Affinage

GPAT3

Glycerol-3-phosphate acyltransferase 3 · UniProt Q53EU6

Length
434 aa
Mass
48.7 kDa
Annotated
2026-06-10
48 papers in source corpus 10 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 5/5 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2006 Medium

    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

    PMID:17002884

    Open questions at the time
    • mTOR-pathway effect shown only by overexpression without mutagenesis or epistasis
    • no direct demonstration that catalytic activity drives the signaling effect
  2. 2010 High

    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

    PMID:20181984

    Open questions at the time
    • specific kinase mediating insulin-driven phosphorylation not identified
    • phosphosite-to-activity causality (Medium-confidence arm) not resolved by mutagenesis
  3. 2014 High

    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

    PMID:24714397

    Open questions at the time
    • mechanism linking GPAT3 loss to altered cholesterol metabolism unresolved
    • tissue-specific contributions outside white adipose not dissected
  4. 2020 High

    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

    PMID:31873720 PMID:32094408

    Open questions at the time
    • structural basis of the seipin-GPAT3-AGPAT2 assembly not determined
    • interaction and epistasis data derive from single labs
  5. 2023 Medium

    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

    PMID:36964139

    Open questions at the time
    • direct causal link between GPAT3-derived LPA and ERK activation not isolated from other lipid changes
    • single-lab study
  6. 2021 High

    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

    PMID:33770127

    Open questions at the time
    • transcriptional inducer of GPAT3 upon M. leprae infection not identified
    • whether TAG itself or downstream lipids support bacterial survival unresolved
  7. 2024 Medium

    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

    PMID:38185063 PMID:38948063

    Open questions at the time
    • whether GPAT3 catalytic product or protein scaffolding drives NF-κB/Bcl2 and GSK3β/Nrf2 effects not separated
    • single-lab findings for each disease context
  8. 2025 High

    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

    PMID:41392190

    Open questions at the time
    • interplay between ATF4/AP-1, GR, and STAT3 inputs at the GPAT3 locus not integrated
    • physiological stressors engaging this element in vivo not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 2
Localization
GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-1430728 Metabolism 3
Partners
AGPAT2BSCL2

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 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. shRNA knockdown in 3T3-L1 adipocytes, GPAT activity assay, overexpression in insect and mammalian cells Journal of lipid research High 20181984
2010 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. Phosphorylation assay after insulin stimulation, wortmannin inhibition, overexpression in mammalian cells Journal of lipid research Medium 20181984
2006 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. EGFP fusion protein subcellular localization in COS-7 cells, western blot of p70S6K and 4EBP1 phosphorylation upon overexpression in HEK293T cells Journal of biochemistry and molecular biology Medium 17002884
2014 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. Gpat3 knockout mice, GPAT activity assays in multiple tissues, metabolic phenotyping under standard and high-fat diet conditions American journal of physiology. Endocrinology and metabolism High 24714397
2020 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. Co-immunoprecipitation, direct interaction assays, siRNA knockdown in cultured preadipocytes, assessment of adipogenic marker expression Scientific reports Medium 32094408
2020 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. Double knockout mouse model (Seipin-/-Gpat3-/-), metabolic phenotyping, histology, insulin tolerance tests Human molecular genetics High 31873720
2023 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. GPAT3 siRNA/KO in Kupffer cells, LPA measurement, ERK pathway western blot, LPS stimulation model in vivo and in vitro Cell death & disease Medium 36964139
2021 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. CRISPR/Cas9 GPAT3 knockout in THP-1 cells, [14C] stearic acid tracing, HPTLC lipid analysis, bacterial viability assay PloS one High 33770127
2024 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. 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 Theranostics Medium 38948063
2024 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. GPAT3 siRNA in AML12 cells and Gpat3-/- mice, GR binding to GPAT3 promoter, western blot for GSK3β/Nrf2, ROS measurement, mitochondrial membrane potential assay Biochimica et biophysica acta. Molecular basis of disease Medium 38185063
2025 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. CRISPR/Cas9 ATF4 disruption, luciferase reporter assays with mutational analysis, CRISPR deletion of intronic AP-1 region, transcriptome profiling, triglyceride measurement Scientific reports High 41392190

Source papers

Stage 0 corpus · 48 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 GPAT3 and GPAT4 are regulated by insulin-stimulated phosphorylation and play distinct roles in adipogenesis. Journal of lipid research 94 20181984
2004 The Toxoplasma gondii bradyzoite antigens BAG1 and MAG1 induce early humoral and cell-mediated immune responses upon human infection. Microbes and infection 66 14998514
2000 mag-1, a homolog of Drosophila mago nashi, regulates hermaphrodite germ-line sex determination in Caenorhabditis elegans. Developmental biology 47 10656761
2007 Use of MAG1 recombinant antigen for diagnosis of Toxoplasma gondii infection in humans. Clinical and vaccine immunology : CVI 46 17202305
2014 Mice deleted for GPAT3 have reduced GPAT activity in white adipose tissue and altered energy and cholesterol homeostasis in diet-induced obesity. American journal of physiology. Endocrinology and metabolism 45 24714397
2006 Identification of a novel human lysophosphatidic acid acyltransferase, LPAAT-theta, which activates mTOR pathway. Journal of biochemistry and molecular biology 44 17002884
2001 Deletion of the MAG1 DNA glycosylase gene suppresses alkylation-induced killing and mutagenesis in yeast cells lacking AP endonucleases. Mutation research 42 11738940
2016 Behavioral Abnormalities in a Mouse Model of Chronic Toxoplasmosis Are Associated with MAG1 Antibody Levels and Cyst Burden. PLoS neglected tropical diseases 39 27124472
2005 Biochemical characterization and DNA repair pathway interactions of Mag1-mediated base excision repair in Schizosaccharomyces pombe. Nucleic acids research 33 15722486
2011 A new MIC1-MAG1 recombinant chimeric antigen can be used instead of the Toxoplasma gondii lysate antigen in serodiagnosis of human toxoplasmosis. Clinical and vaccine immunology : CVI 32 22116686
1997 Bidirectional regulation of two DNA-damage-inducible genes, MAG1 and DDI1, from Saccharomyces cerevisiae. Molecular microbiology 32 9157248
2012 The Toxoplasma MAG1 peptides induce sex-based humoral immune response in mice and distinguish active from chronic human infection. Microbes and infection 25 23142034
2020 Oligomers of the lipodystrophy protein seipin may co-ordinate GPAT3 and AGPAT2 enzymes to facilitate adipocyte differentiation. Scientific reports 24 32094408
2004 Pdr3 is required for DNA damage induction of MAG1 and DDI1 via a bi-directional promoter element. Nucleic acids research 24 15452273
2020 GPAT3 deficiency alleviates insulin resistance and hepatic steatosis in a mouse model of severe congenital generalized lipodystrophy. Human molecular genetics 23 31873720
2002 The S. cerevisiae Mag1 3-methyladenine DNA glycosylase modulates susceptibility to homologous recombination. DNA repair 23 12509287
2012 MIC1-MAG1-SAG1 chimeric protein, a most effective antigen for detection of human toxoplasmosis. Clinical and vaccine immunology : CVI 22 23035174
2001 Sensitisation to the lipid-binding apolipophorin allergen Der p 14 and the peptide Mag-1. International archives of allergy and immunology 21 11306926
2010 The immune responses of sheep after DNA immunization with, Toxoplasma gondii MAG1 antigen-with and without co-expression of ovine interleukin 6. Veterinary immunology and immunopathology 20 20409592
2023 GPAT3 regulates the synthesis of lipid intermediate LPA and exacerbates Kupffer cell inflammation mediated by the ERK signaling pathway. Cell death & disease 19 36964139
2001 Two alternative cell cycle checkpoint pathways differentially control DNA damage-dependent induction of MAG1 and DDI1 expression in yeast. Molecular genetics and genomics : MGG 19 11713673
2015 New recombinant chimeric antigens, P35-MAG1, MIC1-ROP1, and MAG1-ROP1, for the serodiagnosis of human toxoplasmosis. Diagnostic microbiology and infectious disease 18 25702523
1997 UAS(MAG1), a yeast cis-acting element that regulates the expression of MAG1, is located within the protein coding region of DDI1. Molecular & general genetics : MGG 18 9294038
2010 Molecular characterization of Neospora caninum MAG1, a dense granule protein secreted into the parasitophorous vacuole, and associated with the cyst wall and the cyst matrix. Parasitology 17 20444303
1998 Differential regulation of two closely clustered yeast genes, MAG1 and DDI1, by cell-cycle checkpoints. Nucleic acids research 17 9826765
2023 The Heat Shock Transcription Factor PtHSF1 Mediates Triacylglycerol and Fucoxanthin Synthesis by Regulating the Expression of GPAT3 and DXS in Phaeodactylum tricornutum. Plant & cell physiology 15 36947404
2011 Analysis of substrate specificity of Schizosaccharomyces pombe Mag1 alkylpurine DNA glycosylase. EMBO reports 14 21960007
2024 GPAT3 is a potential therapeutic target to overcome sorafenib resistance in hepatocellular carcinoma. Theranostics 13 38948063
2024 GPAT3 deficiency attenuates corticosterone-caused hepatic steatosis and oxidative stress through GSK3β/Nrf2 signals. Biochimica et biophysica acta. Molecular basis of disease 12 38185063
2002 Targeting the neurophysin-related cell surface antigen on small cell lung cancer cells using a monoclonal antibody against the glycopeptide region (MAG-1) of provasopressin. Molecular cancer therapeutics 10 12479696
2021 Mycobacterium leprae promotes triacylglycerol de novo synthesis through induction of GPAT3 expression in human premonocytic THP-1 cells. PloS one 8 33770127
2008 Deletion of MAG1 and MRE11 enhances the sensitivity of the Saccharomyces cerevisiae HUG1P-GFP promoter-reporter construct to genotoxicity. Biosensors & bioelectronics 8 18693109
2017 Development and Application of an Indirect Enzyme-Linked Immunosorbent Assay Using Recombinant Mag1 for Serodiagnosis of Toxoplasma gondii In Dogs. The Journal of parasitology 6 28335675
2017 A post-GWAS confirming GPAT3 gene associated with pig growth and a significant SNP influencing its promoter activity. Animal genetics 5 28597956
2014 Growth Impairment of Small-Cell Cancer by Targeting Pro-Vasopressin with MAG-1 Antibody. Frontiers in oncology 4 24575387
2012 Metastasis-associated gene, mag-1 improves tumour microenvironmental adaptation and potentiates tumour metastasis. Journal of cellular and molecular medicine 4 22985252
2010 Detection of Provasopressin in Invasive and Non-invasive (DCIS) Human Breast Cancer Using a Monoclonal Antibody Directed Against the C-terminus (MAG1). Breast cancer : basic and clinical research 4 20697529
2015 Recombinant MAG1 Protein of Toxoplasma gondii as a Diagnostic Antigen. Polish journal of microbiology 3 26094316
2005 Immunohistochemical detection of NRSA on small cell lung cancer with a monoclonal antibody (MAG-1) that recognizes the carboxyl terminus of provasopressin. Applied immunohistochemistry & molecular morphology : AIMM 3 16280667
1994 The MAG1* 3-methyladenine DNA glycosylase gene is closely linked to the SPT15 TATA-binding TFIID gene on chromosome V-R in Saccharomyces cerevisiae. Yeast (Chichester, England) 3 7941752
2009 [Promotion of MAG-1 on Metastasis of Lung Cancer Cells in vitro and Its Expression in Lung Cancer Tissue of 24 Cases.]. Zhongguo fei ai za zhi = Chinese journal of lung cancer 2 20716399
2023 Protective efficacy of Toxoplasma gondii bivalent MAG1 and SAG1 DNA vaccine against acute toxoplasmosis in BALB/c mice. Parasitology research 1 36600165
2026 Evaluation of recombinant Toxoplasma gondii matrix antigen MAG1 for toxoplasmosis screening in HIV/AIDS patients. Acta tropica 0 41547406
2026 Babaodan alleviates MAFLD through hepatic glycerophospholipid metabolism and PPARγ/RXRA/GPAT3 based on spatial metabolomics and proteomics analysis. Journal of ethnopharmacology 0 41791621
2026 GPAT3 facilitates AHPND-causing Vibrio parahaemolyticus pathogenesis by driving lipid droplets accumulation in shrimp. Fish & shellfish immunology 0 41962784
2025 Isolation and Characterization of GPAT3 Gene from Jojoba Plant and its Inferior Early Diagnosis of Sex. Pakistan journal of biological sciences : PJBS 0 39820567
2025 AP-1 elements in the promoter and second intron mediate endoplasmic reticulum stress-induced expression of the GPAT3 gene. Scientific reports 0 41392190
2003 [Identification of novel metastasis associated genes MAG-1 and MAG-2]. Zhongguo fei ai za zhi = Chinese journal of lung cancer 0 21310131

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