{"gene":"MBOAT7","run_date":"2026-04-28T18:30:28","timeline":{"discoveries":[{"year":2012,"finding":"LPIAT1/MBOAT7 is a lysophosphatidylinositol acyltransferase that selectively incorporates arachidonic acid (AA) into phosphatidylinositol (PI). Lpiat1 knockout mice show almost no LPIAT activity with arachidonoyl-CoA as acyl donor, reduced AA content in PI and PI phosphates, and die within a month with atrophy of the cerebral cortex and hippocampus, disordered cortical lamination, delayed neuronal migration, and reduced neurite outgrowth in vitro.","method":"Mouse knockout (Lpiat1-/-), lipid mass spectrometry, immunohistochemistry, in vitro neurite outgrowth assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 — clean KO with multiple orthogonal readouts (lipidomics, histology, functional neurite assay), replicated in a second KO study","pmids":["23097495"],"is_preprint":false},{"year":2013,"finding":"LPIAT1/MBOAT7 plays a non-redundant role in maintaining physiological levels of PtdIns and PtdInsP2 through an active deacylation/reacylation cycle. LPIAT1 knockout mice show reduced C38:4 PtdIns and PtdInsP2 (26-44% reduction) and markedly elevated C18:0 lyso-PtdIns in both brain and liver, confirming a substrate-specific reacylation function.","method":"Mouse knockout (LPIAT1-/-), LC-ESI/MS lipidomics of brain and liver","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1-2 — in vivo KO with quantitative mass spectrometry lipidomics, orthogonal to prior KO study","pmids":["23472195"],"is_preprint":false},{"year":2016,"finding":"The MBOAT7 rs641738 T risk allele is associated with reduced MBOAT7 protein expression in the liver and changes in plasma phosphatidylinositol species consistent with decreased MBOAT7 acyltransferase function, linking the variant to impaired hepatic phosphatidylinositol acyl-chain remodeling.","method":"Human cohort genotyping, hepatic protein expression measurement, plasma lipidomics","journal":"Gastroenterology","confidence":"Medium","confidence_rationale":"Tier 2 — human cohort with protein expression and lipidomic readouts, single study","pmids":["26850495"],"is_preprint":false},{"year":2016,"finding":"Homozygous inactivating variants in MBOAT7 (encoding LPIAT1, a membrane-bound phospholipid-remodeling enzyme that transfers arachidonic acid to lysophosphatidylinositol) cause autosomal recessive intellectual disability accompanied by epilepsy and autistic features, establishing a direct role for AA-containing phosphatidylinositols in brain development.","method":"Human genetics (whole-exome sequencing, Sanger sequencing) in six consanguineous families","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 — multiple independent families with loss-of-function variants in the same gene and consistent phenotype","pmids":["27616480"],"is_preprint":false},{"year":2019,"finding":"MBOAT7 is an integral membrane protein anchored to endomembranes by six transmembrane domains. Its predicted catalytic dyad—Asn-321 and His-356—faces the lumen of endomembranes, consistent with acylation of lysophospholipid substrates on the lumenal side.","method":"Membrane fractionation, in silico topology prediction, GFP/FLAG-tagged truncation constructs in live cells, co-immunofluorescence, fluorescence protease protection (FPP) assay, selective membrane permeabilization","journal":"Journal of structural biology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal experimental methods (FPP, selective permeabilization, truncation constructs) converging on same topology model","pmids":["30959108"],"is_preprint":false},{"year":2019,"finding":"Mboat7 loss of function (but not Tmc4 loss) in mice is sufficient to promote NAFLD progression under high-fat diet. Mboat7 loss is associated with accumulation of its substrate lysophosphatidylinositol (LPI), and direct LPI administration promotes hepatic inflammatory and fibrotic transcriptional changes in an Mboat7-dependent manner, establishing the MBOAT7-driven acylation of LPI as a suppressor of NAFLD progression.","method":"Mouse whole-body knockout, antisense oligonucleotide knockdown, direct LPI administration, hepatic gene expression, histology","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — gene-specific KO (ruling out Tmc4), substrate accumulation demonstrated, causal rescue by substrate administration tested","pmids":["31621579"],"is_preprint":false},{"year":2020,"finding":"Hepatocyte-specific deletion of Mboat7 in mice causes spontaneous hepatic steatosis (increased cholesterol ester content) and increased fibrosis on high-fat diet, with accumulation of lysophosphatidylinositol species, via an inflammation-independent pathway of liver fibrosis mediated by lipid signaling.","method":"Hepatocyte-specific Mboat7 knockout mouse (Mboat7Δhep), histology (picrosirius red, hydroxyproline), flow cytometry, RNA-seq, lipidomics of mouse and human biopsies","journal":"Gut","confidence":"High","confidence_rationale":"Tier 1-2 — cell-type-specific KO with multiple orthogonal readouts including human lipidomic validation","pmids":["32591434"],"is_preprint":false},{"year":2020,"finding":"MBOAT7 depletion in hepatocytes increases triglyceride synthesis via a non-canonical pathway: reduced PI acyl-chain remodeling causes high PI turnover (simultaneous stimulation of PI synthesis and breakdown), and PI degradation by phospholipase C produces diacylglycerol (DAG), a triglyceride precursor, directly fueling hepatic fat accumulation.","method":"Hepatocyte-specific Lpiat1 KO mice, CRISPR-Cas9 and siRNA depletion in human hepatic cells and liver spheroids, radiolabeled glycerol/fatty acid flux, LC-ESI-MS lipidomics","journal":"Gut","confidence":"High","confidence_rationale":"Tier 1 — reconstitution of the metabolic pathway with isotope tracing plus in vivo and in vitro models","pmids":["32253259"],"is_preprint":false},{"year":2020,"finding":"Hyperinsulinemia downregulates Mboat7 expression (via insulin signaling activation after refeeding), and acute Mboat7 silencing promotes hepatic steatosis in vivo by reducing arachidonic acid incorporation into PI, resulting in accumulation of saturated triglycerides, enhanced lipogenesis, and upregulation of fatty acid transporter FATP1; FATP1 deletion rescues the steatotic phenotype.","method":"Antisense oligonucleotide silencing in C57Bl/6 mice, CRISPR-Cas9 deletion in HepG2 cells, radiolabeled fatty acid incorporation assay, in vivo insulin treatment, FATP1 rescue experiment","journal":"EBioMedicine","confidence":"High","confidence_rationale":"Tier 1-2 — enzymatic activity assay, genetic rescue (FATP1 KO reversal), multiple models","pmids":["32058943"],"is_preprint":false},{"year":2020,"finding":"MBOAT7 deletion in clear cell renal cell carcinoma (ccRCC) cells decreases proliferation, induces cell cycle arrest, and prevents tumor formation in vivo; MBOAT7-/- RNAseq reveals alterations in cell migration and extracellular matrix organization, functionally validated in migration assays. ccRCC tumors accumulate arachidonic acid-enriched phosphatidylinositols (AA-PI) in an MBOAT7-dependent manner.","method":"Genome editing (CRISPR) in ccRCC cell lines, proliferation assays, in vivo tumor formation, RNA-seq, migration assays, shotgun lipidomics","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 1-2 — genetic KO with multiple functional readouts and lipidomic mechanistic link","pmids":["32180553"],"is_preprint":false},{"year":2020,"finding":"ACSL3 channels arachidonic acid into phosphatidylinositols to provide LPIAT1/MBOAT7 with a pool of AA for sustained prostaglandin synthesis in lung cancer cells. LPIAT1 knockdown suppresses proliferation, anchorage-independent growth, and in vivo tumorigenesis in lung cancer, defining an ACSL3-LPIAT1 axis.","method":"Lung cancer cell line KD, KrasG12D mouse models, proliferation/colony assays, in vivo tumor models","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 — KD in multiple systems including in vivo, with mechanistic pathway placement (ACSL3 upstream of LPIAT1)","pmids":["32034305"],"is_preprint":false},{"year":2021,"finding":"MBOAT7 (LPIAT1) preferentially transfers 20:4 (arachidonic acid) and 20:5 polyunsaturated fatty acids to lysophosphatidylinositol. Missense mutations at the putative catalytic dyad (N321A, H356A, and N321A+H356A double mutant) abolish O-acyltransferase activity, confirming these residues as essential for catalysis.","method":"Recombinant MBOAT7 and mutants expressed in Pichia pastoris, Ni-affinity purification, in vitro acyltransferase assay with radiolabeled fatty acids","journal":"Biochimica et biophysica acta. Molecular and cell biology of lipids","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstituted enzymatic assay with site-directed mutagenesis of catalytic residues","pmids":["33513444"],"is_preprint":false},{"year":2021,"finding":"Hepatic deletion of Mboat7 causes activation of SREBP-1c and de novo lipogenesis as the mechanism underlying fatty liver. Lipidomics showed selective reduction in 20-carbon PUFA-containing phosphatidylinositols but not other phospholipids. Dual deletion of Scap (required for SREBP processing) and Mboat7 normalized hepatic triglycerides, establishing that increased SREBP-1c processing is required for Mboat7-induced steatosis.","method":"Liver-specific Mboat7 KO mice (Mboat7 LSKO), hepatic lipidomics by MS, dual Scap/Mboat7 liver KO genetic epistasis, gene expression analysis","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 1-2 — genetic epistasis (double KO rescues phenotype) plus lipidomics, identifying SREBP-1c as effector","pmids":["32859645"],"is_preprint":false},{"year":2022,"finding":"MBOAT7 functions as a negative regulator of toll-like receptor (TLR) signaling in macrophages. MBOAT7 deficiency alters membrane phospholipid composition, redistributes arachidonic acid toward proinflammatory eicosanoids, induces ER stress and mitochondrial dysfunction, and remodels the accessible inflammatory chromatin landscape, culminating in exaggerated macrophage TLR responses. Activation of MBOAT7 reverses these effects.","method":"MBOAT7 KD/KO in macrophages, lipidomics, eicosanoid measurement, ER stress and mitochondrial function assays, chromatin accessibility (ATAC-seq), TLR stimulation assays","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods in primary macrophages with gain-of-function reversal validation","pmids":["36473860"],"is_preprint":false},{"year":2023,"finding":"Cryo-EM structure of human MBOAT7 reveals that arachidonyl-CoA and lyso-PI access the catalytic center through a twisted tunnel from the cytosol and lumenal sides, respectively. N-terminal residues on the ER lumenal side determine phospholipid headgroup selectivity: swapping N-terminal regions between MBOATs 1, 5, and 7 converts enzyme specificity for different lyso-phospholipid substrates. Structure-based virtual screening identified small-molecule inhibitors.","method":"Cryo-EM structure determination, domain-swap mutagenesis with acyltransferase activity assays, virtual screening","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — high-resolution structure with functional mutagenesis validating mechanism and headgroup selectivity","pmids":["37316513"],"is_preprint":false},{"year":2023,"finding":"Golgi-resident scaffold protein MMD physically interacts with both ACSL4 and MBOAT7 and promotes flux of arachidonic acid into phosphatidylinositol. MMD promotes ferroptosis susceptibility in ovarian and renal carcinoma cells in an ACSL4- and MBOAT7-dependent manner, identifying a MMD-ACSL4-MBOAT7 complex that increases AA-PI levels and pro-ferroptotic phospholipid peroxidation.","method":"Co-immunoprecipitation, genetic KO of MMD/ACSL4/MBOAT7, ferroptosis assays, lipidomics","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP establishing complex, genetic epistasis (ACSL4/MBOAT7-dependent rescue), lipidomics","pmids":["37691145"],"is_preprint":false},{"year":2023,"finding":"MBOAT7-driven lysophosphatidylinositol acylation in adipocytes is the major source of arachidonic acid-containing PI pools in adipose tissue. Adipocyte-specific Mboat7 KO promotes hyperinsulinemia, systemic insulin resistance, and mild fatty liver in mice fed high-fat/high-sucrose diet, demonstrating a cell-autonomous role in glucose homeostasis distinct from hepatocyte MBOAT7 function.","method":"Floxed Mboat7 mice crossed to adiponectin-Cre and albumin-Cre, metabolic phenotyping, adipose/hepatic lipidomics, panel of ~100 inbred mouse strains","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 2 — cell-type-specific KO with metabolic phenotyping and lipidomic mechanistic readouts","pmids":["36806709"],"is_preprint":false},{"year":2024,"finding":"Hepatocyte MBOAT7 loss promotes liver fibrosis via a cholesterol trafficking pathway that upregulates TAZ (WWTR1) and TAZ-induced profibrotic factor Indian hedgehog (IHH). MBOAT7 restoration in MASH mice lowers hepatocyte TAZ levels and slows fibrosis progression; MBOAT7 silencing in established steatohepatitis exacerbates fibrosis and increases nuclear TAZ and IHH mRNA, a finding validated in human MASH livers carrying the rs641738-T allele.","method":"Hepatocyte-specific MBOAT7 overexpression/silencing in MASH mice (AAV, ASO), TAZ/IHH protein and mRNA measurement, human liver biopsy TAZ immunostaining","journal":"Hepatology","confidence":"High","confidence_rationale":"Tier 2 — gain- and loss-of-function in vivo with mechanistic pathway (MBOAT7→PI remodeling→cholesterol trafficking→TAZ→IHH), validated in humans","pmids":["38776184"],"is_preprint":false},{"year":2024,"finding":"Hepatocyte-specific (but not myeloid-specific) deletion of Mboat7 exacerbates ethanol-induced liver injury. Mboat7-HSKO livers show reorganization of the hepatic lipidome with increased endosomal/lysosomal lipids, dysregulated autophagic flux, impaired TFEB-mediated lysosomal biogenesis, and autophagosome accumulation, revealing that MBOAT7 shapes lysosomal lipid homeostasis to control alcohol-associated liver disease.","method":"Hepatocyte-specific and myeloid-specific Mboat7 KO mice, ethanol feeding, lipidomics, autophagic flux assays, TFEB pathway analysis, flow cytometry","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 — cell-type-specific KO (hepatocyte vs. myeloid), multiple orthogonal mechanistic readouts","pmids":["38648183"],"is_preprint":false}],"current_model":"MBOAT7 (LPIAT1) is an integral endomembrane acyltransferase with six transmembrane domains and a lumenally-oriented catalytic dyad (Asn-321, His-356) that, together with ACSL4 (and scaffold protein MMD), transfers polyunsaturated fatty acids—preferentially arachidonic acid—from arachidonoyl-CoA onto lysophosphatidylinositol to produce AA-enriched phosphatidylinositol via the Lands cycle; loss of this PI remodeling activity elevates lysophosphatidylinositol, activates SREBP-1c-driven de novo lipogenesis and a phospholipase C/DAG pathway that fuels triglyceride synthesis, promotes a TAZ/IHH profibrotic axis, disrupts lysosomal biogenesis and autophagic flux, redistributes arachidonic acid toward proinflammatory eicosanoids in macrophages (exacerbating TLR signaling), alters adipose PI homeostasis causing insulin resistance, and—when completely absent from birth—disrupts cortical neuronal migration and PI phosphate levels required for normal brain development."},"narrative":{"teleology":[{"year":2012,"claim":"Establishing that MBOAT7/LPIAT1 is the non-redundant lysophosphatidylinositol acyltransferase that incorporates arachidonic acid into PI, and that its absence disrupts brain PI composition, cortical lamination, and neuronal migration","evidence":"Lpiat1 knockout mice with lipidomics, histology, and neurite outgrowth assays","pmids":["23097495"],"confidence":"High","gaps":["Catalytic mechanism and substrate specificity not biochemically defined","Whether brain phenotype reflects PI or PIP2 depletion unresolved","Role in non-neural tissues not explored"]},{"year":2013,"claim":"Demonstrating that MBOAT7 loss reduces not only PI but also PIP2 species and elevates lyso-PI in both brain and liver, establishing a broader role in phosphoinositide homeostasis","evidence":"Lpiat1 KO mouse tissues analyzed by LC-ESI/MS lipidomics","pmids":["23472195"],"confidence":"High","gaps":["Liver functional consequences of altered PI not yet studied","Whether lyso-PI itself has signaling properties unknown"]},{"year":2016,"claim":"Linking the common MBOAT7 rs641738 variant to reduced hepatic MBOAT7 expression and altered plasma PI species in humans, connecting the enzyme to human liver disease susceptibility; simultaneously, rare biallelic MBOAT7 loss-of-function variants were shown to cause autosomal recessive intellectual disability with epilepsy","evidence":"Human cohort genotyping with hepatic protein/plasma lipidomics; whole-exome sequencing in six consanguineous families","pmids":["26850495","27616480"],"confidence":"High","gaps":["Mechanism linking reduced MBOAT7 to steatosis/fibrosis not defined","No animal model recapitulating rs641738 partial loss"]},{"year":2019,"claim":"Resolving MBOAT7 membrane topology—six transmembrane domains with a lumenally oriented catalytic dyad—and showing that Mboat7 loss is sufficient to promote NAFLD progression, with accumulated lyso-PI acting as a causal lipotoxic mediator","evidence":"Fluorescence protease protection and selective permeabilization in cells; Mboat7 KO and ASO knockdown mice with direct LPI administration","pmids":["30959108","31621579"],"confidence":"High","gaps":["High-resolution structure not yet available","Downstream signaling pathways from lyso-PI not mapped"]},{"year":2020,"claim":"Elucidating hepatocyte-autonomous mechanisms: MBOAT7 loss drives steatosis via both SREBP-1c activation (requiring Scap) and a PLC/DAG pathway that directly fuels triglyceride synthesis from PI breakdown; insulin signaling represses MBOAT7 expression, with FATP1 upregulation as a rescuable effector","evidence":"Hepatocyte-specific KO, Scap/Mboat7 double KO epistasis, isotope-tracing in hepatocytes and liver spheroids, FATP1 genetic rescue","pmids":["32591434","32253259","32859645","32058943"],"confidence":"High","gaps":["Relative contribution of SREBP-1c vs. PLC/DAG pathway not quantified","Whether insulin-mediated downregulation operates transcriptionally or post-transcriptionally unclear"]},{"year":2020,"claim":"Demonstrating that MBOAT7-generated AA-PI pools are required for cancer cell proliferation, with ACSL3 acting upstream to channel arachidonic acid into PI for MBOAT7 remodeling","evidence":"CRISPR KO in ccRCC and lung cancer cells, in vivo tumor models, lipidomics","pmids":["32180553","32034305"],"confidence":"High","gaps":["Whether pro-tumorigenic role is via eicosanoid generation, PI signaling, or ferroptosis sensitivity not resolved","Cancer-type specificity not established"]},{"year":2021,"claim":"Confirming MBOAT7 substrate preference for 20:4/20:5 PUFAs and the essentiality of the Asn-321/His-356 catalytic dyad through in vitro reconstitution with purified enzyme","evidence":"Recombinant MBOAT7 and site-directed mutants expressed in Pichia pastoris, radiolabeled acyltransferase assays","pmids":["33513444"],"confidence":"High","gaps":["Structural basis for PUFA selectivity unknown","Kinetic parameters not fully determined"]},{"year":2022,"claim":"Revealing that MBOAT7 is a negative regulator of TLR signaling in macrophages: its deficiency redistributes arachidonic acid toward proinflammatory eicosanoids, induces ER stress, and remodels chromatin accessibility at inflammatory loci","evidence":"MBOAT7 KO/KD in macrophages with lipidomics, eicosanoid profiling, ATAC-seq, gain-of-function rescue","pmids":["36473860"],"confidence":"High","gaps":["Which specific eicosanoid species drive the phenotype not pinpointed","In vivo macrophage-specific KO not tested"]},{"year":2023,"claim":"High-resolution cryo-EM structure revealed the twisted tunnel architecture for dual substrate access and showed that lumenal N-terminal residues determine PI headgroup selectivity; simultaneously, the Golgi-resident MMD–ACSL4–MBOAT7 complex was defined as a functional unit channeling AA into PI and sensitizing cells to ferroptosis","evidence":"Cryo-EM structure with domain-swap mutagenesis; reciprocal co-IP and genetic epistasis with ferroptosis assays","pmids":["37316513","37691145"],"confidence":"High","gaps":["Structure of the ternary MMD–ACSL4–MBOAT7 complex not resolved","Whether ferroptosis sensitization operates in hepatocytes in vivo unknown"]},{"year":2023,"claim":"Establishing a cell-autonomous metabolic role in adipocytes: adipocyte-specific MBOAT7 loss depletes AA-PI, promotes hyperinsulinemia and systemic insulin resistance independent of hepatocyte MBOAT7","evidence":"Adipocyte-specific Mboat7 KO mice with metabolic phenotyping and lipidomics","pmids":["36806709"],"confidence":"High","gaps":["Signaling pathway from adipocyte PI depletion to insulin resistance not defined","Contribution to human metabolic syndrome unknown"]},{"year":2024,"claim":"Identifying downstream pathways of hepatocyte MBOAT7 loss in chronic liver disease: a cholesterol trafficking–TAZ–IHH profibrotic axis drives fibrosis in MASH, while impaired TFEB-mediated lysosomal biogenesis and autophagic flux exacerbate alcohol-associated liver injury","evidence":"Hepatocyte-specific MBOAT7 overexpression/silencing in MASH mice with human biopsy validation; hepatocyte-specific KO with ethanol feeding and autophagic flux/TFEB analysis","pmids":["38776184","38648183"],"confidence":"High","gaps":["How altered PI composition mechanistically activates TAZ not resolved","Whether lysosomal defects and TAZ activation represent parallel or sequential pathways unknown"]},{"year":null,"claim":"Key open questions include the structural basis of the MMD–ACSL4–MBOAT7 ternary complex, the precise lipid signaling intermediate linking PI depletion to SREBP-1c processing, the mechanism by which altered PI composition disrupts lysosomal biogenesis and TFEB activity, and whether pharmacological MBOAT7 activation can reverse established liver fibrosis in humans","evidence":"","pmids":[],"confidence":"Low","gaps":["No ternary complex structure available","Lipid intermediate between PI depletion and SREBP-1c unknown","No clinical intervention data"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,7,11,14]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,11,14]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[4,14]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[15]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,1,7,11,12,16]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[12,17]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[5,6,17,18]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[18]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[15]}],"complexes":["MMD-ACSL4-MBOAT7"],"partners":["ACSL4","MMD","ACSL3","FATP1"],"other_free_text":[]},"mechanistic_narrative":"MBOAT7 (LPIAT1) is an integral endomembrane acyltransferase that selectively transfers arachidonic acid from arachidonoyl-CoA onto lysophosphatidylinositol to generate AA-enriched phosphatidylinositol, thereby maintaining the acyl-chain composition of PI and PI phosphates via the Lands cycle [PMID:23097495, PMID:33513444, PMID:37316513]. Its six-transmembrane topology positions the catalytic dyad (Asn-321/His-356) on the lumenal side, where arachidonyl-CoA and lyso-PI access the active site through a twisted tunnel, and N-terminal lumenal residues determine headgroup selectivity; MBOAT7 operates within a Golgi-localized MMD–ACSL4–MBOAT7 complex that channels arachidonic acid into PI [PMID:30959108, PMID:37316513, PMID:37691145]. Loss of MBOAT7 activity accumulates lysophosphatidylinositol and depletes AA-PI, triggering SREBP-1c–driven de novo lipogenesis and PLC/DAG-mediated triglyceride synthesis in hepatocytes, a TAZ/IHH profibrotic axis, impaired TFEB-dependent lysosomal biogenesis, redistribution of arachidonic acid toward proinflammatory eicosanoids in macrophages, and adipose insulin resistance—collectively driving NAFLD/MASH, alcohol-associated liver disease, and metabolic dysfunction [PMID:32859645, PMID:32253259, PMID:38776184, PMID:38648183, PMID:36473860, PMID:36806709]. Homozygous inactivating MBOAT7 variants cause autosomal recessive intellectual disability with epilepsy and autistic features, reflecting a requirement for AA-containing PI in cortical neuronal migration [PMID:27616480, PMID:23097495]."},"prefetch_data":{"uniprot":{"accession":"Q96N66","full_name":"Membrane-bound acylglycerophosphatidylinositol O-acyltransferase MBOAT7","aliases":["1-acylglycerophosphatidylinositol O-acyltransferase","Bladder and breast carcinoma-overexpressed gene 1 protein","Leukocyte receptor cluster member 4","Lysophosphatidylinositol acyltransferase","LPIAT","Lyso-PI acyltransferase","Lysophospholipid acyltransferase 7","LPLAT 7","Membrane-bound O-acyltransferase domain-containing protein 7","O-acyltransferase domain-containing protein 7","h-mboa-7"],"length_aa":472,"mass_kda":52.8,"function":"Acyltransferase which catalyzes the transfer of an acyl group from an acyl-CoA to a lysophosphatidylinositol (1-acylglycerophosphatidylinositol or LPI) leading to the production of a phosphatidylinositol (1,2-diacyl-sn-glycero-3-phosphoinositol or PI) and participates in the reacylation step of the phospholipid remodeling pathway also known as the Lands cycle (PubMed:18094042, PubMed:18772128). Prefers arachidonoyl-CoA as the acyl donor, thus contributing to the regulation of free levels arachidonic acid in cell (PubMed:18094042, PubMed:18772128). In liver, participates in the regulation of triglyceride metabolism through the phosphatidylinositol acyl-chain remodeling regulation (PubMed:32253259)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q96N66/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MBOAT7","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000125505","cell_line_id":"CID000338","localizations":[{"compartment":"er","grade":3}],"interactors":[{"gene":"LBR","stoichiometry":4.0},{"gene":"SGPL1","stoichiometry":0.2},{"gene":"CCDC47","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000338","total_profiled":1310},"omim":[{"mim_id":"617188","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL RECESSIVE 57; MRT57","url":"https://www.omim.org/entry/617188"},{"mim_id":"606048","title":"MEMBRANE-BOUND O-ACETYLTRANSFERASE DOMAIN-CONTAINING PROTEIN 7; MBOAT7","url":"https://www.omim.org/entry/606048"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"adrenal gland","ntpm":127.7}],"url":"https://www.proteinatlas.org/search/MBOAT7"},"hgnc":{"alias_symbol":["BB1","hMBOA-7","LPLAT","LPIAT1","LPLAT11"],"prev_symbol":["LENG4"]},"alphafold":{"accession":"Q96N66","domains":[{"cath_id":"-","chopping":"4-179","consensus_level":"high","plddt":93.4382,"start":4,"end":179},{"cath_id":"-","chopping":"304-448","consensus_level":"medium","plddt":95.4188,"start":304,"end":448}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96N66","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96N66-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96N66-F1-predicted_aligned_error_v6.png","plddt_mean":92.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MBOAT7","jax_strain_url":"https://www.jax.org/strain/search?query=MBOAT7"},"sequence":{"accession":"Q96N66","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96N66.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96N66/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96N66"}},"corpus_meta":[{"pmid":"7681471","id":"PMC_7681471","title":"Activated T cells induce expression of B7/BB1 on normal or leukemic B cells through a CD40-dependent signal.","date":"1993","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/7681471","citation_count":541,"is_preprint":false},{"pmid":"26850495","id":"PMC_26850495","title":"The MBOAT7-TMC4 Variant rs641738 Increases Risk of Nonalcoholic Fatty Liver Disease in Individuals of European Descent.","date":"2016","source":"Gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/26850495","citation_count":526,"is_preprint":false},{"pmid":"7678111","id":"PMC_7678111","title":"Induction of alloantigen-specific hyporesponsiveness in human T lymphocytes by blocking interaction of CD28 with its natural ligand B7/BB1.","date":"1993","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/7678111","citation_count":501,"is_preprint":false},{"pmid":"1847724","id":"PMC_1847724","title":"The CD28 ligand B7/BB1 provides costimulatory signal for alloactivation of CD4+ T cells.","date":"1991","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/1847724","citation_count":390,"is_preprint":false},{"pmid":"6274961","id":"PMC_6274961","title":"B lymphoblast antigen (BB-1) expressed on Epstein-Barr virus-activated B cell blasts, B lymphoblastoid cell lines, and Burkitt's lymphomas.","date":"1982","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/6274961","citation_count":345,"is_preprint":false},{"pmid":"1328465","id":"PMC_1328465","title":"Functional expression of the costimulatory molecule, B7/BB1, on murine dendritic cell populations.","date":"1992","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/1328465","citation_count":324,"is_preprint":false},{"pmid":"1378854","id":"PMC_1378854","title":"The B7/BB1 antigen provides one of several costimulatory signals for the activation of CD4+ T lymphocytes by human blood dendritic cells in vitro.","date":"1992","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/1378854","citation_count":294,"is_preprint":false},{"pmid":"7679711","id":"PMC_7679711","title":"Functional expression of B7/BB1 on activated T lymphocytes.","date":"1993","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/7679711","citation_count":283,"is_preprint":false},{"pmid":"7515723","id":"PMC_7515723","title":"In vivo blockade of CD28/CTLA4: B7/BB1 interaction with CTLA4-Ig reduces lethal murine graft-versus-host disease across the major histocompatibility complex barrier in mice.","date":"1994","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/7515723","citation_count":228,"is_preprint":false},{"pmid":"28674415","id":"PMC_28674415","title":"MBOAT7 rs641738 variant and hepatocellular carcinoma in non-cirrhotic individuals.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/28674415","citation_count":200,"is_preprint":false},{"pmid":"7511683","id":"PMC_7511683","title":"T cell costimulation by B7/BB1 induces CD8 T cell-dependent tumor rejection: an important role of B7/BB1 in the induction, recruitment, and effector function of antitumor T cells.","date":"1994","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/7511683","citation_count":188,"is_preprint":false},{"pmid":"1372649","id":"PMC_1372649","title":"Antibody and B7/BB1-mediated ligation of the CD28 receptor induces tyrosine phosphorylation in human T cells.","date":"1992","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/1372649","citation_count":144,"is_preprint":false},{"pmid":"23097495","id":"PMC_23097495","title":"LPIAT1 regulates arachidonic acid content in phosphatidylinositol and is required for cortical lamination in mice.","date":"2012","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/23097495","citation_count":123,"is_preprint":false},{"pmid":"7678229","id":"PMC_7678229","title":"B7/BB1, the ligand for CD28, is expressed on repeatedly activated human T cells in vitro.","date":"1993","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/7678229","citation_count":123,"is_preprint":false},{"pmid":"7682758","id":"PMC_7682758","title":"Discordant expression of CD28 ligands, BB-1, and B7 on keratinocytes in vitro and psoriatic cells in vivo.","date":"1993","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/7682758","citation_count":117,"is_preprint":false},{"pmid":"8244464","id":"PMC_8244464","title":"Expression and functional properties of mouse B7/BB1 using a fusion protein between mouse CTLA4 and human gamma 1.","date":"1993","source":"Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/8244464","citation_count":106,"is_preprint":false},{"pmid":"27630043","id":"PMC_27630043","title":"MBOAT7 rs641738 increases risk of liver inflammation and transition to fibrosis in chronic hepatitis C.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/27630043","citation_count":105,"is_preprint":false},{"pmid":"31621579","id":"PMC_31621579","title":"Obesity-linked suppression of membrane-bound O-acyltransferase 7 (MBOAT7) drives non-alcoholic fatty liver disease.","date":"2019","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/31621579","citation_count":104,"is_preprint":false},{"pmid":"32882372","id":"PMC_32882372","title":"rs641738C>T near MBOAT7 is associated with liver fat, ALT and fibrosis in NAFLD: A meta-analysis.","date":"2020","source":"Journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/32882372","citation_count":103,"is_preprint":false},{"pmid":"7535733","id":"PMC_7535733","title":"Abnormal expression of the E2 component of the pyruvate dehydrogenase complex on the luminal surface of biliary epithelium occurs before major histocompatibility complex class II and BB1/B7 expression.","date":"1995","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/7535733","citation_count":102,"is_preprint":false},{"pmid":"32253259","id":"PMC_32253259","title":"LPIAT1/MBOAT7 depletion increases triglyceride synthesis fueled by high phosphatidylinositol turnover.","date":"2020","source":"Gut","url":"https://pubmed.ncbi.nlm.nih.gov/32253259","citation_count":101,"is_preprint":false},{"pmid":"10433938","id":"PMC_10433938","title":"Expression of the costimulatory molecule BB-1, the ligands CTLA-4 and CD28, and their mRNA in inflammatory myopathies.","date":"1999","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/10433938","citation_count":97,"is_preprint":false},{"pmid":"34823063","id":"PMC_34823063","title":"TM6SF2/PNPLA3/MBOAT7 Loss-of-Function Genetic Variants Impact on NAFLD Development and Progression Both in Patients and in In Vitro Models.","date":"2021","source":"Cellular and molecular gastroenterology and hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/34823063","citation_count":88,"is_preprint":false},{"pmid":"32591434","id":"PMC_32591434","title":"Loss of hepatic Mboat7 leads to liver fibrosis.","date":"2020","source":"Gut","url":"https://pubmed.ncbi.nlm.nih.gov/32591434","citation_count":87,"is_preprint":false},{"pmid":"7682106","id":"PMC_7682106","title":"In situ expression of B7/BB1 on antigen-presenting cells and activated B cells: an immunohistochemical study.","date":"1993","source":"International immunology","url":"https://pubmed.ncbi.nlm.nih.gov/7682106","citation_count":79,"is_preprint":false},{"pmid":"7693051","id":"PMC_7693051","title":"The B7/BB1 antigen is expressed by Reed-Sternberg cells of Hodgkin's disease and contributes to the stimulating capacity of Hodgkin's disease-derived cell lines.","date":"1993","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/7693051","citation_count":78,"is_preprint":false},{"pmid":"7504055","id":"PMC_7504055","title":"Follicular dendritic cells help resting B cells to become effective antigen-presenting cells: induction of B7/BB1 and upregulation of major histocompatibility complex class II molecules.","date":"1993","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/7504055","citation_count":77,"is_preprint":false},{"pmid":"27616480","id":"PMC_27616480","title":"Mutations in MBOAT7, Encoding Lysophosphatidylinositol Acyltransferase I, Lead to Intellectual Disability Accompanied by Epilepsy and Autistic Features.","date":"2016","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27616480","citation_count":71,"is_preprint":false},{"pmid":"23472195","id":"PMC_23472195","title":"Lysophosphatidylinositol-acyltransferase-1 (LPIAT1) is required to maintain physiological levels of PtdIns and PtdInsP(2) in the mouse.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23472195","citation_count":68,"is_preprint":false},{"pmid":"32058943","id":"PMC_32058943","title":"Mboat7 down-regulation by hyper-insulinemia induces fat accumulation in hepatocytes.","date":"2020","source":"EBioMedicine","url":"https://pubmed.ncbi.nlm.nih.gov/32058943","citation_count":67,"is_preprint":false},{"pmid":"7682237","id":"PMC_7682237","title":"CD28 ligation by monoclonal antibodies or B7/BB1 provides an accessory signal for the cyclosporin A-resistant generation of cytotoxic T cell activity.","date":"1993","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/7682237","citation_count":64,"is_preprint":false},{"pmid":"7526869","id":"PMC_7526869","title":"Elevated expression of CD80 (B7/BB1) and other accessory molecules on synovial fluid mononuclear cell subsets in rheumatoid arthritis.","date":"1994","source":"Arthritis and rheumatism","url":"https://pubmed.ncbi.nlm.nih.gov/7526869","citation_count":63,"is_preprint":false},{"pmid":"17035523","id":"PMC_17035523","title":"Bombesin receptors as a novel anti-anxiety therapeutic target: BB1 receptor actions on anxiety through alterations of serotonin activity.","date":"2006","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/17035523","citation_count":60,"is_preprint":false},{"pmid":"7523532","id":"PMC_7523532","title":"Expression of the B7/BB1 activation antigen and its ligand CD28 in T-cell-mediated skin diseases.","date":"1994","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/7523532","citation_count":59,"is_preprint":false},{"pmid":"7770080","id":"PMC_7770080","title":"Genetic and antigenic characterization of Babesia bovis merozoite spherical body protein Bb-1.","date":"1995","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/7770080","citation_count":59,"is_preprint":false},{"pmid":"10908195","id":"PMC_10908195","title":"Expression of the co-stimulatory molecule BB-1, the ligands CTLA-4 and CD28 and their mRNAs in chronic inflammatory demyelinating polyneuropathy.","date":"2000","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/10908195","citation_count":57,"is_preprint":false},{"pmid":"32629394","id":"PMC_32629394","title":"MBOAT7 down-regulation by genetic and environmental factors predisposes to MAFLD.","date":"2020","source":"EBioMedicine","url":"https://pubmed.ncbi.nlm.nih.gov/32629394","citation_count":56,"is_preprint":false},{"pmid":"16195335","id":"PMC_16195335","title":"Dihydroflavonol BB-1, an extract of natural plant Blumea balsamifera, abrogates TRAIL resistance in leukemia cells.","date":"2005","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/16195335","citation_count":54,"is_preprint":false},{"pmid":"32859645","id":"PMC_32859645","title":"Hepatic deletion of Mboat7 (LPIAT1) causes activation of SREBP-1c and fatty liver.","date":"2021","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/32859645","citation_count":48,"is_preprint":false},{"pmid":"7516083","id":"PMC_7516083","title":"Expression of the costimulatory molecule B7/BB1 in autoimmune thyroid disease.","date":"1994","source":"The Quarterly journal of medicine","url":"https://pubmed.ncbi.nlm.nih.gov/7516083","citation_count":46,"is_preprint":false},{"pmid":"30959108","id":"PMC_30959108","title":"MBOAT7 is anchored to endomembranes by six transmembrane domains.","date":"2019","source":"Journal of structural biology","url":"https://pubmed.ncbi.nlm.nih.gov/30959108","citation_count":44,"is_preprint":false},{"pmid":"29572551","id":"PMC_29572551","title":"Lack of evidence supporting a role of TMC4-rs641738 missense variant-MBOAT7- intergenic downstream variant-in the Susceptibility to Nonalcoholic Fatty Liver Disease.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29572551","citation_count":44,"is_preprint":false},{"pmid":"37691145","id":"PMC_37691145","title":"MMD collaborates with ACSL4 and MBOAT7 to promote polyunsaturated phosphatidylinositol remodeling and susceptibility to ferroptosis.","date":"2023","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/37691145","citation_count":43,"is_preprint":false},{"pmid":"29485130","id":"PMC_29485130","title":"The rs626283 Variant in the MBOAT7 Gene is Associated with Insulin Resistance and Fatty Liver in Caucasian Obese Youth.","date":"2018","source":"The American journal of gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/29485130","citation_count":43,"is_preprint":false},{"pmid":"7678098","id":"PMC_7678098","title":"Identification of two Th1 cell epitopes on the Babesia bovis-encoded 77-kilodalton merozoite protein (Bb-1) by use of truncated recombinant fusion proteins.","date":"1993","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/7678098","citation_count":41,"is_preprint":false},{"pmid":"27411039","id":"PMC_27411039","title":"Association of MBOAT7 gene variant with plasma ALT levels in children: the PANIC study.","date":"2016","source":"Pediatric research","url":"https://pubmed.ncbi.nlm.nih.gov/27411039","citation_count":40,"is_preprint":false},{"pmid":"32034305","id":"PMC_32034305","title":"The ACSL3-LPIAT1 signaling drives prostaglandin synthesis in non-small cell lung cancer.","date":"2020","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/32034305","citation_count":38,"is_preprint":false},{"pmid":"36473860","id":"PMC_36473860","title":"A metabolic associated fatty liver disease risk variant in MBOAT7 regulates toll like receptor induced outcomes.","date":"2022","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/36473860","citation_count":37,"is_preprint":false},{"pmid":"9743327","id":"PMC_9743327","title":"The BB1 monoclonal antibody recognizes both cell surface CD74 (MHC class II-associated invariant chain) as well as B7-1 (CD80), resolving the question regarding a third CD28/CTLA-4 counterreceptor.","date":"1998","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/9743327","citation_count":35,"is_preprint":false},{"pmid":"30875804","id":"PMC_30875804","title":"TM6SF2 and MBOAT7 Gene Variants in Liver Fibrosis and Cirrhosis.","date":"2019","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30875804","citation_count":33,"is_preprint":false},{"pmid":"8923872","id":"PMC_8923872","title":"Lack of B7-1/BB1 and B7-2/B70 expression on thyrocytes of patients with Graves' disease. Delivery of costimulatory signals from bystander professional antigen-presenting cells.","date":"1996","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/8923872","citation_count":30,"is_preprint":false},{"pmid":"16393678","id":"PMC_16393678","title":"Identification of basogranulin (BB1) as a novel immunohistochemical marker of basophils in normal bone marrow and patients with myeloproliferative disorders.","date":"2006","source":"American journal of clinical pathology","url":"https://pubmed.ncbi.nlm.nih.gov/16393678","citation_count":30,"is_preprint":false},{"pmid":"1730498","id":"PMC_1730498","title":"Induction of proliferative responses of T cells from Babesia bovis-immune cattle with a recombinant 77-kilodalton merozoite protein (Bb-1).","date":"1992","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/1730498","citation_count":30,"is_preprint":false},{"pmid":"30824369","id":"PMC_30824369","title":"Meta-analysis of the association between MBOAT7 rs641738, TM6SF2 rs58542926 and nonalcoholic fatty liver disease susceptibility.","date":"2019","source":"Clinics and research in hepatology and gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/30824369","citation_count":29,"is_preprint":false},{"pmid":"9028793","id":"PMC_9028793","title":"Human keratinocytes constitutively express IL-4 receptor molecules and respond to IL-4 with an increase in B7/BB1 expression.","date":"1996","source":"Experimental dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/9028793","citation_count":28,"is_preprint":false},{"pmid":"22129429","id":"PMC_22129429","title":"Structure and activity of exo-1,3/1,4-β-glucanase from marine bacterium Pseudoalteromonas sp. BB1 showing a novel C-terminal domain.","date":"2011","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/22129429","citation_count":27,"is_preprint":false},{"pmid":"35636492","id":"PMC_35636492","title":"Membrane-bound O-acyltransferase 7 (MBOAT7)-driven phosphatidylinositol remodeling in advanced liver disease.","date":"2022","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/35636492","citation_count":26,"is_preprint":false},{"pmid":"27811049","id":"PMC_27811049","title":"Phage-mediated horizontal gene transfer of both prophage and heterologous DNA by ϕBB-1, a bacteriophage of Borrelia burgdorferi.","date":"2016","source":"Pathogens and disease","url":"https://pubmed.ncbi.nlm.nih.gov/27811049","citation_count":26,"is_preprint":false},{"pmid":"11344351","id":"PMC_11344351","title":"Mass, charge, and subcellular localization of a unique secretory product identified by the basophil-specific antibody BB1.","date":"2001","source":"The Journal of allergy and clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/11344351","citation_count":25,"is_preprint":false},{"pmid":"7690242","id":"PMC_7690242","title":"Interleukin-7 specifically induces the B7/BB1 antigen on human cord blood and peripheral blood T cells and T cell clones.","date":"1993","source":"International immunology","url":"https://pubmed.ncbi.nlm.nih.gov/7690242","citation_count":25,"is_preprint":false},{"pmid":"33513444","id":"PMC_33513444","title":"LPIAT1/MBOAT7 contains a catalytic dyad transferring polyunsaturated fatty acids to lysophosphatidylinositol.","date":"2021","source":"Biochimica et biophysica acta. Molecular and cell biology of lipids","url":"https://pubmed.ncbi.nlm.nih.gov/33513444","citation_count":24,"is_preprint":false},{"pmid":"7490112","id":"PMC_7490112","title":"Signal transduction by B7/BB1 expressed on activated T lymphocytes: cross-linking of B7/BB1 induces protein tyrosine phosphorylation and synergizes with signalling through T-cell receptor/CD3.","date":"1995","source":"Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/7490112","citation_count":24,"is_preprint":false},{"pmid":"7512010","id":"PMC_7512010","title":"B7/BB1 provides an important costimulatory signal for CD3-mediated T lymphocyte proliferation in patients with systemic lupus erythematosus (SLE).","date":"1994","source":"Clinical and experimental immunology","url":"https://pubmed.ncbi.nlm.nih.gov/7512010","citation_count":24,"is_preprint":false},{"pmid":"32645526","id":"PMC_32645526","title":"Identification of novel loss of function variants in MBOAT7 resulting in intellectual disability.","date":"2020","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/32645526","citation_count":21,"is_preprint":false},{"pmid":"37605540","id":"PMC_37605540","title":"MBOAT7 in liver and extrahepatic diseases.","date":"2023","source":"Liver international : official journal of the International Association for the Study of the Liver","url":"https://pubmed.ncbi.nlm.nih.gov/37605540","citation_count":20,"is_preprint":false},{"pmid":"32180553","id":"PMC_32180553","title":"MBOAT7-driven phosphatidylinositol remodeling promotes the progression of clear cell renal carcinoma.","date":"2020","source":"Molecular metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/32180553","citation_count":20,"is_preprint":false},{"pmid":"30701556","id":"PMC_30701556","title":"Expanding the phenotype of phospholipid remodelling disease due to MBOAT7 gene defect.","date":"2019","source":"Journal of inherited metabolic disease","url":"https://pubmed.ncbi.nlm.nih.gov/30701556","citation_count":20,"is_preprint":false},{"pmid":"34692725","id":"PMC_34692725","title":"PNPLA3, TM6SF2, and MBOAT7 Influence on Nutraceutical Therapy Response for Non-alcoholic Fatty Liver Disease: A Randomized Controlled Trial.","date":"2021","source":"Frontiers in medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34692725","citation_count":20,"is_preprint":false},{"pmid":"31852446","id":"PMC_31852446","title":"Homozygous variants in the HEXB and MBOAT7 genes underlie neurological diseases in consanguineous families.","date":"2019","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31852446","citation_count":19,"is_preprint":false},{"pmid":"30191681","id":"PMC_30191681","title":"Evidence for PTGER4, PSCA, and MBOAT7 as risk genes for gastric cancer on the genome and transcriptome level.","date":"2018","source":"Cancer medicine","url":"https://pubmed.ncbi.nlm.nih.gov/30191681","citation_count":18,"is_preprint":false},{"pmid":"37316513","id":"PMC_37316513","title":"The structure of phosphatidylinositol remodeling MBOAT7 reveals its catalytic mechanism and enables inhibitor identification.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/37316513","citation_count":17,"is_preprint":false},{"pmid":"22955356","id":"PMC_22955356","title":"Selenium and zinc internalized by Lactobacillus buchneri Lb26 (DSM 16341) and Bifidobacterium lactis Bb1 (DSM 17850): improved bioavailability using a new biological approach.","date":"2012","source":"Journal of clinical gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/22955356","citation_count":17,"is_preprint":false},{"pmid":"31282596","id":"PMC_31282596","title":"Expanding the phenotypic spectrum of MBOAT7-related intellectual disability.","date":"2019","source":"American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31282596","citation_count":16,"is_preprint":false},{"pmid":"33810963","id":"PMC_33810963","title":"Association between MBOAT7 rs641738 polymorphism and non-alcoholic fatty liver in overweight or obese children.","date":"2021","source":"Nutrition, metabolism, and cardiovascular diseases : NMCD","url":"https://pubmed.ncbi.nlm.nih.gov/33810963","citation_count":15,"is_preprint":false},{"pmid":"20729316","id":"PMC_20729316","title":"Discovery and characterization of a distinctive exo-1,3/1,4-{beta}-glucanase from the marine bacterium Pseudoalteromonas sp. strain BB1.","date":"2010","source":"Applied and environmental microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/20729316","citation_count":15,"is_preprint":false},{"pmid":"38776184","id":"PMC_38776184","title":"Low MBOAT7 expression, a genetic risk for MASH, promotes a profibrotic pathway involving hepatocyte TAZ upregulation.","date":"2024","source":"Hepatology (Baltimore, Md.)","url":"https://pubmed.ncbi.nlm.nih.gov/38776184","citation_count":14,"is_preprint":false},{"pmid":"30116012","id":"PMC_30116012","title":"Effect of MBOAT7 variant on hepatitis B and C infections in Moroccan patients.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30116012","citation_count":13,"is_preprint":false},{"pmid":"38558079","id":"PMC_38558079","title":"Characterization and genomic analysis of the Lyme disease spirochete bacteriophage ϕBB-1.","date":"2024","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/38558079","citation_count":13,"is_preprint":false},{"pmid":"6187858","id":"PMC_6187858","title":"Studies on the B lymphoblast antigen No. 1 (BB-1) on a series of Burkitt lymphoma lines differing in the expression of the EBV/C3 receptor complex.","date":"1983","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/6187858","citation_count":13,"is_preprint":false},{"pmid":"37293574","id":"PMC_37293574","title":"Enhancing Hepatic MBOAT7 Expression in Mice With Nonalcoholic Steatohepatitis.","date":"2023","source":"Gastro hep advances","url":"https://pubmed.ncbi.nlm.nih.gov/37293574","citation_count":12,"is_preprint":false},{"pmid":"37424875","id":"PMC_37424875","title":"MBOAT7 rs641738 (C>T) is associated with NAFLD progression in men and decreased ASCVD risk in elder Chinese population.","date":"2023","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/37424875","citation_count":12,"is_preprint":false},{"pmid":"36806709","id":"PMC_36806709","title":"MBOAT7-driven lysophosphatidylinositol acylation in adipocytes contributes to systemic glucose homeostasis.","date":"2023","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/36806709","citation_count":12,"is_preprint":false},{"pmid":"32744787","id":"PMC_32744787","title":"A patient with novel MBOAT7 variant: The cerebellar atrophy is progressive and displays a peculiar neurometabolic profile.","date":"2020","source":"American journal of medical genetics. Part A","url":"https://pubmed.ncbi.nlm.nih.gov/32744787","citation_count":12,"is_preprint":false},{"pmid":"35509994","id":"PMC_35509994","title":"Functional and Structural Changes in the Membrane-Bound O-Acyltransferase Family Member 7 (MBOAT7) Protein: The Pathomechanism of a Novel MBOAT7 Variant in Patients With Intellectual Disability.","date":"2022","source":"Frontiers in neurology","url":"https://pubmed.ncbi.nlm.nih.gov/35509994","citation_count":12,"is_preprint":false},{"pmid":"8978970","id":"PMC_8978970","title":"Elevated in vivo expression of the costimulatory molecule B7-BB1 (CD80) on antigen presenting cells from a patient with SLE.","date":"1996","source":"Clinical and experimental rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/8978970","citation_count":12,"is_preprint":false},{"pmid":"38648183","id":"PMC_38648183","title":"Membrane-bound O-acyltransferase 7 (MBOAT7) shapes lysosomal lipid homeostasis and function to control alcohol-associated liver injury.","date":"2024","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/38648183","citation_count":11,"is_preprint":false},{"pmid":"34557398","id":"PMC_34557398","title":"The PNPLA3 rs738409 Variant but not MBOAT7 rs641738 is a Risk Factor for Nonalcoholic Fatty Liver Disease in Obese U.S. Children of Hispanic Ethnicity.","date":"2021","source":"Pediatric gastroenterology, hepatology & nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/34557398","citation_count":11,"is_preprint":false},{"pmid":"31484306","id":"PMC_31484306","title":"In Vitro Release of Bioactive Bone Morphogenetic Proteins (GDF5, BB-1, and BMP-2) from a PLGA Fiber-Reinforced, Brushite-Forming Calcium Phosphate Cement.","date":"2019","source":"Pharmaceutics","url":"https://pubmed.ncbi.nlm.nih.gov/31484306","citation_count":11,"is_preprint":false},{"pmid":"33335874","id":"PMC_33335874","title":"Phenotypic Characterization of Intellectual Disability Caused by MBOAT7 Mutation in Two Consanguineous Pakistani Families.","date":"2020","source":"Frontiers in pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/33335874","citation_count":10,"is_preprint":false},{"pmid":"35743824","id":"PMC_35743824","title":"A Seed-Borne Bacterium of Rice, Pantoea dispersa BB1, Protects Rice from the Seedling Rot Caused by the Bacterial Pathogen Burkholderia glumae.","date":"2022","source":"Life (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/35743824","citation_count":10,"is_preprint":false},{"pmid":"31928970","id":"PMC_31928970","title":"The MBOAT7 rs641738 variant is associated with an improved outcome in primary sclerosing cholangitis.","date":"2020","source":"Clinics and research in hepatology and gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/31928970","citation_count":10,"is_preprint":false},{"pmid":"7507002","id":"PMC_7507002","title":"IL-7 induces surface expression of B7/BB1 on pre-B cells and an associated increase in their costimulatory effects on T cell proliferation.","date":"1994","source":"Cellular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/7507002","citation_count":10,"is_preprint":false},{"pmid":"29031993","id":"PMC_29031993","title":"The GDF5 mutant BB-1 enhances the bone formation induced by an injectable, poly(l-lactide-co-glycolide) acid (PLGA) fiber-reinforced, brushite-forming cement in a sheep defect model of lumbar osteopenia.","date":"2017","source":"The spine journal : official journal of the North American Spine Society","url":"https://pubmed.ncbi.nlm.nih.gov/29031993","citation_count":9,"is_preprint":false},{"pmid":"8702217","id":"PMC_8702217","title":"Molecular analysis of a gene, BB1, overexpressed in bladder and breast carcinoma.","date":"1996","source":"Anticancer research","url":"https://pubmed.ncbi.nlm.nih.gov/8702217","citation_count":7,"is_preprint":false},{"pmid":"34426151","id":"PMC_34426151","title":"Phomaligols F-I, polyoxygenated cyclohexenone derivatives from marine-derived fungus Aspergillus flavus BB1.","date":"2021","source":"Bioorganic chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34426151","citation_count":7,"is_preprint":false},{"pmid":"38088234","id":"PMC_38088234","title":"Exome sequencing identifies homozygous variants in MBOAT7 associated with neurodevelopmental disorder.","date":"2023","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38088234","citation_count":6,"is_preprint":false},{"pmid":"38885924","id":"PMC_38885924","title":"Bifidobacterium bifidum Strain BB1 Inhibits Tumor Necrosis Factor-α-Induced Increase in Intestinal Epithelial Tight Junction Permeability via Toll-Like Receptor-2/Toll-Like Receptor-6 Receptor Complex-Dependent Stimulation of Peroxisome Proliferator-Activated Receptor γ and Suppression of NF-κB p65.","date":"2024","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/38885924","citation_count":6,"is_preprint":false},{"pmid":"12409186","id":"PMC_12409186","title":"Expression of the costimulatory molecule BB-1 and its receptors in patients with scleroderma-polymyositis overlap syndrome.","date":"2002","source":"Journal of the neurological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/12409186","citation_count":6,"is_preprint":false},{"pmid":"37628684","id":"PMC_37628684","title":"Liver Involvement in Patients with Rare MBOAT7 Variants and Intellectual Disability: A Case Report and Literature Review.","date":"2023","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/37628684","citation_count":5,"is_preprint":false},{"pmid":"34113561","id":"PMC_34113561","title":"MBOAT7-TMC4 rs641738 Is Not Associated With the Risk of Hepatocellular Carcinoma or Persistent Hepatitis B Infection.","date":"2021","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/34113561","citation_count":5,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":54457,"output_tokens":5180,"usd":0.120536},"stage2":{"model":"claude-opus-4-6","input_tokens":8681,"output_tokens":3172,"usd":0.184058},"total_usd":0.304594,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2012,\n      \"finding\": \"LPIAT1/MBOAT7 is a lysophosphatidylinositol acyltransferase that selectively incorporates arachidonic acid (AA) into phosphatidylinositol (PI). Lpiat1 knockout mice show almost no LPIAT activity with arachidonoyl-CoA as acyl donor, reduced AA content in PI and PI phosphates, and die within a month with atrophy of the cerebral cortex and hippocampus, disordered cortical lamination, delayed neuronal migration, and reduced neurite outgrowth in vitro.\",\n      \"method\": \"Mouse knockout (Lpiat1-/-), lipid mass spectrometry, immunohistochemistry, in vitro neurite outgrowth assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — clean KO with multiple orthogonal readouts (lipidomics, histology, functional neurite assay), replicated in a second KO study\",\n      \"pmids\": [\"23097495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"LPIAT1/MBOAT7 plays a non-redundant role in maintaining physiological levels of PtdIns and PtdInsP2 through an active deacylation/reacylation cycle. LPIAT1 knockout mice show reduced C38:4 PtdIns and PtdInsP2 (26-44% reduction) and markedly elevated C18:0 lyso-PtdIns in both brain and liver, confirming a substrate-specific reacylation function.\",\n      \"method\": \"Mouse knockout (LPIAT1-/-), LC-ESI/MS lipidomics of brain and liver\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vivo KO with quantitative mass spectrometry lipidomics, orthogonal to prior KO study\",\n      \"pmids\": [\"23472195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The MBOAT7 rs641738 T risk allele is associated with reduced MBOAT7 protein expression in the liver and changes in plasma phosphatidylinositol species consistent with decreased MBOAT7 acyltransferase function, linking the variant to impaired hepatic phosphatidylinositol acyl-chain remodeling.\",\n      \"method\": \"Human cohort genotyping, hepatic protein expression measurement, plasma lipidomics\",\n      \"journal\": \"Gastroenterology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — human cohort with protein expression and lipidomic readouts, single study\",\n      \"pmids\": [\"26850495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Homozygous inactivating variants in MBOAT7 (encoding LPIAT1, a membrane-bound phospholipid-remodeling enzyme that transfers arachidonic acid to lysophosphatidylinositol) cause autosomal recessive intellectual disability accompanied by epilepsy and autistic features, establishing a direct role for AA-containing phosphatidylinositols in brain development.\",\n      \"method\": \"Human genetics (whole-exome sequencing, Sanger sequencing) in six consanguineous families\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple independent families with loss-of-function variants in the same gene and consistent phenotype\",\n      \"pmids\": [\"27616480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MBOAT7 is an integral membrane protein anchored to endomembranes by six transmembrane domains. Its predicted catalytic dyad—Asn-321 and His-356—faces the lumen of endomembranes, consistent with acylation of lysophospholipid substrates on the lumenal side.\",\n      \"method\": \"Membrane fractionation, in silico topology prediction, GFP/FLAG-tagged truncation constructs in live cells, co-immunofluorescence, fluorescence protease protection (FPP) assay, selective membrane permeabilization\",\n      \"journal\": \"Journal of structural biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal experimental methods (FPP, selective permeabilization, truncation constructs) converging on same topology model\",\n      \"pmids\": [\"30959108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Mboat7 loss of function (but not Tmc4 loss) in mice is sufficient to promote NAFLD progression under high-fat diet. Mboat7 loss is associated with accumulation of its substrate lysophosphatidylinositol (LPI), and direct LPI administration promotes hepatic inflammatory and fibrotic transcriptional changes in an Mboat7-dependent manner, establishing the MBOAT7-driven acylation of LPI as a suppressor of NAFLD progression.\",\n      \"method\": \"Mouse whole-body knockout, antisense oligonucleotide knockdown, direct LPI administration, hepatic gene expression, histology\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — gene-specific KO (ruling out Tmc4), substrate accumulation demonstrated, causal rescue by substrate administration tested\",\n      \"pmids\": [\"31621579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Hepatocyte-specific deletion of Mboat7 in mice causes spontaneous hepatic steatosis (increased cholesterol ester content) and increased fibrosis on high-fat diet, with accumulation of lysophosphatidylinositol species, via an inflammation-independent pathway of liver fibrosis mediated by lipid signaling.\",\n      \"method\": \"Hepatocyte-specific Mboat7 knockout mouse (Mboat7Δhep), histology (picrosirius red, hydroxyproline), flow cytometry, RNA-seq, lipidomics of mouse and human biopsies\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — cell-type-specific KO with multiple orthogonal readouts including human lipidomic validation\",\n      \"pmids\": [\"32591434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MBOAT7 depletion in hepatocytes increases triglyceride synthesis via a non-canonical pathway: reduced PI acyl-chain remodeling causes high PI turnover (simultaneous stimulation of PI synthesis and breakdown), and PI degradation by phospholipase C produces diacylglycerol (DAG), a triglyceride precursor, directly fueling hepatic fat accumulation.\",\n      \"method\": \"Hepatocyte-specific Lpiat1 KO mice, CRISPR-Cas9 and siRNA depletion in human hepatic cells and liver spheroids, radiolabeled glycerol/fatty acid flux, LC-ESI-MS lipidomics\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution of the metabolic pathway with isotope tracing plus in vivo and in vitro models\",\n      \"pmids\": [\"32253259\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Hyperinsulinemia downregulates Mboat7 expression (via insulin signaling activation after refeeding), and acute Mboat7 silencing promotes hepatic steatosis in vivo by reducing arachidonic acid incorporation into PI, resulting in accumulation of saturated triglycerides, enhanced lipogenesis, and upregulation of fatty acid transporter FATP1; FATP1 deletion rescues the steatotic phenotype.\",\n      \"method\": \"Antisense oligonucleotide silencing in C57Bl/6 mice, CRISPR-Cas9 deletion in HepG2 cells, radiolabeled fatty acid incorporation assay, in vivo insulin treatment, FATP1 rescue experiment\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — enzymatic activity assay, genetic rescue (FATP1 KO reversal), multiple models\",\n      \"pmids\": [\"32058943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MBOAT7 deletion in clear cell renal cell carcinoma (ccRCC) cells decreases proliferation, induces cell cycle arrest, and prevents tumor formation in vivo; MBOAT7-/- RNAseq reveals alterations in cell migration and extracellular matrix organization, functionally validated in migration assays. ccRCC tumors accumulate arachidonic acid-enriched phosphatidylinositols (AA-PI) in an MBOAT7-dependent manner.\",\n      \"method\": \"Genome editing (CRISPR) in ccRCC cell lines, proliferation assays, in vivo tumor formation, RNA-seq, migration assays, shotgun lipidomics\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic KO with multiple functional readouts and lipidomic mechanistic link\",\n      \"pmids\": [\"32180553\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ACSL3 channels arachidonic acid into phosphatidylinositols to provide LPIAT1/MBOAT7 with a pool of AA for sustained prostaglandin synthesis in lung cancer cells. LPIAT1 knockdown suppresses proliferation, anchorage-independent growth, and in vivo tumorigenesis in lung cancer, defining an ACSL3-LPIAT1 axis.\",\n      \"method\": \"Lung cancer cell line KD, KrasG12D mouse models, proliferation/colony assays, in vivo tumor models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KD in multiple systems including in vivo, with mechanistic pathway placement (ACSL3 upstream of LPIAT1)\",\n      \"pmids\": [\"32034305\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"MBOAT7 (LPIAT1) preferentially transfers 20:4 (arachidonic acid) and 20:5 polyunsaturated fatty acids to lysophosphatidylinositol. Missense mutations at the putative catalytic dyad (N321A, H356A, and N321A+H356A double mutant) abolish O-acyltransferase activity, confirming these residues as essential for catalysis.\",\n      \"method\": \"Recombinant MBOAT7 and mutants expressed in Pichia pastoris, Ni-affinity purification, in vitro acyltransferase assay with radiolabeled fatty acids\",\n      \"journal\": \"Biochimica et biophysica acta. Molecular and cell biology of lipids\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstituted enzymatic assay with site-directed mutagenesis of catalytic residues\",\n      \"pmids\": [\"33513444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Hepatic deletion of Mboat7 causes activation of SREBP-1c and de novo lipogenesis as the mechanism underlying fatty liver. Lipidomics showed selective reduction in 20-carbon PUFA-containing phosphatidylinositols but not other phospholipids. Dual deletion of Scap (required for SREBP processing) and Mboat7 normalized hepatic triglycerides, establishing that increased SREBP-1c processing is required for Mboat7-induced steatosis.\",\n      \"method\": \"Liver-specific Mboat7 KO mice (Mboat7 LSKO), hepatic lipidomics by MS, dual Scap/Mboat7 liver KO genetic epistasis, gene expression analysis\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic epistasis (double KO rescues phenotype) plus lipidomics, identifying SREBP-1c as effector\",\n      \"pmids\": [\"32859645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"MBOAT7 functions as a negative regulator of toll-like receptor (TLR) signaling in macrophages. MBOAT7 deficiency alters membrane phospholipid composition, redistributes arachidonic acid toward proinflammatory eicosanoids, induces ER stress and mitochondrial dysfunction, and remodels the accessible inflammatory chromatin landscape, culminating in exaggerated macrophage TLR responses. Activation of MBOAT7 reverses these effects.\",\n      \"method\": \"MBOAT7 KD/KO in macrophages, lipidomics, eicosanoid measurement, ER stress and mitochondrial function assays, chromatin accessibility (ATAC-seq), TLR stimulation assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in primary macrophages with gain-of-function reversal validation\",\n      \"pmids\": [\"36473860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cryo-EM structure of human MBOAT7 reveals that arachidonyl-CoA and lyso-PI access the catalytic center through a twisted tunnel from the cytosol and lumenal sides, respectively. N-terminal residues on the ER lumenal side determine phospholipid headgroup selectivity: swapping N-terminal regions between MBOATs 1, 5, and 7 converts enzyme specificity for different lyso-phospholipid substrates. Structure-based virtual screening identified small-molecule inhibitors.\",\n      \"method\": \"Cryo-EM structure determination, domain-swap mutagenesis with acyltransferase activity assays, virtual screening\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution structure with functional mutagenesis validating mechanism and headgroup selectivity\",\n      \"pmids\": [\"37316513\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Golgi-resident scaffold protein MMD physically interacts with both ACSL4 and MBOAT7 and promotes flux of arachidonic acid into phosphatidylinositol. MMD promotes ferroptosis susceptibility in ovarian and renal carcinoma cells in an ACSL4- and MBOAT7-dependent manner, identifying a MMD-ACSL4-MBOAT7 complex that increases AA-PI levels and pro-ferroptotic phospholipid peroxidation.\",\n      \"method\": \"Co-immunoprecipitation, genetic KO of MMD/ACSL4/MBOAT7, ferroptosis assays, lipidomics\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP establishing complex, genetic epistasis (ACSL4/MBOAT7-dependent rescue), lipidomics\",\n      \"pmids\": [\"37691145\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MBOAT7-driven lysophosphatidylinositol acylation in adipocytes is the major source of arachidonic acid-containing PI pools in adipose tissue. Adipocyte-specific Mboat7 KO promotes hyperinsulinemia, systemic insulin resistance, and mild fatty liver in mice fed high-fat/high-sucrose diet, demonstrating a cell-autonomous role in glucose homeostasis distinct from hepatocyte MBOAT7 function.\",\n      \"method\": \"Floxed Mboat7 mice crossed to adiponectin-Cre and albumin-Cre, metabolic phenotyping, adipose/hepatic lipidomics, panel of ~100 inbred mouse strains\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific KO with metabolic phenotyping and lipidomic mechanistic readouts\",\n      \"pmids\": [\"36806709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Hepatocyte MBOAT7 loss promotes liver fibrosis via a cholesterol trafficking pathway that upregulates TAZ (WWTR1) and TAZ-induced profibrotic factor Indian hedgehog (IHH). MBOAT7 restoration in MASH mice lowers hepatocyte TAZ levels and slows fibrosis progression; MBOAT7 silencing in established steatohepatitis exacerbates fibrosis and increases nuclear TAZ and IHH mRNA, a finding validated in human MASH livers carrying the rs641738-T allele.\",\n      \"method\": \"Hepatocyte-specific MBOAT7 overexpression/silencing in MASH mice (AAV, ASO), TAZ/IHH protein and mRNA measurement, human liver biopsy TAZ immunostaining\",\n      \"journal\": \"Hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — gain- and loss-of-function in vivo with mechanistic pathway (MBOAT7→PI remodeling→cholesterol trafficking→TAZ→IHH), validated in humans\",\n      \"pmids\": [\"38776184\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Hepatocyte-specific (but not myeloid-specific) deletion of Mboat7 exacerbates ethanol-induced liver injury. Mboat7-HSKO livers show reorganization of the hepatic lipidome with increased endosomal/lysosomal lipids, dysregulated autophagic flux, impaired TFEB-mediated lysosomal biogenesis, and autophagosome accumulation, revealing that MBOAT7 shapes lysosomal lipid homeostasis to control alcohol-associated liver disease.\",\n      \"method\": \"Hepatocyte-specific and myeloid-specific Mboat7 KO mice, ethanol feeding, lipidomics, autophagic flux assays, TFEB pathway analysis, flow cytometry\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific KO (hepatocyte vs. myeloid), multiple orthogonal mechanistic readouts\",\n      \"pmids\": [\"38648183\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MBOAT7 (LPIAT1) is an integral endomembrane acyltransferase with six transmembrane domains and a lumenally-oriented catalytic dyad (Asn-321, His-356) that, together with ACSL4 (and scaffold protein MMD), transfers polyunsaturated fatty acids—preferentially arachidonic acid—from arachidonoyl-CoA onto lysophosphatidylinositol to produce AA-enriched phosphatidylinositol via the Lands cycle; loss of this PI remodeling activity elevates lysophosphatidylinositol, activates SREBP-1c-driven de novo lipogenesis and a phospholipase C/DAG pathway that fuels triglyceride synthesis, promotes a TAZ/IHH profibrotic axis, disrupts lysosomal biogenesis and autophagic flux, redistributes arachidonic acid toward proinflammatory eicosanoids in macrophages (exacerbating TLR signaling), alters adipose PI homeostasis causing insulin resistance, and—when completely absent from birth—disrupts cortical neuronal migration and PI phosphate levels required for normal brain development.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MBOAT7 (LPIAT1) is an integral endomembrane acyltransferase that selectively transfers arachidonic acid from arachidonoyl-CoA onto lysophosphatidylinositol to generate AA-enriched phosphatidylinositol, thereby maintaining the acyl-chain composition of PI and PI phosphates via the Lands cycle [PMID:23097495, PMID:33513444, PMID:37316513]. Its six-transmembrane topology positions the catalytic dyad (Asn-321/His-356) on the lumenal side, where arachidonyl-CoA and lyso-PI access the active site through a twisted tunnel, and N-terminal lumenal residues determine headgroup selectivity; MBOAT7 operates within a Golgi-localized MMD–ACSL4–MBOAT7 complex that channels arachidonic acid into PI [PMID:30959108, PMID:37316513, PMID:37691145]. Loss of MBOAT7 activity accumulates lysophosphatidylinositol and depletes AA-PI, triggering SREBP-1c–driven de novo lipogenesis and PLC/DAG-mediated triglyceride synthesis in hepatocytes, a TAZ/IHH profibrotic axis, impaired TFEB-dependent lysosomal biogenesis, redistribution of arachidonic acid toward proinflammatory eicosanoids in macrophages, and adipose insulin resistance—collectively driving NAFLD/MASH, alcohol-associated liver disease, and metabolic dysfunction [PMID:32859645, PMID:32253259, PMID:38776184, PMID:38648183, PMID:36473860, PMID:36806709]. Homozygous inactivating MBOAT7 variants cause autosomal recessive intellectual disability with epilepsy and autistic features, reflecting a requirement for AA-containing PI in cortical neuronal migration [PMID:27616480, PMID:23097495].\",\n  \"teleology\": [\n    {\n      \"year\": 2012,\n      \"claim\": \"Establishing that MBOAT7/LPIAT1 is the non-redundant lysophosphatidylinositol acyltransferase that incorporates arachidonic acid into PI, and that its absence disrupts brain PI composition, cortical lamination, and neuronal migration\",\n      \"evidence\": \"Lpiat1 knockout mice with lipidomics, histology, and neurite outgrowth assays\",\n      \"pmids\": [\"23097495\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Catalytic mechanism and substrate specificity not biochemically defined\", \"Whether brain phenotype reflects PI or PIP2 depletion unresolved\", \"Role in non-neural tissues not explored\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrating that MBOAT7 loss reduces not only PI but also PIP2 species and elevates lyso-PI in both brain and liver, establishing a broader role in phosphoinositide homeostasis\",\n      \"evidence\": \"Lpiat1 KO mouse tissues analyzed by LC-ESI/MS lipidomics\",\n      \"pmids\": [\"23472195\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Liver functional consequences of altered PI not yet studied\", \"Whether lyso-PI itself has signaling properties unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linking the common MBOAT7 rs641738 variant to reduced hepatic MBOAT7 expression and altered plasma PI species in humans, connecting the enzyme to human liver disease susceptibility; simultaneously, rare biallelic MBOAT7 loss-of-function variants were shown to cause autosomal recessive intellectual disability with epilepsy\",\n      \"evidence\": \"Human cohort genotyping with hepatic protein/plasma lipidomics; whole-exome sequencing in six consanguineous families\",\n      \"pmids\": [\"26850495\", \"27616480\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking reduced MBOAT7 to steatosis/fibrosis not defined\", \"No animal model recapitulating rs641738 partial loss\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Resolving MBOAT7 membrane topology—six transmembrane domains with a lumenally oriented catalytic dyad—and showing that Mboat7 loss is sufficient to promote NAFLD progression, with accumulated lyso-PI acting as a causal lipotoxic mediator\",\n      \"evidence\": \"Fluorescence protease protection and selective permeabilization in cells; Mboat7 KO and ASO knockdown mice with direct LPI administration\",\n      \"pmids\": [\"30959108\", \"31621579\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"High-resolution structure not yet available\", \"Downstream signaling pathways from lyso-PI not mapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Elucidating hepatocyte-autonomous mechanisms: MBOAT7 loss drives steatosis via both SREBP-1c activation (requiring Scap) and a PLC/DAG pathway that directly fuels triglyceride synthesis from PI breakdown; insulin signaling represses MBOAT7 expression, with FATP1 upregulation as a rescuable effector\",\n      \"evidence\": \"Hepatocyte-specific KO, Scap/Mboat7 double KO epistasis, isotope-tracing in hepatocytes and liver spheroids, FATP1 genetic rescue\",\n      \"pmids\": [\"32591434\", \"32253259\", \"32859645\", \"32058943\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of SREBP-1c vs. PLC/DAG pathway not quantified\", \"Whether insulin-mediated downregulation operates transcriptionally or post-transcriptionally unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrating that MBOAT7-generated AA-PI pools are required for cancer cell proliferation, with ACSL3 acting upstream to channel arachidonic acid into PI for MBOAT7 remodeling\",\n      \"evidence\": \"CRISPR KO in ccRCC and lung cancer cells, in vivo tumor models, lipidomics\",\n      \"pmids\": [\"32180553\", \"32034305\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether pro-tumorigenic role is via eicosanoid generation, PI signaling, or ferroptosis sensitivity not resolved\", \"Cancer-type specificity not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Confirming MBOAT7 substrate preference for 20:4/20:5 PUFAs and the essentiality of the Asn-321/His-356 catalytic dyad through in vitro reconstitution with purified enzyme\",\n      \"evidence\": \"Recombinant MBOAT7 and site-directed mutants expressed in Pichia pastoris, radiolabeled acyltransferase assays\",\n      \"pmids\": [\"33513444\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for PUFA selectivity unknown\", \"Kinetic parameters not fully determined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealing that MBOAT7 is a negative regulator of TLR signaling in macrophages: its deficiency redistributes arachidonic acid toward proinflammatory eicosanoids, induces ER stress, and remodels chromatin accessibility at inflammatory loci\",\n      \"evidence\": \"MBOAT7 KO/KD in macrophages with lipidomics, eicosanoid profiling, ATAC-seq, gain-of-function rescue\",\n      \"pmids\": [\"36473860\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which specific eicosanoid species drive the phenotype not pinpointed\", \"In vivo macrophage-specific KO not tested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"High-resolution cryo-EM structure revealed the twisted tunnel architecture for dual substrate access and showed that lumenal N-terminal residues determine PI headgroup selectivity; simultaneously, the Golgi-resident MMD–ACSL4–MBOAT7 complex was defined as a functional unit channeling AA into PI and sensitizing cells to ferroptosis\",\n      \"evidence\": \"Cryo-EM structure with domain-swap mutagenesis; reciprocal co-IP and genetic epistasis with ferroptosis assays\",\n      \"pmids\": [\"37316513\", \"37691145\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the ternary MMD–ACSL4–MBOAT7 complex not resolved\", \"Whether ferroptosis sensitization operates in hepatocytes in vivo unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Establishing a cell-autonomous metabolic role in adipocytes: adipocyte-specific MBOAT7 loss depletes AA-PI, promotes hyperinsulinemia and systemic insulin resistance independent of hepatocyte MBOAT7\",\n      \"evidence\": \"Adipocyte-specific Mboat7 KO mice with metabolic phenotyping and lipidomics\",\n      \"pmids\": [\"36806709\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling pathway from adipocyte PI depletion to insulin resistance not defined\", \"Contribution to human metabolic syndrome unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identifying downstream pathways of hepatocyte MBOAT7 loss in chronic liver disease: a cholesterol trafficking–TAZ–IHH profibrotic axis drives fibrosis in MASH, while impaired TFEB-mediated lysosomal biogenesis and autophagic flux exacerbate alcohol-associated liver injury\",\n      \"evidence\": \"Hepatocyte-specific MBOAT7 overexpression/silencing in MASH mice with human biopsy validation; hepatocyte-specific KO with ethanol feeding and autophagic flux/TFEB analysis\",\n      \"pmids\": [\"38776184\", \"38648183\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How altered PI composition mechanistically activates TAZ not resolved\", \"Whether lysosomal defects and TAZ activation represent parallel or sequential pathways unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include the structural basis of the MMD–ACSL4–MBOAT7 ternary complex, the precise lipid signaling intermediate linking PI depletion to SREBP-1c processing, the mechanism by which altered PI composition disrupts lysosomal biogenesis and TFEB activity, and whether pharmacological MBOAT7 activation can reverse established liver fibrosis in humans\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No ternary complex structure available\", \"Lipid intermediate between PI depletion and SREBP-1c unknown\", \"No clinical intervention data\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 7, 11, 14]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 11, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [4, 14]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 1, 7, 11, 12, 16]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [12, 17]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 6, 17, 18]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [18]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"complexes\": [\n      \"MMD-ACSL4-MBOAT7\"\n    ],\n    \"partners\": [\n      \"ACSL4\",\n      \"MMD\",\n      \"ACSL3\",\n      \"FATP1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}