Affinage

GPAT3

Glycerol-3-phosphate acyltransferase 3 · UniProt Q53EU6

Length
434 aa
Mass
48.7 kDa
Annotated
2026-04-28
48 papers in source corpus 10 papers cited in narrative 13 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

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

    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

    PMID:17002884

    Open questions at the time
    • Overexpression-only system; endogenous localization not confirmed
    • mTOR activation not linked to a specific enzymatic product
    • Enzymatic substrate specificity not demonstrated
  2. 2010 High

    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

    PMID:20181984

    Open questions at the time
    • Specific phosphorylation sites and the responsible kinase(s) downstream of PI3K not identified
    • In vivo confirmation of adipogenic role pending
  3. 2014 High

    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

    PMID:24714397

    Open questions at the time
    • 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
  4. 2020 High

    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

    PMID:31873720 PMID:32094408

    Open questions at the time
    • 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
  5. 2021 High

    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

    PMID:33770127

    Open questions at the time
    • Mechanism by which M. leprae induces GPAT3 expression not defined
    • Generalizability to other intracellular pathogens not tested
  6. 2023 Medium

    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

    PMID:36964139

    Open questions at the time
    • LPA receptor(s) mediating ERK activation downstream of GPAT3 not identified
    • Relative contribution of GPAT3 vs. other LPA sources in Kupffer cells not quantified
  7. 2024 Medium

    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

    PMID:38185063 PMID:38948063

    Open questions at the time
    • 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
  8. 2025 High

    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

    PMID:41392190

    Open questions at the time
    • 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

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 4 GO:0008289 lipid binding 2
Localization
GO:0005783 endoplasmic reticulum 1
Pathway
R-HSA-1430728 Metabolism 7 R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 2
Partners
AGPAT2ATF4BSCL2STAT3
Complex memberships
Seipin-GPAT3-AGPAT2 glycerolipid biosynthetic complex

Evidence

Reading pass · 13 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 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. 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 of lipid research High 20181984
2010 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. Insulin stimulation of cells expressing GPAT3 with phosphorylation detection (Ser/Thr), GPAT activity assay, wortmannin inhibition Journal of lipid research High 20181984
2014 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. Gpat3 knockout mice with tissue-specific GPAT activity assays (total and NEM-sensitive fractions) American journal of physiology. Endocrinology and metabolism High 24714397
2014 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. Gpat3-/- mice on high-fat diet with metabolic phenotyping (body weight, adiposity, energy expenditure, glucose tolerance tests) American journal of physiology. Endocrinology and metabolism High 24714397
2020 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. Co-immunoprecipitation and direct interaction assays demonstrating seipin-GPAT3 and simultaneous seipin-GPAT3-AGPAT2 association Scientific reports Medium 32094408
2020 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. siRNA/shRNA knockdown of GPAT3 in cultured preadipocytes with differentiation marker assays; genetic interaction with seipin-deficient cells Scientific reports Medium 32094408
2020 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. Double-knockout mouse model (Seipin-/-Gpat3-/-) with tissue mass, histology, and metabolic phenotyping compared to single knockouts Human molecular genetics High 31873720
2006 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. EGFP fusion protein subcellular localization imaging; overexpression with western blot for mTOR pathway phosphorylation Journal of biochemistry and molecular biology Medium 17002884
2023 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. GPAT3 KO/knockdown in Kupffer cells with LPA measurement, ERK phosphorylation assay, mitochondrial function assays, in vivo LPS model Cell death & disease Medium 36964139
2021 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. CRISPR/Cas9 GPAT3 knockout in THP-1 cells with [14C] stearic acid tracing, HPTLC lipid analysis, intracellular bacterial load quantification PloS one High 33770127
2024 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. 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 Theranostics Medium 38948063
2024 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). 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 Biochimica et biophysica acta. Molecular basis of disease Medium 38185063
2025 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. CRISPR/Cas9 ATF4 disruption, luciferase reporter assays with mutational analysis of AP-1 sites, CRISPR deletion of genomic AP-1 region, transcriptome profiling 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 90 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 44 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 38 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 24 23142034
2020 Oligomers of the lipodystrophy protein seipin may co-ordinate GPAT3 and AGPAT2 enzymes to facilitate adipocyte differentiation. Scientific reports 23 32094408
2004 Pdr3 is required for DNA damage induction of MAG1 and DDI1 via a bi-directional promoter element. Nucleic acids research 23 15452273
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
2020 GPAT3 deficiency alleviates insulin resistance and hepatic steatosis in a mouse model of severe congenital generalized lipodystrophy. Human molecular genetics 21 31873720
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
2001 Sensitisation to the lipid-binding apolipophorin allergen Der p 14 and the peptide Mag-1. International archives of allergy and immunology 20 11306926
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 GPAT3 regulates the synthesis of lipid intermediate LPA and exacerbates Kupffer cell inflammation mediated by the ERK signaling pathway. Cell death & disease 16 36964139
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 10 38948063
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
2024 GPAT3 deficiency attenuates corticosterone-caused hepatic steatosis and oxidative stress through GSK3β/Nrf2 signals. Biochimica et biophysica acta. Molecular basis of disease 9 38185063
2008 Deletion of MAG1 and MRE11 enhances the sensitivity of the Saccharomyces cerevisiae HUG1P-GFP promoter-reporter construct to genotoxicity. Biosensors & bioelectronics 8 18693109
2021 Mycobacterium leprae promotes triacylglycerol de novo synthesis through induction of GPAT3 expression in human premonocytic THP-1 cells. PloS one 7 33770127
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
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
2012 Metastasis-associated gene, mag-1 improves tumour microenvironmental adaptation and potentiates tumour metastasis. Journal of cellular and molecular medicine 3 22985252
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