPAT3 expression in human THP-1 macrophages, leading to increased triacylglycerol (TAG) synthesis; CRISPR/Cas9 knockout of GPAT3 dramatically reduced TAG accumulation, intracellular mycobacterial load, and bacterial viability, demonstrating that GPAT3-mediated TAG synthesis supports intracellular M. leprae survival.","method":"CRISPR/Cas9 GPAT3 knockout in THP-1 cells with [14C] stearic acid tracing, HPTLC lipid analysis, intracellular bacterial load quantification","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 — CRISPR KO with isotopic tracing and direct bacterial load readout, multiple orthogonal methods","pmids":["33770127"],"is_preprint":false},{"year":2024,"finding":"GPAT3 upregulation in sorafenib-resistant HCC cells is driven by STAT3 transcriptional activation; GPAT3 increases triglyceride synthesis and activates the NF-κB/Bcl2 signaling pathway, resulting in apoptosis resistance to sorafenib.","method":"ChIP assay for STAT3 binding to GPAT3 promoter; gain- and loss-of-function studies with flow cytometry, CCK8 viability assay, and in vivo tumor xenografts; proteomics and metabolomics","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP for transcriptional regulation plus functional epistasis with NF-κB/Bcl2 pathway, single lab","pmids":["38948063"],"is_preprint":false},{"year":2024,"finding":"GPAT3 deletion alleviates corticosterone-induced hepatic steatosis and oxidative stress by promoting activation of the GSK3β/Nrf2 signaling pathway; GPAT3 expression is directly regulated at the transcriptional level by the glucocorticoid receptor (GR).","method":"Gpat3-/- mice and siRNA knockdown in AML12 cells with CORT treatment; ROS measurement, mitochondrial membrane potential assay, Nrf2 pathway western blot; GR-GPAT3 transcriptional regulation analysis","journal":"Biochimica et biophysica acta. Molecular basis of disease","confidence":"Medium","confidence_rationale":"Tier 2 — KO plus in vitro KD with mechanistic pathway analysis, GR-mediated transcriptional control demonstrated","pmids":["38185063"],"is_preprint":false},{"year":2025,"finding":"GPAT3 gene expression is induced by ER stress through ATF4-mediated activation of AP-1 elements located in the GPAT3 promoter and second intron; CRISPR/Cas9 deletion of the intron 2 AP-1 region reduced both GPAT3 expression and triglyceride content in hepatoma cells.","method":"CRISPR/Cas9 ATF4 disruption, luciferase reporter assays with mutational analysis of AP-1 sites, CRISPR deletion of genomic AP-1 region, transcriptome profiling","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal methods including genomic deletion, reporter assays with mutagenesis, and ATF4 KO, all in the same study","pmids":["41392190"],"is_preprint":false}],"current_model":"GPAT3 is an endoplasmic reticulum-localized acyl-CoA:glycerol-3-phosphate acyltransferase that catalyzes the first and rate-limiting step in de novo glycerolipid/triglyceride synthesis; it is the predominant GPAT isoform in white adipose tissue, is regulated by insulin-stimulated phosphorylation via PI3K signaling and by ER stress via ATF4/AP-1 transcription factors and by glucocorticoid receptor, directly interacts with the lipodystrophy scaffold protein seipin (which also binds AGPAT2), produces the lipid intermediate LPA to activate ERK signaling in macrophages, and its activity is required for adipogenesis, energy homeostasis, and supports intracellular pathogen survival through TAG accumulation."},"narrative":{"teleology":[{"year":2006,"claim":"Initial characterization established that GPAT3 (then called LPAAT-theta) localizes to the endoplasmic reticulum and can activate mTOR-dependent signaling when overexpressed, placing it as an ER-resident lipid-metabolizing enzyme with potential signaling functions.","evidence":"EGFP fusion imaging and overexpression with mTOR pathway phosphorylation readouts in HEK293T cells","pmids":["17002884"],"confidence":"Medium","gaps":["Overexpression-only system; endogenous localization not confirmed","mTOR activation not linked to a specific enzymatic product","Enzymatic substrate specificity not demonstrated"]},{"year":2010,"claim":"GPAT3 was established as the major GPAT isoform in adipocytes, catalyzing glycerol-3-phosphate acylation essential for lipid accumulation and adipogenic differentiation, with its activity regulated by insulin-stimulated phosphorylation through PI3K signaling.","evidence":"shRNA knockdown in 3T3-L1 adipocytes with GPAT activity assays, lipid accumulation measurements, adipogenic markers; insulin/wortmannin phosphorylation studies","pmids":["20181984"],"confidence":"High","gaps":["Specific phosphorylation sites and the responsible kinase(s) downstream of PI3K not identified","In vivo confirmation of adipogenic role pending"]},{"year":2014,"claim":"In vivo knockout confirmed GPAT3 as the predominant white adipose GPAT isoform and demonstrated its requirement for normal body weight gain, adiposity, and glucose homeostasis under high-fat diet conditions.","evidence":"Gpat3-/- mice with tissue-specific enzyme activity assays and comprehensive metabolic phenotyping on high-fat diet","pmids":["24714397"],"confidence":"High","gaps":["Compensatory roles of other GPAT isoforms (GPAT1, GPAT2, GPAT4) in KO tissues not fully delineated","Mechanism linking reduced GPAT3 activity to increased energy expenditure unclear"]},{"year":2020,"claim":"The lipodystrophy scaffold protein seipin was shown to directly bind GPAT3 and simultaneously associate with AGPAT2, forming a multi-enzyme glycerolipid biosynthetic complex; in vivo genetic epistasis between seipin and GPAT3 confirmed their functional interdependence in adipose tissue maintenance and metabolic homeostasis.","evidence":"Co-immunoprecipitation for direct seipin-GPAT3-AGPAT2 interaction; Seipin-/-Gpat3-/- double-knockout mice with tissue mass, histology, and metabolic phenotyping","pmids":["32094408","31873720"],"confidence":"High","gaps":["Structural basis of seipin-GPAT3 interaction unknown","Whether seipin regulates GPAT3 catalytic activity or merely co-localizes it with AGPAT2 is unresolved","Reciprocal IP validation not described"]},{"year":2021,"claim":"GPAT3-mediated TAG synthesis was identified as a host metabolic pathway exploited by Mycobacterium leprae for intracellular survival, expanding GPAT3's functional significance beyond adipogenesis to host-pathogen interactions.","evidence":"CRISPR/Cas9 GPAT3 knockout in THP-1 macrophages with radiolabeled lipid tracing and intracellular bacterial load quantification","pmids":["33770127"],"confidence":"High","gaps":["Mechanism by which M. leprae induces GPAT3 expression not defined","Generalizability to other intracellular pathogens not tested"]},{"year":2023,"claim":"GPAT3 was shown to produce lysophosphatidic acid (LPA) as a signaling intermediate that activates ERK in Kupffer cells, linking GPAT3 enzymatic activity to inflammatory macrophage activation beyond its role in bulk TAG synthesis.","evidence":"GPAT3 KO/knockdown in Kupffer cells with LPA quantification, ERK phosphorylation, mitochondrial function assays, and in vivo LPS challenge","pmids":["36964139"],"confidence":"Medium","gaps":["LPA receptor(s) mediating ERK activation downstream of GPAT3 not identified","Relative contribution of GPAT3 vs. other LPA sources in Kupffer cells not quantified"]},{"year":2024,"claim":"Transcriptional regulation of GPAT3 was expanded to include STAT3 (in sorafenib-resistant hepatocellular carcinoma, linking GPAT3 to NF-κB/Bcl2-mediated apoptosis resistance) and the glucocorticoid receptor (mediating corticosterone-induced hepatic steatosis countered by GSK3β/Nrf2 signaling upon GPAT3 deletion).","evidence":"ChIP for STAT3 at GPAT3 promoter with gain/loss-of-function in HCC cells and xenografts; Gpat3-/- mice and siRNA in AML12 cells with CORT treatment and Nrf2 pathway analysis","pmids":["38948063","38185063"],"confidence":"Medium","gaps":["Whether STAT3 and GR regulation of GPAT3 occurs in normal physiological contexts beyond disease models is unclear","Direct versus indirect effects of GPAT3 on NF-κB and Nrf2 pathways not distinguished"]},{"year":2025,"claim":"ER stress was identified as a transcriptional inducer of GPAT3 through ATF4-mediated activation of AP-1 elements in the promoter and second intron, with genomic deletion of the intronic AP-1 region reducing both GPAT3 expression and cellular triglyceride content.","evidence":"CRISPR/Cas9 ATF4 disruption, luciferase reporters with AP-1 site mutagenesis, genomic CRISPR deletion of intronic regulatory region in hepatoma cells","pmids":["41392190"],"confidence":"High","gaps":["Whether ATF4/AP-1 regulation operates in adipose tissue in addition to hepatoma cells not shown","Interaction between ER stress and insulin/PI3K regulation of GPAT3 not explored"]},{"year":null,"claim":"Key unresolved questions include the structural basis of GPAT3's interaction with seipin and AGPAT2, the identity of the kinase(s) that phosphorylate GPAT3 downstream of PI3K, the specific LPA receptor(s) mediating GPAT3-dependent ERK activation, and whether GPAT3's diverse transcriptional inputs (insulin, GR, STAT3, ATF4) are integrated in a tissue-specific or context-dependent manner.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of GPAT3 or its complex with seipin","Kinase identity for insulin-stimulated phosphorylation remains unknown","Integrated model of multi-input transcriptional regulation lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,2,9]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,8]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,2,3,9,10,11,12]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,7,8,10]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8,9]}],"complexes":["Seipin-GPAT3-AGPAT2 glycerolipid biosynthetic complex"],"partners":["BSCL2","AGPAT2","ATF4","STAT3"],"other_free_text":[]},"mechanistic_narrative":"GPAT3 is an endoplasmic reticulum-localized acyl-CoA:glycerol-3-phosphate acyltransferase that catalyzes the first and rate-limiting step in de novo glycerolipid and triglyceride synthesis, functioning as the predominant GPAT isoform in white adipose tissue where it is essential for adipogenesis and energy homeostasis [PMID:20181984, PMID:24714397]. Its enzymatic activity is stimulated by insulin-dependent phosphorylation via PI3K signaling, and its transcription is regulated by the glucocorticoid receptor, STAT3, and by ER stress through ATF4-mediated activation of AP-1 elements [PMID:20181984, PMID:38185063, PMID:38948063, PMID:41392190]. GPAT3 physically interacts with the lipodystrophy scaffold protein seipin, which simultaneously binds GPAT3 and AGPAT2 to organize sequential glycerolipid biosynthetic enzymes, and genetic epistasis in double-knockout mice confirms this functional relationship in vivo [PMID:32094408, PMID:31873720]. Beyond adipose tissue, GPAT3-derived lysophosphatidic acid activates ERK signaling in Kupffer cells to drive inflammatory responses, and GPAT3-mediated TAG accumulation supports intracellular Mycobacterium leprae survival in macrophages [PMID:36964139, PMID:33770127]."},"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":90,"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":"17002884","id":"PMC_17002884","title":"Identification of a novel human lysophosphatidic acid acyltransferase, LPAAT-theta, which activates mTOR pathway.","date":"2006","source":"Journal of biochemistry and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17002884","citation_count":44,"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. Endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/24714397","citation_count":44,"is_preprint":false},{"pmid":"11738940","id":"PMC_11738940","title":"Deletion of the MAG1 DNA glycosylase gene suppresses alkylation-induced killing and mutagenesis in yeast cells lacking AP endonucleases.","date":"2001","source":"Mutation research","url":"https://pubmed.ncbi.nlm.nih.gov/11738940","citation_count":42,"is_preprint":false},{"pmid":"27124472","id":"PMC_27124472","title":"Behavioral Abnormalities in a Mouse Model of Chronic Toxoplasmosis Are Associated with MAG1 Antibody Levels and Cyst Burden.","date":"2016","source":"PLoS neglected tropical diseases","url":"https://pubmed.ncbi.nlm.nih.gov/27124472","citation_count":38,"is_preprint":false},{"pmid":"15722486","id":"PMC_15722486","title":"Biochemical characterization and DNA repair pathway interactions of Mag1-mediated base excision repair in Schizosaccharomyces pombe.","date":"2005","source":"Nucleic acids 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parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/28335675","citation_count":6,"is_preprint":false},{"pmid":"28597956","id":"PMC_28597956","title":"A post-GWAS confirming GPAT3 gene associated with pig growth and a significant SNP influencing its promoter activity.","date":"2017","source":"Animal genetics","url":"https://pubmed.ncbi.nlm.nih.gov/28597956","citation_count":5,"is_preprint":false},{"pmid":"20697529","id":"PMC_20697529","title":"Detection of Provasopressin in Invasive and Non-invasive (DCIS) Human Breast Cancer Using a Monoclonal Antibody Directed Against the C-terminus (MAG1).","date":"2010","source":"Breast cancer : basic and clinical research","url":"https://pubmed.ncbi.nlm.nih.gov/20697529","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":"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":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":"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":"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":"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":"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":"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":"41962784","id":"PMC_41962784","title":"GPAT3 facilitates AHPND-causing Vibrio parahaemolyticus pathogenesis by driving lipid droplets accumulation in shrimp.","date":"2026","source":"Fish & shellfish 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glycerolipid synthesis (acylation of glycerol-3-phosphate) and is the major GPAT isoform in adipocytes; shRNA-mediated knockdown of GPAT3 in 3T3-L1 adipocytes significantly decreased GPAT activity, inhibited lipid accumulation, and blocked expression of adipogenic markers during differentiation.\",\n      \"method\": \"shRNA knockdown in 3T3-L1 adipocytes with GPAT activity assay, lipid accumulation measurement, and adipogenic marker expression analysis; overexpression in insect and mammalian cells\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (KD phenotype, activity assay, OE) in a single study with clear mechanistic readouts\",\n      \"pmids\": [\"20181984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"GPAT3 is phosphorylated at Ser and Thr residues in response to insulin stimulation, leading to increased GPAT enzymatic activity; this phosphorylation is sensitive to the PI3K inhibitor wortmannin, placing GPAT3 downstream of insulin/PI3K signaling.\",\n      \"method\": \"Insulin stimulation of cells expressing GPAT3 with phosphorylation detection (Ser/Thr), GPAT activity assay, wortmannin inhibition\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — phosphorylation event linked to functional activity change with pharmacological inhibitor confirmation\",\n      \"pmids\": [\"20181984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"GPAT3 is the predominant GPAT isoform in white adipose tissue; Gpat3-/- mice showed 80% reduction in total GPAT activity in white adipose tissue, with no impact on liver total GPAT activity but a 30% reduction in N-ethylmaleimide-sensitive hepatic GPAT activity.\",\n      \"method\": \"Gpat3 knockout mice with tissue-specific GPAT activity assays (total and NEM-sensitive fractions)\",\n      \"journal\": \"American journal of physiology. Endocrinology and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with direct enzyme activity measurement in multiple tissues\",\n      \"pmids\": [\"24714397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"GPAT3 deficiency in mice fed a high-fat diet leads to decreased body weight gain, reduced adiposity, and increased energy expenditure, with lowered fed glucose levels and improved glucose tolerance, establishing GPAT3 as a regulator of energy, glucose, and lipid homeostasis in vivo.\",\n      \"method\": \"Gpat3-/- mice on high-fat diet with metabolic phenotyping (body weight, adiposity, energy expenditure, glucose tolerance tests)\",\n      \"journal\": \"American journal of physiology. Endocrinology and metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO with multiple defined metabolic phenotypic readouts\",\n      \"pmids\": [\"24714397\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Seipin directly interacts with GPAT3 and can simultaneously bind both GPAT3 and AGPAT2, forming a multi-enzyme complex; seipin acts as a scaffold that associates with GPAT3 via direct protein-protein interaction.\",\n      \"method\": \"Co-immunoprecipitation and direct interaction assays demonstrating seipin-GPAT3 and simultaneous seipin-GPAT3-AGPAT2 association\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — direct binding shown by pulldown/Co-IP but single lab study\",\n      \"pmids\": [\"32094408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Inhibition of GPAT3 expression impairs induction of early markers of adipocyte differentiation in cultured cells; loss of GPAT3 in seipin-deficient preadipocytes exacerbates failure of adipogenesis, indicating GPAT3 plays a positive modulatory role in adipogenesis downstream of seipin.\",\n      \"method\": \"siRNA/shRNA knockdown of GPAT3 in cultured preadipocytes with differentiation marker assays; genetic interaction with seipin-deficient cells\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — epistasis between seipin and GPAT3 in adipogenesis with cellular phenotype, single lab\",\n      \"pmids\": [\"32094408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In vivo genetic interaction: Seipin-/-Gpat3-/- double-knockout mice showed partial recovery of white adipose tissue mass and near-complete restoration of brown adipose tissue mass compared to Seipin-/- single knockouts, with significant improvement in liver steatosis and insulin sensitivity, establishing a functional link between seipin and GPAT3 in vivo.\",\n      \"method\": \"Double-knockout mouse model (Seipin-/-Gpat3-/-) with tissue mass, histology, and metabolic phenotyping compared to single knockouts\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in vivo with multiple orthogonal phenotypic readouts, independently confirming seipin-GPAT3 interaction\",\n      \"pmids\": [\"31873720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"GPAT3 (identified as LPAAT-theta) localizes primarily to the endoplasmic reticulum and overexpression activates mTOR-dependent p70S6K phosphorylation on Thr389 and 4EBP1 phosphorylation on Ser65 in HEK293T cells.\",\n      \"method\": \"EGFP fusion protein subcellular localization imaging; overexpression with western blot for mTOR pathway phosphorylation\",\n      \"journal\": \"Journal of biochemistry and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — localization by fusion protein imaging and OE signaling assay, single lab\",\n      \"pmids\": [\"17002884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"GPAT3 promotes Kupffer cell inflammatory activation by synthesizing the lipid intermediate lysophosphatidic acid (LPA), which activates the ERK signaling pathway; loss of GPAT3 function reduced LPA production, improved mitochondrial function, and decreased inflammatory cytokine production both in vivo and in vitro.\",\n      \"method\": \"GPAT3 KO/knockdown in Kupffer cells with LPA measurement, ERK phosphorylation assay, mitochondrial function assays, in vivo LPS model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined substrate (LPA) and pathway (ERK) readouts in both in vitro and in vivo settings\",\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, leading to increased triacylglycerol (TAG) synthesis; CRISPR/Cas9 knockout of GPAT3 dramatically reduced TAG accumulation, intracellular mycobacterial load, and bacterial viability, demonstrating that GPAT3-mediated TAG synthesis supports intracellular M. leprae survival.\",\n      \"method\": \"CRISPR/Cas9 GPAT3 knockout in THP-1 cells with [14C] stearic acid tracing, HPTLC lipid analysis, intracellular bacterial load quantification\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR KO with isotopic tracing and direct bacterial load readout, multiple orthogonal methods\",\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; GPAT3 increases triglyceride synthesis and activates the NF-κB/Bcl2 signaling pathway, resulting in apoptosis resistance to sorafenib.\",\n      \"method\": \"ChIP assay for STAT3 binding to GPAT3 promoter; gain- and loss-of-function studies with flow cytometry, CCK8 viability assay, and in vivo tumor xenografts; proteomics and metabolomics\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP for transcriptional regulation plus functional epistasis with NF-κB/Bcl2 pathway, single lab\",\n      \"pmids\": [\"38948063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GPAT3 deletion alleviates corticosterone-induced hepatic steatosis and oxidative stress by promoting activation of the GSK3β/Nrf2 signaling pathway; GPAT3 expression is directly regulated at the transcriptional level by the glucocorticoid receptor (GR).\",\n      \"method\": \"Gpat3-/- mice and siRNA knockdown in AML12 cells with CORT treatment; ROS measurement, mitochondrial membrane potential assay, Nrf2 pathway western blot; GR-GPAT3 transcriptional regulation analysis\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular basis of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO plus in vitro KD with mechanistic pathway analysis, GR-mediated transcriptional control demonstrated\",\n      \"pmids\": [\"38185063\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GPAT3 gene expression is induced by ER stress through ATF4-mediated activation of AP-1 elements located in the GPAT3 promoter and second intron; CRISPR/Cas9 deletion of the intron 2 AP-1 region reduced both GPAT3 expression and triglyceride content in hepatoma cells.\",\n      \"method\": \"CRISPR/Cas9 ATF4 disruption, luciferase reporter assays with mutational analysis of AP-1 sites, CRISPR deletion of genomic AP-1 region, transcriptome profiling\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods including genomic deletion, reporter assays with mutagenesis, and ATF4 KO, all in the same study\",\n      \"pmids\": [\"41392190\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"GPAT3 is an endoplasmic reticulum-localized acyl-CoA:glycerol-3-phosphate acyltransferase that catalyzes the first and rate-limiting step in de novo glycerolipid/triglyceride synthesis; it is the predominant GPAT isoform in white adipose tissue, is regulated by insulin-stimulated phosphorylation via PI3K signaling and by ER stress via ATF4/AP-1 transcription factors and by glucocorticoid receptor, directly interacts with the lipodystrophy scaffold protein seipin (which also binds AGPAT2), produces the lipid intermediate LPA to activate ERK signaling in macrophages, and its activity is required for adipogenesis, energy homeostasis, and supports intracellular pathogen survival through TAG accumulation.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"GPAT3 is an endoplasmic reticulum-localized acyl-CoA:glycerol-3-phosphate acyltransferase that catalyzes the first and rate-limiting step in de novo glycerolipid and triglyceride synthesis, functioning as the predominant GPAT isoform in white adipose tissue where it is essential for adipogenesis and energy homeostasis [PMID:20181984, PMID:24714397]. Its enzymatic activity is stimulated by insulin-dependent phosphorylation via PI3K signaling, and its transcription is regulated by the glucocorticoid receptor, STAT3, and by ER stress through ATF4-mediated activation of AP-1 elements [PMID:20181984, PMID:38185063, PMID:38948063, PMID:41392190]. GPAT3 physically interacts with the lipodystrophy scaffold protein seipin, which simultaneously binds GPAT3 and AGPAT2 to organize sequential glycerolipid biosynthetic enzymes, and genetic epistasis in double-knockout mice confirms this functional relationship in vivo [PMID:32094408, PMID:31873720]. Beyond adipose tissue, GPAT3-derived lysophosphatidic acid activates ERK signaling in Kupffer cells to drive inflammatory responses, and GPAT3-mediated TAG accumulation supports intracellular Mycobacterium leprae survival in macrophages [PMID:36964139, PMID:33770127].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Initial characterization established that GPAT3 (then called LPAAT-theta) localizes to the endoplasmic reticulum and can activate mTOR-dependent signaling when overexpressed, placing it as an ER-resident lipid-metabolizing enzyme with potential signaling functions.\",\n      \"evidence\": \"EGFP fusion imaging and overexpression with mTOR pathway phosphorylation readouts in HEK293T cells\",\n      \"pmids\": [\"17002884\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Overexpression-only system; endogenous localization not confirmed\", \"mTOR activation not linked to a specific enzymatic product\", \"Enzymatic substrate specificity not demonstrated\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"GPAT3 was established as the major GPAT isoform in adipocytes, catalyzing glycerol-3-phosphate acylation essential for lipid accumulation and adipogenic differentiation, with its activity regulated by insulin-stimulated phosphorylation through PI3K signaling.\",\n      \"evidence\": \"shRNA knockdown in 3T3-L1 adipocytes with GPAT activity assays, lipid accumulation measurements, adipogenic markers; insulin/wortmannin phosphorylation studies\",\n      \"pmids\": [\"20181984\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific phosphorylation sites and the responsible kinase(s) downstream of PI3K not identified\", \"In vivo confirmation of adipogenic role pending\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"In vivo knockout confirmed GPAT3 as the predominant white adipose GPAT isoform and demonstrated its requirement for normal body weight gain, adiposity, and glucose homeostasis under high-fat diet conditions.\",\n      \"evidence\": \"Gpat3-/- mice with tissue-specific enzyme activity assays and comprehensive metabolic phenotyping on high-fat diet\",\n      \"pmids\": [\"24714397\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Compensatory roles of other GPAT isoforms (GPAT1, GPAT2, GPAT4) in KO tissues not fully delineated\", \"Mechanism linking reduced GPAT3 activity to increased energy expenditure unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The lipodystrophy scaffold protein seipin was shown to directly bind GPAT3 and simultaneously associate with AGPAT2, forming a multi-enzyme glycerolipid biosynthetic complex; in vivo genetic epistasis between seipin and GPAT3 confirmed their functional interdependence in adipose tissue maintenance and metabolic homeostasis.\",\n      \"evidence\": \"Co-immunoprecipitation for direct seipin-GPAT3-AGPAT2 interaction; Seipin-/-Gpat3-/- double-knockout mice with tissue mass, histology, and metabolic phenotyping\",\n      \"pmids\": [\"32094408\", \"31873720\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of seipin-GPAT3 interaction unknown\", \"Whether seipin regulates GPAT3 catalytic activity or merely co-localizes it with AGPAT2 is unresolved\", \"Reciprocal IP validation not described\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"GPAT3-mediated TAG synthesis was identified as a host metabolic pathway exploited by Mycobacterium leprae for intracellular survival, expanding GPAT3's functional significance beyond adipogenesis to host-pathogen interactions.\",\n      \"evidence\": \"CRISPR/Cas9 GPAT3 knockout in THP-1 macrophages with radiolabeled lipid tracing and intracellular bacterial load quantification\",\n      \"pmids\": [\"33770127\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which M. leprae induces GPAT3 expression not defined\", \"Generalizability to other intracellular pathogens not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"GPAT3 was shown to produce lysophosphatidic acid (LPA) as a signaling intermediate that activates ERK in Kupffer cells, linking GPAT3 enzymatic activity to inflammatory macrophage activation beyond its role in bulk TAG synthesis.\",\n      \"evidence\": \"GPAT3 KO/knockdown in Kupffer cells with LPA quantification, ERK phosphorylation, mitochondrial function assays, and in vivo LPS challenge\",\n      \"pmids\": [\"36964139\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"LPA receptor(s) mediating ERK activation downstream of GPAT3 not identified\", \"Relative contribution of GPAT3 vs. other LPA sources in Kupffer cells not quantified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Transcriptional regulation of GPAT3 was expanded to include STAT3 (in sorafenib-resistant hepatocellular carcinoma, linking GPAT3 to NF-κB/Bcl2-mediated apoptosis resistance) and the glucocorticoid receptor (mediating corticosterone-induced hepatic steatosis countered by GSK3β/Nrf2 signaling upon GPAT3 deletion).\",\n      \"evidence\": \"ChIP for STAT3 at GPAT3 promoter with gain/loss-of-function in HCC cells and xenografts; Gpat3-/- mice and siRNA in AML12 cells with CORT treatment and Nrf2 pathway analysis\",\n      \"pmids\": [\"38948063\", \"38185063\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether STAT3 and GR regulation of GPAT3 occurs in normal physiological contexts beyond disease models is unclear\", \"Direct versus indirect effects of GPAT3 on NF-κB and Nrf2 pathways not distinguished\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"ER stress was identified as a transcriptional inducer of GPAT3 through ATF4-mediated activation of AP-1 elements in the promoter and second intron, with genomic deletion of the intronic AP-1 region reducing both GPAT3 expression and cellular triglyceride content.\",\n      \"evidence\": \"CRISPR/Cas9 ATF4 disruption, luciferase reporters with AP-1 site mutagenesis, genomic CRISPR deletion of intronic regulatory region in hepatoma cells\",\n      \"pmids\": [\"41392190\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ATF4/AP-1 regulation operates in adipose tissue in addition to hepatoma cells not shown\", \"Interaction between ER stress and insulin/PI3K regulation of GPAT3 not explored\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of GPAT3's interaction with seipin and AGPAT2, the identity of the kinase(s) that phosphorylate GPAT3 downstream of PI3K, the specific LPA receptor(s) mediating GPAT3-dependent ERK activation, and whether GPAT3's diverse transcriptional inputs (insulin, GR, STAT3, ATF4) are integrated in a tissue-specific or context-dependent manner.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal or cryo-EM structure of GPAT3 or its complex with seipin\", \"Kinase identity for insulin-stimulated phosphorylation remains unknown\", \"Integrated model of multi-input transcriptional regulation lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 2, 9]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 8]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 2, 3, 9, 10, 11, 12]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 7, 8, 10]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8, 9]}\n    ],\n    \"complexes\": [\n      \"Seipin-GPAT3-AGPAT2 glycerolipid biosynthetic complex\"\n    ],\n    \"partners\": [\n      \"BSCL2\",\n      \"AGPAT2\",\n      \"ATF4\",\n      \"STAT3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}