LPGAT1, increasingly termed LPLAT7, is an integral endoplasmic-reticulum membrane lysophospholipid acyltransferase that restores saturated fatty acids to the sn-1 position of membrane phospholipids. Position-resolved human-enzyme assays show preferential use of unsaturated 1-lyso-2-acyl lysophosphatidylcholine and lysophosphatidylethanolamine acceptors, weaker activity toward lysophosphatidylserine, and a strong preference for stearoyl-CoA over palmitoyl- or oleoyl-CoA. Human Huh7 knockout and tracer experiments indicate that lysosomal phospholipid degradation is a major source of these substrates: PLA1 products generated from endocytosed phospholipids are delivered to ER-localized LPGAT1 and reacylated to 1-stearoyl-2-unsaturated PC, PE, and PS. This salvage reaction couples lysosomal phospholipid turnover to ER membrane regeneration and partitions lipid flux away from triglyceride and lipid-droplet accumulation in the tested hepatic-cell and mouse systems. Historical studies also report LPG acylation and mouse monoacylglycerol acyltransferase activity. Their efficiencies and physiological contributions differ among expression systems and experimental conditions; strong PC/PE preference does not establish absolute loss of these secondary capacities.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005783 endoplasmic reticulum | IBA GO_REF:0000033 | ACCEPT | Summary: ER, endomembrane, membrane and acyltransferase terms describe established core properties of LPGAT1. Reason: Human LPGAT1 localizes to the ER and catalyzes acyl-CoA-dependent lysophospholipid acylation. The broader existing terms remain correct alongside more precise location and activity terms. PTHR10983 places ER at PTN000105011 and endomembrane/acyltransferase at PTN000105009; target experimental evidence contributing to that latter IBD is legitimate, not circular. Supporting Evidence: PMID:15485873 LPGAT1 was localized to the endoplasmic reticulum by subcellular fractionation and immunohistochemical analyses. |
| GO:0012505 endomembrane system | IBA GO_REF:0000033 | ACCEPT | Summary: ER, endomembrane, membrane and acyltransferase terms describe established core properties of LPGAT1. Reason: Human LPGAT1 localizes to the ER and catalyzes acyl-CoA-dependent lysophospholipid acylation. The broader existing terms remain correct alongside more precise location and activity terms. PTHR10983 places ER at PTN000105011 and endomembrane/acyltransferase at PTN000105009; target experimental evidence contributing to that latter IBD is legitimate, not circular. Supporting Evidence: PMID:15485873 LPGAT1 was localized to the endoplasmic reticulum by subcellular fractionation and immunohistochemical analyses. |
| GO:0016746 acyltransferase activity | IBA GO_REF:0000033 | ACCEPT | Summary: ER, endomembrane, membrane and acyltransferase terms describe established core properties of LPGAT1. Reason: Human LPGAT1 localizes to the ER and catalyzes acyl-CoA-dependent lysophospholipid acylation. The broader existing terms remain correct alongside more precise location and activity terms. PTHR10983 places ER at PTN000105011 and endomembrane/acyltransferase at PTN000105009; target experimental evidence contributing to that latter IBD is legitimate, not circular. Supporting Evidence: PMID:15485873 LPGAT1 was localized to the endoplasmic reticulum by subcellular fractionation and immunohistochemical analyses. |
| GO:0036149 phosphatidylinositol acyl-chain remodeling | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Retain inherited PI remodeling as a secondary capacity compatible with the weak target LPI activity. Reason: Live PTHR10983 places Q92604 leaf PTN002475324 below PI-remodeling IBD PTN000105011, grounded in SGD:S000000246. Full PMID:36049524 finds LPI to be poor but not excluded, and reports reduced residual LPI-directed sn-1 activity after knockout, including similar changes in human-cell membrane assays. No target-specific loss was established. The report’s proposed ALCAT1 paralog mix-up is speculative: shared family membership and absence of a separate UniProt RHEA entry do not negate this ancestral placement. Retain as non-core without asserting substantial normal-human PI flux. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN000105011 · PTN000105011 SUPPORTS TRANSFER Verified target path and actual yeast-descendant IBD, with target weak-substrate and knockout compatibility. The report does not demonstrate a target-specific loss or a source annotation error. Supporting Evidence: PMID:36049524 The sn-1 LPLAT activities for LPI and LPG were also lower but still present in the KO mice. file:human/LPGAT1/LPGAT1-hypotheses/secondary-acylation-capacities-and-lipid-pathway-scope/openscientist.md LPI/LPG are weak but detectable intrinsic substrates |
| GO:0003846 2-acylglycerol O-acyltransferase activity | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Retain mouse-ortholog-supported monoacylglycerol acyltransferase as a secondary human capacity. Reason: Full PMID:20018982 cloned mouse Lpgat1 and expressed it in CHO cells: lysate MGAT activity rose fivefold over empty vector, with preference for sn-2 monoacylglycerol, while AGPAT/DGAT/ACAT did not significantly increase. The assay measures radiolabeled DAG product; this is not a purified-human-enzyme experiment. Hepatic shRNA also reduced MGAT activity. The focused report correctly identifies the mouse provenance but supplies no human-specific loss. Retain the existing orthology-based secondary activity with these assay limits. Supporting Evidence: PMID:20018982 MGAT activity was 5-fold higher than that in the lysates of cells transfected with the empty vector |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Accepted as the experimentally established membrane location of LPGAT1. Reason: The UniProt subcellular-location mapping agrees with direct ER localization and multi-pass membrane topology reported in PMID:15485873. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0097 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPGAT1 evidence. |
| GO:0016746 acyltransferase activity | IEA GO_REF:0000002 | ACCEPT | Summary: ER, endomembrane, membrane and acyltransferase terms describe established core properties of LPGAT1. Reason: Human LPGAT1 localizes to the ER and catalyzes acyl-CoA-dependent lysophospholipid acylation. The broader existing terms remain correct alongside more precise location and activity terms. PTHR10983 places ER at PTN000105011 and endomembrane/acyltransferase at PTN000105009; target experimental evidence contributing to that latter IBD is legitimate, not circular. Supporting Evidence: PMID:15485873 LPGAT1 was localized to the endoplasmic reticulum by subcellular fractionation and immunohistochemical analyses. |
| GO:0047190 2-acylglycerophosphocholine O-acyltransferase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Accepted as directly supported sn-2-acyl LPC acyltransferase activity. Reason: PMID:36049524 directly shows human LPLAT7/LPGAT1 incorporates fatty acids at the sn-1 position of sn-2 LPC, with strong stearoyl-CoA-dependent activity. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q91YX5 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPGAT1 evidence. ensembl:ENSMUSP00000106479 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPGAT1 evidence. RHEA:10332 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPGAT1 evidence. RHEA:74799 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPGAT1 evidence. RHEA:74803 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPGAT1 evidence. RHEA:74807 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPGAT1 evidence. RHEA:74811 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPGAT1 evidence. RHEA:74823 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPGAT1 evidence. EC:2.3.1.62 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPGAT1 evidence. |
| GO:0106263 1-acylglycerophosphoserine O-acyltransferase activity | IEA GO_REF:0000116 | UNDECIDED | Summary: LPS acceptance is established, but the exact 1-acyl-LPS-to-sn-2-acylated-product reaction remains unresolved. Reason: The report correctly distinguishes RHEA:37403 (1-acyl acceptor/sn-2 addition) from RHEA:74815 (2-acyl acceptor/sn-1 addition), but then recommends the specific GO term from database provenance rather than a new positional assay. Full PMID:36049524 calls LPS a moderate substrate and prepares sn-2-rich LPS; its detailed isotope/PLA2 positional product analysis is performed on LPC. That is strong evidence for LPS acceptance and sn-1 preference, not a definitive test of the opposite LPS reaction. Keep the specific GO:0106263 claim uncertain; neither substrate preference nor a curated reaction label settles this chemical position. Supporting Evidence: PMID:36049524 LPS was a moderate substrate. file:human/LPGAT1/LPGAT1-hypotheses/secondary-acylation-capacities-and-lipid-pathway-scope/openscientist.md the seed's "1-acyl-LPS" phrasing corresponds to the sn-2 reaction RHEA:37403 |
| GO:0019432 triglyceride biosynthetic process | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Retain a context-dependent triacylglycerol-biosynthesis contribution through the reported MGAT step. Reason: MGAT converts monoacylglycerol to DAG, a catalytic step feeding the TAG pathway; it need not perform the final DGAT reaction. Full PMID:20018982 combines mouse-expression MGAT assays and reduced hepatic MGAT after shRNA with lower serum TAG. Hepatic TAG instead slightly increased nonsignificantly, so the report’s comparison with later hepatic accumulation does not establish opposite results. The original synthesis/secretion interpretation remains a model without direct isotope flux. PMID:42173283 supports a predominant phospholipid-salvage role and altered lipid partitioning, which can coexist with a secondary MGAT pathway contribution. Retain the existing transfer as non-core, without claiming predominant human TAG synthesis. Supporting Evidence: PMID:20018982 MGAT activity was 5-fold higher than that in the lysates of cells transfected with the empty vector PMID:20018982 Hepatic TAG level slightly increased in LPGAT1 shRNA adenovirus-treated animals; however, this increase was not statistically significant |
| GO:0036152 phosphatidylethanolamine acyl-chain remodeling | IEA GO_REF:0000107 | ACCEPT | Summary: Accepted as a core phosphatidylethanolamine acyl-chain remodeling process. Reason: Mouse orthology transfer is independently supported by direct human LPLAT7 LPE acylation and by loss-of-function lipidomics showing altered stearate-containing PE in PMID:36049524. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q91YX5 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPGAT1 evidence. ensembl:ENSMUSP00000106479 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPGAT1 evidence. |
| GO:0071617 lysophospholipid acyltransferase activity | IEA GO_REF:0000107 | ACCEPT | Summary: Accepted as the broad catalytic activity encompassing LPGAT1/LPLAT7 lysophospholipid substrates. Reason: Direct human studies support acyl-CoA-dependent reacylation of LPG and, in modern position-resolved assays, LPC, LPE, and LPS. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q91YX5 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPGAT1 evidence. ensembl:ENSMUSP00000106479 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPGAT1 evidence. |
| GO:0071618 lysophosphatidylethanolamine acyltransferase activity | IEA GO_REF:0000107 | ACCEPT | Summary: Accepted as a central lysophosphatidylethanolamine acyltransferase activity. Reason: PMID:36049524 identifies LPE as a strong sn-2 lysophospholipid acceptor and shows a physiological preference for stearoyl-CoA incorporation into PE. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q91YX5 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPGAT1 evidence. ensembl:ENSMUSP00000106479 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPGAT1 evidence. |
| GO:0036148 phosphatidylglycerol acyl-chain remodeling | TAS Reactome:R-HSA-1482925 | KEEP AS NON CORE | Summary: Retain reported PG remodeling as a secondary capacity whose physiological importance differs among models. Reason: Human expression experiments in PMID:15485873 directly increase LPG acylation, while full PMID:36049524 reports poor LPG acceptance and reduced residual LPG-directed activity in knockout tissue. PMID:37917582 provides the competing PG-remodeling/mitochondrial model. PMID:42173283 finds no significant PG lipidomic contribution in its tested systems and explicitly speculates about acyl migration; it does not demonstrate that the original LPG reaction was artifactual. Acyl migration could alter positional interpretation while leaving PG formation real. The focused report reasonably retains secondary PG activity. Keep this existing process non-core without presenting the contested PG-specific disease mechanism as settled. Supporting Evidence: PMID:15485873 Expression of the LPGAT1 cDNA in Sf9 insect and COS-7 cells led to a significant increase in LPG acyltransferase activity. PMID:42173283 We speculate that LPLAT7 was misidentified as LPGAT1 |
| GO:0003841 1-acylglycerol-3-phosphate O-acyltransferase activity | TAS Reactome:R-HSA-1482539 | MODIFY | Summary: The cited remodeling event concerns lysophosphatidylglycerol or other lysophospholipid acylation, not the named lysophosphatidic-acid reaction. Reason: The existing Reactome mapping uses phosphatidic-acid acyltransferase terms for a lysophosphatidylglycerol-remodeling event. LPA and LPG have different head groups, so these reactions are not interchangeable. Replace the event-derived assertion with the supported broad lysophospholipid acyltransferase function. PMID:36049524 also finds very poor LPA activity and no appreciable knockout-dependent LPA acylation; this correction does not assert that every possible trace LPA reaction is absent. Proposed replacements: lysophospholipid acyltransferase activity Supporting Evidence: PMID:36049524 LPLAT7 did not contribute to an LPLAT activity for LPA, suggesting that it contributes to the fatty acid remodeling of PLs rather than to the de novo synthesis of PLs. |
| GO:0047144 2-acylglycerol-3-phosphate O-acyltransferase activity | TAS Reactome:R-HSA-1482635 | MODIFY | Summary: The cited remodeling event concerns lysophosphatidylglycerol or other lysophospholipid acylation, not the named lysophosphatidic-acid reaction. Reason: The existing Reactome mapping uses phosphatidic-acid acyltransferase terms for a lysophosphatidylglycerol-remodeling event. LPA and LPG have different head groups, so these reactions are not interchangeable. Replace the event-derived assertion with the supported broad lysophospholipid acyltransferase function. PMID:36049524 also finds very poor LPA activity and no appreciable knockout-dependent LPA acylation; this correction does not assert that every possible trace LPA reaction is absent. Proposed replacements: lysophospholipid acyltransferase activity Supporting Evidence: PMID:36049524 LPLAT7 did not contribute to an LPLAT activity for LPA, suggesting that it contributes to the fatty acid remodeling of PLs rather than to the de novo synthesis of PLs. |
| GO:0003846 2-acylglycerol O-acyltransferase activity | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Retain mouse-ortholog-supported monoacylglycerol acyltransferase as a secondary human capacity. Reason: Full PMID:20018982 cloned mouse Lpgat1 and expressed it in CHO cells: lysate MGAT activity rose fivefold over empty vector, with preference for sn-2 monoacylglycerol, while AGPAT/DGAT/ACAT did not significantly increase. The assay measures radiolabeled DAG product; this is not a purified-human-enzyme experiment. Hepatic shRNA also reduced MGAT activity. The focused report correctly identifies the mouse provenance but supplies no human-specific loss. Retain the existing orthology-based secondary activity with these assay limits. Supporting Evidence: PMID:20018982 MGAT activity was 5-fold higher than that in the lysates of cells transfected with the empty vector |
| GO:0047190 2-acylglycerophosphocholine O-acyltransferase activity | IDA PMID:36049524 Identification and characterization of LPLAT7 as an sn-1-spe... | ACCEPT | Summary: Accepted as direct evidence for sn-1 reacylation of 2-acyl LPC. Reason: PMID:36049524 uses position-defined substrates and shows human LPLAT7/LPGAT1 incorporates fatty acid almost exclusively at the sn-1 position, including robust activity toward unsaturated 2-acyl LPC. |
| GO:0071617 lysophospholipid acyltransferase activity | IDA PMID:36049524 Identification and characterization of LPLAT7 as an sn-1-spe... | ACCEPT | Summary: Accepted as the direct broad lysophospholipid acyltransferase activity of LPGAT1/LPLAT7. Reason: PMID:36049524 directly tests human enzyme and identifies LPC, LPE, and LPS as acceptors for sn-1 reacylation, with strongest physiological effects on stearate-containing PC and PE. |
| GO:0036152 phosphatidylethanolamine acyl-chain remodeling | ISS GO_REF:0000024 | ACCEPT | Summary: Accepted as orthology support for phosphatidylethanolamine acyl-chain remodeling. Reason: The mouse inference agrees with direct human LPE reacylation and cross-species loss-of-function lipidomics in PMID:36049524. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q91YX5 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPGAT1 evidence. |
| GO:0071618 lysophosphatidylethanolamine acyltransferase activity | ISS GO_REF:0000024 | ACCEPT | Summary: Accepted as orthology support for lysophosphatidylethanolamine acyltransferase activity. Reason: Mouse Lpgat1 transfer is concordant with direct human LPLAT7 activity toward position-defined LPE in PMID:36049524. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q91YX5 SUPPORTS TRANSFER Exact WITH/FROM source; the propagated assignment agrees with direct human LPGAT1 evidence. |
| GO:0005789 endoplasmic reticulum membrane | IMP PMID:15485873 Identification and characterization of a gene encoding human... | ACCEPT | Summary: Accepted as the ER-membrane localization of human LPGAT1. Reason: PMID:15485873 localized human LPGAT1 to the endoplasmic reticulum by subcellular fractionation and immunohistochemical analyses; multi-pass topology supports the membrane-specific term. |
| GO:0019432 triglyceride biosynthetic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Retain a context-dependent triacylglycerol-biosynthesis contribution through the reported MGAT step. Reason: MGAT converts monoacylglycerol to DAG, a catalytic step feeding the TAG pathway; it need not perform the final DGAT reaction. Full PMID:20018982 combines mouse-expression MGAT assays and reduced hepatic MGAT after shRNA with lower serum TAG. Hepatic TAG instead slightly increased nonsignificantly, so the report’s comparison with later hepatic accumulation does not establish opposite results. The original synthesis/secretion interpretation remains a model without direct isotope flux. PMID:42173283 supports a predominant phospholipid-salvage role and altered lipid partitioning, which can coexist with a secondary MGAT pathway contribution. Retain the existing transfer as non-core, without claiming predominant human TAG synthesis. Supporting Evidence: PMID:20018982 MGAT activity was 5-fold higher than that in the lysates of cells transfected with the empty vector PMID:20018982 Hepatic TAG level slightly increased in LPGAT1 shRNA adenovirus-treated animals; however, this increase was not statistically significant |
| GO:0071617 lysophospholipid acyltransferase activity | IMP PMID:15485873 Identification and characterization of a gene encoding human... | ACCEPT | Summary: Accepted with curator deference as perturbation support for human lysophospholipid acyltransferase activity. Reason: PMID:15485873 directly characterizes human LPGAT1-dependent LPG acylation. Although the cached abstract does not expose why the curator selected IMP, the assigned broad catalytic activity is independently coherent with both defining studies. |
| GO:0045723 positive regulation of fatty acid biosynthetic process | IMP PMID:23749231 MicroRNA-30c reduces hyperlipidemia and atherosclerosis in m... | KEEP AS NON CORE | Summary: Retained as a context-dependent positive effect on fatty-acid biosynthesis rather than a core catalytic function. Reason: In Huh-7 cells, LPGAT1 knockdown reduced fatty-acid synthesis and prevented further suppression by miR-30c, supporting a positive contribution in this hepatic-cell context. The phenotype is downstream of lipid remodeling and does not define LPGAT1’s molecular activity. |
| GO:0016020 membrane | HDA PMID:19946888 Defining the membrane proteome of NK cells. | ACCEPT | Summary: ER, endomembrane, membrane and acyltransferase terms describe established core properties of LPGAT1. Reason: Human LPGAT1 localizes to the ER and catalyzes acyl-CoA-dependent lysophospholipid acylation. The broader existing terms remain correct alongside more precise location and activity terms. PTHR10983 places ER at PTN000105011 and endomembrane/acyltransferase at PTN000105009; target experimental evidence contributing to that latter IBD is legitimate, not circular. Supporting Evidence: PMID:15485873 LPGAT1 was localized to the endoplasmic reticulum by subcellular fractionation and immunohistochemical analyses. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-1482539 | ACCEPT | Summary: Accepted as the ER-membrane location of the curated 1-acyl LPG reaction. Reason: Reactome places LPGAT1 in an ER-membrane LPG reacylation event, consistent with direct localization in PMID:15485873. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-1482635 | ACCEPT | Summary: Accepted as the ER-membrane location of the curated 2-acyl LPG reaction. Reason: Reactome places LPGAT1 in an ER-membrane LPG reacylation event, consistent with direct localization in PMID:15485873. |
| GO:0005737 cytoplasm | IDA PMID:10942595 A visual intracellular classification strategy for uncharact... | UNDECIDED | Summary: Undecided with curator deference because the abstract-only systematic localization paper does not expose the LPGAT1-specific image. Reason: PMID:10942595 describes GFP-fusion localization of 25 uncharacterized proteins but does not identify which construct produced the cytoplasmic signal in the cached abstract. Later direct work places LPGAT1 at the ER membrane, but incomplete access is not sufficient to overrule the experimental curator assignment. |
| GO:0036151 phosphatidylcholine acyl-chain remodeling | IMP PMID:42173283 LPLAT7 reutilizes unsaturated 1-lysophospholipids formed dur... | NEW | Summary: Proposed as a new annotation for LPGAT1-dependent recycling of lysosome-derived unsaturated LPC into stearoyl-unsaturated PC. Reason: Retain this pre-existing proposal: LPGAT1 directly catalyzes lysophospholipid reacylation, so it participates in remodeling rather than merely being a substrate or a necessary upstream factor. Position-defined enzyme assays and the Huh7 knockout lipidomic result support PC and PS remodeling. These sibling processes add substrate-specific coverage alongside existing PE remodeling; no additional parent or child process is proposed. Supporting Evidence: PMID:42173283 Huh7 cells with Lplat7 deletion had lower proportions of 1-stearoyl-2-unsaturated species of PC and PS PMID:36049524 LPS was a moderate substrate. |
| GO:0036150 phosphatidylserine acyl-chain remodeling | IMP PMID:42173283 LPLAT7 reutilizes unsaturated 1-lysophospholipids formed dur... | NEW | Summary: Proposed as a new annotation for LPGAT1-dependent maintenance of stearoyl-unsaturated PS composition. Reason: Retain this pre-existing proposal: LPGAT1 directly catalyzes lysophospholipid reacylation, so it participates in remodeling rather than merely being a substrate or a necessary upstream factor. Position-defined enzyme assays and the Huh7 knockout lipidomic result support PC and PS remodeling. These sibling processes add substrate-specific coverage alongside existing PE remodeling; no additional parent or child process is proposed. Supporting Evidence: PMID:42173283 Huh7 cells with Lplat7 deletion had lower proportions of 1-stearoyl-2-unsaturated species of PC and PS PMID:36049524 LPS was a moderate substrate. |
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Download this section (compressed HTML)Q: Is lysosomal degradation the dominant source of LPGAT1 substrates in intact human tissues, and which PLA1/export components supply them?
Q: What are the endogenous LPC, LPE, LPS, and acyl-CoA preference hierarchies of human LPGAT1 across cell types?
Q: Can rigorously position-defined assays reproduce any direct LPGAT1-dependent LPG acylation or PG remodeling in human cells?
Q: Does human LPGAT1 directly catalyze monoacylglycerol acylation, or are triglyceride phenotypes secondary to altered membrane-lipid salvage?
Q: Which regenerated PC, PE, or PS species account for mitochondrial and hepatic phenotypes, and is PHB/TIMM14 association causal or transient?
Q: Are any endogenous LPGAT1 isoforms, orientations, or stable regulatory partners functionally distinct?
Experiment: Combine isotope-labeled endocytic PC/PE/PS pulse-chase experiments with endogenous knockout/rescue of LPGAT1, PLA1 candidates, PLA2G15, PLBD2, and SPNS1 in primary human hepatic and cardiac models, tracking positional lysolipids and regenerated phospholipids across lysosome and ER fractions.
Hypothesis: Endocytic lysosomal PLA1 processing supplies most endogenous unsaturated 1-lyso-2-acyl substrates to ER-localized LPGAT1 in human cells.
Type: lysosome-to-ER phospholipid salvage tracing
Experiment: Use endogenous LPGAT1 knockout and expression-matched rescue with wild-type or catalytic-null protein, then quantify kinetic competition among position-defined LPC/LPE/LPS acceptors and C18:0-, C16:0-, and C18:1-CoA donors by targeted fluxomics.
Hypothesis: Native human LPGAT1 preferentially installs stearate into unsaturated 1-lyso-2-acyl LPC and LPE, with weaker but genuine LPS flux.
Type: endogenous positional substrate competition
Experiment: Prepare stabilized, analytically verified 1- and 2-acyl LPG isomers, monitor acyl migration throughout the assay, and compare product formation by purified and native human LPGAT1 with PG flux after knockout and genomic rescue.
Hypothesis: Historical LPG activity reflects acyl migration rather than physiological PG remodeling.
Type: disputed LPG activity resolution
Experiment: Measure direct monoacylglycerol-to-diacylglycerol conversion alongside lysophospholipid reacylation in purified preparations and endogenous human-cell perturbations, then use isotope tracing to distinguish catalytic MGAT flux from secondary triglyceride accumulation.
Hypothesis: LPGAT1-dependent triglyceride changes arise from lipid-flux repartitioning rather than direct human MGAT catalysis.
Type: MGAT versus salvage-flux discrimination
Experiment: Restore individual positional PC/PE/PS species or PG in LPGAT1-null human liver and cardiac organoids, compare catalytic and PHB/TIMM14-interface rescue, and quantify membrane transfer, crista structure, respiration, cardiolipin synthesis, and stress responses.
Hypothesis: Loss of stearoyl-unsaturated PC/PE/PS regeneration, rather than defective PG remodeling, causes mitochondrial dysfunction after LPGAT1 loss.
Type: causal mitochondrial lipid-species rescue
What is not known — curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The contribution of lysosome-to-ER phospholipid salvage to endogenous LPGAT1 activity in intact human tissues is unknown.
OPEN BIOLOGY RESIDUAL_SUBGAP
What is known: Human Huh7 knockout, isotope tracing, and lysosomal-phospholipase perturbations directly support lysosome-derived LPC salvage, but Huh7 is a transformed hepatic cell line. The broader PC/PE/PS membrane-regeneration phenotype is strongly supported in mouse knockout tissues.
Significance: Native flux through this pathway will determine whether lysosomal degradation is the dominant LPGAT1 substrate source in liver, heart, brain, placenta, and other human tissues.
What would resolve it: Perform pulse-chase positional lipidomics after endogenous LPGAT1, PLA1, PLA2G15, PLBD2, and SPNS1 perturbation in primary or organoid human tissues, with genomic rescue and matched endocytic-lipid inputs.
Gap: The quantitative acceptor and acyl-donor specificity of endogenous human LPGAT1 across PC, PE, and PS is incompletely resolved.
OPEN BIOLOGY
What is known: Recombinant and membrane-fraction assays favor unsaturated 1-lyso-2-acyl LPC/LPE and stearoyl-CoA, while PS activity is weaker and some substrate rankings differ across human and murine expression systems.
Significance: Substrate competition determines which membrane species are regenerated and how LPGAT1 controls the stearate-to-palmitate/oleate ratio.
What would resolve it: Measure endogenous isotope-resolved flux through position-defined LPC, LPE, and LPS panels with stearoyl-, palmitoyl-, and oleoyl-CoA in multiple human cell types, using catalytic-null and expression-matched rescue controls.
Gap: Whether human LPGAT1 has physiologically meaningful LPG acyltransferase or PG remodeling activity remains disputed.
OPEN BIOLOGYCURATION
What is known: The 2004 human heterologous-expression study reported LPG-specific activity, but newer position-defined studies favor LPC/LPE/LPS, find no in-vivo PG remodeling, and propose that intramolecular LPG acyl migration confounded the historical assay.
Significance: This conflict changes interpretation of the gene name, Reactome LPG reactions, and mitochondrial phenotypes attributed to PG remodeling.
What would resolve it: Reassay purified and native human LPGAT1 with rigorously stabilized positional LPG isomers and isotope-defined products, then test endogenous PG flux after knockout/rescue without extrapolating from total PG abundance alone.
Gap: The reported monoacylglycerol acyltransferase activity and triglyceride-synthesis role have not been established as direct human LPGAT1 functions.
OPEN BIOLOGYCURATION
What is known: The supporting studies primarily use mouse diabetic liver, orthology transfer, and bulk MGAT assays. Modern human and mouse evidence instead shows robust lysophospholipid reacylation, and LPGAT1 loss can increase triglyceride and lipid droplets by redirecting lipid flux.
Significance: Distinguishing direct MGAT catalysis from secondary flux redistribution prevents an incorrect triglyceride-biosynthesis core assignment.
What would resolve it: Test purified and endogenous human LPGAT1 against position-defined monoacylglycerols with direct diacylglycerol product quantification, catalytic mutants, and parallel lysophospholipid competition assays.
Gap: The mechanism linking LPGAT1-dependent membrane regeneration to mitochondrial dysfunction, hepatopathy, and survival phenotypes is unresolved.
OPEN BIOLOGY
What is known: Mouse knockout phenotypes are reproducible, but a PG-specific PHB/TIMM14-associated transport model is challenged by newer evidence that PC, PE, and PS regeneration is impaired while PG composition is not substantially remodeled. Corresponding causal human disease evidence is absent.
Significance: Resolving the mechanism is necessary before linking human LPGAT1 to MEGDEL-like disease or assigning stable mitochondrial-transport complex membership.
What would resolve it: Compare wild-type, catalytic-dead, and interaction-interface rescue in tissue-specific mouse models and human liver/cardiac organoids while measuring PC/PE/PS salvage, PG/cardiolipin synthesis, organelle lipid transfer, respiration, and PHB/TIMM14 interaction stoichiometry.
Gap: Functionally distinct endogenous LPGAT1 protein isoforms, membrane topology, and constitutive protein-complex membership are not established.
OPEN BIOLOGYCURATION
What is known: Human isoform 1 was the construct tested in one study, but that does not prove isoform-restricted activity. The reviewed record supports a multi-pass ER enzyme, while exact orientation and stable complex assembly remain unresolved.
Significance: Isoform or complex assumptions could incorrectly explain tissue-specific flux or conflate transient lipid-transfer interactions with obligatory catalytic machinery.
What would resolve it: Reconcile full-length transcripts by long-read sequencing and proteomics, map ER topology experimentally, and quantify endogenous interaction dynamics with reciprocal validation and catalytic rescue.
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