{"gene":"ELOVL1","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2010,"finding":"ELOVL1 was identified as the elongase with high activity toward saturated and monounsaturated C20- and C22-CoAs, producing C24-CoAs, and shown to be essential for C24 sphingolipid synthesis; in vitro substrate specificity assays across all seven mammalian ELOVLs established this selectivity","method":"In vitro elongation assays determining substrate specificities of all mammalian ELOVL enzymes; ELOVL1 knockdown in cells","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzymatic assay with defined substrates, replicated across multiple ELOVL family members for comparison, plus cellular knockdown confirmation","pmids":["20937905"],"is_preprint":false},{"year":2010,"finding":"ELOVL1 activity is regulated together with ceramide synthase CERS2 to coordinate C24-CoA production with its utilization in C24 sphingolipid synthesis","method":"Biochemical co-regulation analysis; knockdown experiments linking ELOVL1 and CERS2 activity","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single lab, cellular knockdown showing coordinated regulation with CERS2, but mechanistic detail is limited in the abstract","pmids":["20937905"],"is_preprint":false},{"year":2010,"finding":"Knockdown of ELOVL1 caused a reduction in the activity of Src kinase LYN, establishing that C24-sphingolipids produced by ELOVL1 are important for membrane microdomain (lipid raft) function","method":"ELOVL1 siRNA knockdown followed by measurement of LYN kinase activity","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, single method (knockdown + kinase activity assay), no rescue experiment described","pmids":["20937905"],"is_preprint":false},{"year":2010,"finding":"ELOVL1 is the single elongase responsible for synthesis of both saturated VLCFA (C26:0) and monounsaturated VLCFA (C26:1); ELOVL1 knockdown in X-ALD fibroblasts reduced elongation of C22:0 to C26:0 and lowered C26:0 levels","method":"ELOVL1 siRNA knockdown in X-ALD patient fibroblasts with VLCFA quantification; elongation assays","journal":"EMBO molecular medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional knockdown in disease-relevant cells, independently replicated by multiple labs (PMID 20937905, 20166112, 25499606)","pmids":["20166112"],"is_preprint":false},{"year":2013,"finding":"ELOVL1 is the fatty acid elongase responsible for producing C20–C28 fatty acids in the epidermis; Elovl1 knockout mice showed decreased ceramides with ≥C26 fatty acids and increased ceramides with ≤C24, with severely disrupted lipid lamellae in the stratum corneum and lethal epidermal permeability barrier defects","method":"Elovl1 knockout mouse generation; lipidomic analysis of epidermal ceramides; electron microscopy of stratum corneum","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout with defined biochemical and structural phenotype, multiple orthogonal methods","pmids":["23689133"],"is_preprint":false},{"year":2013,"finding":"Ceramide synthases CerS2 and CerS3, expressed in epidermis layer-specific manner, regulate ELOVL1 to produce acyl-CoAs of different chain lengths in the epidermis","method":"Elovl1 KO mouse analysis with CerS2/CerS3 expression profiling and lipidomic comparison","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single lab, genetic model with lipidomics, but CerS regulatory mechanism on ELOVL1 is inferred rather than directly tested","pmids":["23689133"],"is_preprint":false},{"year":2014,"finding":"Oleic and erucic acids (constituents of Lorenzo's oil) inhibit ELOVL1 via mixed (non-competitive) inhibition kinetics; the 4:1 oleate/erucate mixture (matching Lorenzo's oil composition) exhibits the most potent inhibitory activity and reduces saturated VLCFA-sphingomyelin levels in cells","method":"In vitro ELOVL1 enzyme inhibition kinetics assay; cellular sphingomyelin profiling after Lorenzo's oil treatment","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — kinetic characterization with mode-of-inhibition analysis plus cellular validation, single lab but two orthogonal methods","pmids":["24489110"],"is_preprint":false},{"year":2014,"finding":"The CoA esters of bezafibrate and gemfibrozil specifically inhibit ELOVL1 chain elongation activity; kinetic characterization of ELOVL1 was performed using X-ALD fibroblasts and microsomal fractions from ELOVL1-overexpressing HEK293 cells","method":"ELOVL1 overexpression in HEK293 cells, microsomal fraction preparation, in vitro elongation assay, fibrate inhibition kinetics","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstituted enzyme assay with kinetic analysis, use of both patient fibroblasts and overexpression system","pmids":["25499606"],"is_preprint":false},{"year":2018,"finding":"A de novo dominant ELOVL1 mutation (p.S165F) abrogates ELOVL1 enzymatic activity and reduces ≥C24 ceramides and sphingomyelins in patient fibroblasts; fibroblast loading with C22:0 VLCFAs increased C24:0-ceramides and sphingomyelins, and competitive inhibition between saturated and monounsaturated VLCFAs for ceramide/sphingomyelin synthesis was demonstrated","method":"Stable isotope-labelled [13C]malonyl-CoA elongation assay; LC-MS/MS ceramide and sphingomyelin profiling; VLCFA loading experiments in patient fibroblasts","journal":"Journal of medical genetics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct enzymatic activity assay with patient mutation, multiple orthogonal methods including isotope labeling and lipidomics, single lab","pmids":["30487246"],"is_preprint":false},{"year":2018,"finding":"The p.Ser165Phe ELOVL1 mutation reduces levels of C24:0–C28:0 and C26:1 fatty acids while increasing C20:0 and C22:0 in transfected HEK293 cells and patient fibroblasts, confirming loss of elongase function for C22→C26+ substrates","method":"Stable transfection of HEK293 cells with wild-type or p.S165F ELOVL1; gas chromatography-mass spectrometry VLCFA profiling; patient fibroblast VLCFA profiling","journal":"Journal of medical genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — functional activity assay in transfected cells corroborated by patient fibroblast data, two independent groups identified same mutation and same biochemical effect","pmids":["29496980","30487246"],"is_preprint":false},{"year":2018,"finding":"ELOVL1 is primarily responsible for synthesis of saturated VLCFAs in meibomian gland (meibum), while ELOVL1, ELOVL3, and ELOVL4 redundantly participate in monounsaturated VLCFA synthesis; Elovl1 gene disruption in mice shortened acyl chains in cholesteryl esters and wax esters of meibum, causing dry eye phenotype","method":"Elovl1 conditional knockout mice; lipidomic analysis of meibum; measurement of ocular water evaporation and eye-blink frequency","journal":"FASEB journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic KO with defined biochemical phenotype (lipidomics) and functional readouts, single lab but multiple orthogonal methods","pmids":["29401594"],"is_preprint":false},{"year":2019,"finding":"ELOVL1 deficiency in mice markedly shortened acyl chain length of myelin sphingolipids (galactosylceramides, sulfatides, sphingomyelins, ceramides) in the brain, reduced galactosylceramide levels, caused modest hypomyelination of large-diameter axons, and produced motor coordination deficits and reduced acoustic startle response","method":"Elovl1 mutant mice; lipidomic analysis of brain sphingolipids; electron microscopy of corpus callosum; behavioral testing","journal":"FASEB bioAdvances","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic model with multiple orthogonal methods including lipidomics, ultrastructural analysis, and behavioral phenotyping","pmids":["32123819"],"is_preprint":false},{"year":2016,"finding":"Elovl1 knockdown in zebrafish embryos increased levels of long-chain fatty acids (C14–C20) relative to controls, demonstrating that Elovl1 function in elongating these substrates is conserved in zebrafish; knockdown impaired swim bladder inflation and affected kidney development","method":"Morpholino knockdown of elovl1a and elovl1b in zebrafish; fatty acid profiling; gene expression analysis","journal":"Organogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — morpholino knockdown with biochemical (fatty acid profiling) and developmental phenotype readouts in zebrafish ortholog model","pmids":["27078170"],"is_preprint":false},{"year":2002,"finding":"ELOVL1 encodes a microsomal enzyme belonging to a conserved family involved in very long-chain fatty acid and sphingolipid formation; the mouse Elovl1 gene consists of 8 exons spanning 5.4 kb and is arranged in a tail-to-tail array with cell cycle gene p55Cdc, with both co-expressed during proliferation-differentiation transitions","method":"Genomic lambda phage clone isolation and sequencing; mRNA expression analysis","journal":"The Journal of biological chemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — genomic structure determination and expression analysis, no direct enzymatic or functional assay for ELOVL1 protein mechanism","pmids":["11891222"],"is_preprint":false},{"year":2025,"finding":"Elovl1 inactivation in CD8+ T cells leads to accumulation of saturated long-chain fatty acids, which destabilizes INSIG1, leading to SREBP2 activation, increased plasma membrane cholesterol, and stronger T cell receptor signaling; Elovl1-deficient T cells also exhibit increased mitochondrial fitness and fatty acid oxidation","method":"CRISPR/Cas9 screen in CD8+ T cells; single-cell RNA sequencing; INSIG1/SREBP2 pathway analysis; adoptive transfer experiments; membrane cholesterol measurement","journal":"Nature metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR-based functional screen with multiple mechanistic follow-up assays (SREBP2/INSIG1 pathway, cholesterol measurement, metabolic assays), single lab","pmids":["40065102"],"is_preprint":false},{"year":2024,"finding":"Simvastatin downregulates ELOVL1 expression in astrocytes via inhibition of mTOR signaling; overexpression of ELOVL1 specifically in astrocytes using AAV partially reversed the neuroprotective effects of simvastatin after traumatic brain injury, linking astrocytic ELOVL1 and mTOR signaling to VLCFA-mediated neurotoxicity","method":"Mouse cryogenic TBI model; AAV-mediated astrocyte-specific ELOVL1 overexpression; simvastatin treatment; saturated VLCFA quantification in cortex","journal":"Brain research bulletin","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — genetic gain-of-function with functional readout in vivo, single lab, single study","pmids":["39243948"],"is_preprint":false},{"year":2025,"finding":"CRISPRi screen identified ELOVL1 as a key mediator of 1-deoxy-sphingolipid-induced toxicity; pharmacological inhibition of ELOVL1 alleviated cellular, mitochondrial, and neuronal toxicity induced by 1-deoxy-sphingolipids; the principal toxic species was identified as 1-deoxyDHceramide conjugated to nervonic acid (m18:0/24:1), a VLC ceramide whose synthesis depends on ELOVL1","method":"CRISPRi genetic screen; siRNA knockdown validation; cytotoxicity assays; stable isotope-resolved lipidomics by LC-MS/MS; pharmacological ELOVL1 inhibition","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPRi screen with genetic and pharmacological validation, isotope-resolved lipidomics, preprint not yet peer-reviewed","pmids":["bio_10.1101_2025.05.13.653734"],"is_preprint":true},{"year":2026,"finding":"ELOVL1 disruption in mice (both epidermis-specific transgene-containing KO and tamoxifen-inducible conditional KO) causes time-dependent shortening of acyl chains in meibum cholesteryl esters, wax monoesters, and type 1ω wax diesters, and reduction in type 2ω wax diesters; dry eye phenotypes appear later than lipid composition changes, establishing a causal link between ELOVL1-dependent meibum VLCFA production and tear film barrier function","method":"Two conditional/inducible Elovl1 KO mouse models; lipidomic analysis of meibum lipid classes over time; dry eye phenotype assessment (eye blink frequency, water evaporation, meibomian gland orifice plugging)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — two independent genetic mouse models, time-resolved lipidomics plus multiple functional dry eye readouts, single lab","pmids":["41539567"],"is_preprint":false}],"current_model":"ELOVL1 is a microsomal fatty acid elongase that catalyzes the rate-limiting condensation step of the VLCFA elongation cycle, acting preferentially on saturated and monounsaturated C20–C24 acyl-CoA substrates to produce C22–C28+ VLCFAs; these products are essential precursors for C24/C26 ceramides and sphingomyelins in myelin, epidermis, and meibum, where they maintain membrane structure and barrier function, and ELOVL1 activity is coordinated with ceramide synthases CerS2/CerS3, is inhibited in mixed fashion by oleic and erucic acids (Lorenzo's oil), and controls membrane cholesterol homeostasis via the INSIG1/SREBP2 axis in T cells."},"narrative":{"mechanistic_narrative":"ELOVL1 is the microsomal fatty acid elongase that catalyzes the rate-limiting condensation step of very-long-chain fatty acid (VLCFA) synthesis, acting preferentially on saturated and monounsaturated C20- and C22-acyl-CoAs to generate C24-C28 VLCFAs essential for sphingolipid production [PMID:20937905, PMID:20166112]. Its activity is functionally coupled to the ceramide synthases CerS2 and CerS3, which channel ELOVL1-derived acyl-CoAs of defined chain length into C24/C26 ceramides and sphingomyelins [PMID:20937905, PMID:23689133]. The resulting VLCFA-sphingolipids underpin membrane microdomain function, supporting LYN/Src-family kinase activity [PMID:20937905], and are structurally required across multiple tissues: Elovl1 loss in mice shortens epidermal ceramide chains and disrupts stratum corneum lipid lamellae, producing a lethal skin permeability barrier defect [PMID:23689133]; shortens meibum cholesteryl/wax ester acyl chains, causing a dry-eye phenotype [PMID:29401594, PMID:41539567]; and shortens myelin sphingolipid chains, causing hypomyelination and motor and sensory deficits [PMID:32123819]. A de novo dominant p.S165F mutation that abrogates elongase activity and lowers ≥C24 ceramides/sphingomyelins establishes ELOVL1 as the human disease gene for this loss-of-function condition [PMID:30487246, PMID:29496980]. ELOVL1 is inhibited in mixed (non-competitive) fashion by oleic and erucic acids, the constituents of Lorenzo's oil, and by the CoA esters of bezafibrate and gemfibrozil [PMID:24489110, PMID:25499606]. Beyond fatty acid metabolism, ELOVL1 controls plasma-membrane cholesterol homeostasis in CD8+ T cells through the INSIG1/SREBP2 axis, tuning T cell receptor signaling [PMID:40065102], and its products contribute to 1-deoxy-sphingolipid neurotoxicity [PMID:bio_10.1101_2025.05.13.653734].","teleology":[{"year":2010,"claim":"Established which of the seven mammalian elongases produces C24 VLCFAs, defining ELOVL1's substrate niche and its essentiality for C24 sphingolipid synthesis.","evidence":"In vitro elongation assays of all mammalian ELOVLs with defined acyl-CoA substrates plus cellular knockdown","pmids":["20937905"],"confidence":"High","gaps":["No structural basis for substrate-length selectivity","Catalytic mechanism of condensation not resolved at residue level"]},{"year":2010,"claim":"Linked ELOVL1 output to downstream utilization by showing its co-regulation with CerS2 and a functional consequence for lipid-raft-dependent kinase signaling.","evidence":"Knockdown of ELOVL1 with CERS2 co-regulation analysis and LYN kinase activity measurement","pmids":["20937905"],"confidence":"Medium","gaps":["Mechanism of ELOVL1-CerS2 coordination not directly tested","No rescue experiment for the LYN activity phenotype"]},{"year":2010,"claim":"Demonstrated in disease-relevant cells that ELOVL1 is the single elongase generating both saturated and monounsaturated C26 VLCFAs, implicating it in X-ALD lipid biology.","evidence":"ELOVL1 siRNA knockdown in X-ALD patient fibroblasts with VLCFA quantification","pmids":["20166112"],"confidence":"High","gaps":["Does not address regulation of ELOVL1 in X-ALD","Therapeutic modulation not tested here"]},{"year":2013,"claim":"Genetic knockout established ELOVL1 as physiologically required for epidermal VLCFA/ceramide production and an intact skin permeability barrier.","evidence":"Elovl1 knockout mice with epidermal ceramide lipidomics and stratum corneum electron microscopy","pmids":["23689133"],"confidence":"High","gaps":["CerS2/CerS3 regulation of ELOVL1 inferred rather than directly demonstrated","Layer-specific control mechanism unresolved"]},{"year":2014,"claim":"Defined the pharmacology of ELOVL1, showing Lorenzo's oil components and fibrate-CoAs inhibit the enzyme, providing a mechanistic basis for VLCFA-lowering therapy.","evidence":"In vitro inhibition kinetics with mode-of-inhibition analysis and cellular sphingomyelin profiling","pmids":["24489110","25499606"],"confidence":"High","gaps":["No co-structure of ELOVL1 with inhibitors","In vivo efficacy of inhibition not established here"]},{"year":2018,"claim":"Identified ELOVL1 as a human disease gene by showing a de novo dominant p.S165F mutation abolishes elongase activity and shifts ceramide/sphingomyelin chain lengths.","evidence":"Isotope-labelled malonyl-CoA elongation assay, transfected HEK293 and patient-fibroblast VLCFA/ceramide lipidomics; mutation found by two groups","pmids":["29496980","30487246"],"confidence":"High","gaps":["Dominant-negative versus haploinsufficient mechanism not resolved","Full clinical spectrum and genotype-phenotype not defined"]},{"year":2018,"claim":"Extended ELOVL1's tissue roles to the ocular surface, showing it supplies VLCFAs for meibum lipids required for tear film stability.","evidence":"Elovl1 conditional knockout mice with meibum lipidomics and dry-eye functional readouts","pmids":["29401594"],"confidence":"High","gaps":["Redundancy with ELOVL3/ELOVL4 for monounsaturated species incompletely mapped"]},{"year":2019,"claim":"Established that ELOVL1 sets myelin sphingolipid chain length and that its loss causes hypomyelination and neurological deficits.","evidence":"Elovl1 mutant mice with brain sphingolipid lipidomics, corpus callosum EM, and behavioral testing","pmids":["32123819"],"confidence":"High","gaps":["Cell-autonomous oligodendrocyte requirement not isolated","Link to human neurological disease phenotype not directly tested"]},{"year":2025,"claim":"Revealed a signaling role beyond bulk lipid structure: ELOVL1 controls membrane cholesterol via INSIG1/SREBP2 and tunes CD8+ T cell receptor signaling and metabolism.","evidence":"CRISPR/Cas9 screen in CD8+ T cells, scRNA-seq, INSIG1/SREBP2 pathway analysis, cholesterol measurement, adoptive transfer","pmids":["40065102"],"confidence":"Medium","gaps":["Single lab, not independently replicated","Direct biochemical link between saturated LCFA accumulation and INSIG1 destabilization not fully resolved"]},{"year":2025,"claim":"Implicated ELOVL1 in sphingolipid-driven cytotoxicity by identifying it as required for synthesis of a toxic VLC 1-deoxy-ceramide species.","evidence":"CRISPRi screen, siRNA and pharmacological validation, isotope-resolved lipidomics (preprint)","pmids":["bio_10.1101_2025.05.13.653734"],"confidence":"Medium","gaps":["Preprint, not peer-reviewed","In vivo relevance of the toxic species not established"]},{"year":2026,"claim":"Two independent KO models resolved the temporal order of meibum lipid remodeling, establishing that ELOVL1-dependent VLCFA shortening causally precedes dry-eye pathology.","evidence":"Epidermis-specific transgene KO and tamoxifen-inducible conditional KO mice with time-resolved meibum lipidomics and dry-eye phenotyping","pmids":["41539567"],"confidence":"High","gaps":["Molecular trigger converting altered meibum to barrier failure not defined"]},{"year":null,"claim":"How ELOVL1 substrate-length selectivity and catalysis are encoded structurally, and how its activity is coordinately regulated with ceramide synthases across tissues, remains unresolved.","evidence":"No structural or reconstituted regulatory mechanism in the timeline","pmids":[],"confidence":"Low","gaps":["No experimental structure of ELOVL1","Mechanism of CerS2/CerS3 coupling unproven","Tissue-specific regulatory inputs uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,3,8,9]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[7,13]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,3,4]}],"complexes":[],"partners":["CERS2","CERS3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BW60","full_name":"Very long chain fatty acid elongase 1","aliases":["3-keto acyl-CoA synthase ELOVL1","ELOVL fatty acid elongase 1","ELOVL FA elongase 1","Elongation of very long chain fatty acids protein 1","Very long chain 3-ketoacyl-CoA synthase 1","Very long chain 3-oxoacyl-CoA synthase 1"],"length_aa":279,"mass_kda":32.7,"function":"Catalyzes the first and rate-limiting reaction of the four reactions that constitute the long-chain fatty acids elongation cycle (PubMed:29496980, PubMed:30487246). This endoplasmic reticulum-bound enzymatic process allows the addition of 2 carbons to the chain of long- and very long-chain fatty acids (VLCFAs) per cycle. Condensing enzyme that exhibits activity toward saturated and monounsaturated acyl-CoA substrates, with the highest activity towards C22:0 acyl-CoA. May participate in the production of both saturated and monounsaturated VLCFAs of different chain lengths that are involved in multiple biological processes as precursors of membrane lipids and lipid mediators. Important for saturated C24:0 and monounsaturated C24:1 sphingolipid synthesis (PubMed:20937905). Indirectly inhibits RPE65 via production of VLCFAs","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q9BW60/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ELOVL1","classification":"Not Classified","n_dependent_lines":142,"n_total_lines":1208,"dependency_fraction":0.11754966887417219},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000066322","cell_line_id":"CID000315","localizations":[{"compartment":"vesicles","grade":3}],"interactors":[{"gene":"CANX","stoichiometry":0.2},{"gene":"RAB11B","stoichiometry":0.2},{"gene":"RAE1","stoichiometry":0.2},{"gene":"DCTN2","stoichiometry":0.2},{"gene":"UBE3B","stoichiometry":0.2},{"gene":"ANP32A","stoichiometry":0.2},{"gene":"VDAC1","stoichiometry":0.2},{"gene":"TAGLN2","stoichiometry":0.2},{"gene":"LDHA","stoichiometry":0.2},{"gene":"DHFR","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000315","total_profiled":1310},"omim":[{"mim_id":"618527","title":"ICHTHYOTIC KERATODERMA, SPASTICITY, HYPOMYELINATION, AND DYSMORPHIC FACIAL FEATURES; IKSHD","url":"https://www.omim.org/entry/618527"},{"mim_id":"614451","title":"ELONGATION OF VERY LONG CHAIN FATTY ACIDS-LIKE 7; ELOVL7","url":"https://www.omim.org/entry/614451"},{"mim_id":"611815","title":"ELONGATION OF VERY LONG CHAIN FATTY ACIDS-LIKE 3; ELOVL3","url":"https://www.omim.org/entry/611815"},{"mim_id":"611814","title":"ELONGATION OF VERY LONG CHAIN FATTY ACIDS-LIKE 2; ELOVL2","url":"https://www.omim.org/entry/611814"},{"mim_id":"611813","title":"ELONGATION OF VERY LONG CHAIN FATTY ACIDS-LIKE 1; ELOVL1","url":"https://www.omim.org/entry/611813"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Endoplasmic reticulum","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":357.2}],"url":"https://www.proteinatlas.org/search/ELOVL1"},"hgnc":{"alias_symbol":["Ssc1"],"prev_symbol":[]},"alphafold":{"accession":"Q9BW60","domains":[{"cath_id":"-","chopping":"27-262","consensus_level":"high","plddt":93.6972,"start":27,"end":262}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BW60","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BW60-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BW60-F1-predicted_aligned_error_v6.png","plddt_mean":89.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ELOVL1","jax_strain_url":"https://www.jax.org/strain/search?query=ELOVL1"},"sequence":{"accession":"Q9BW60","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BW60.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BW60/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BW60"}},"corpus_meta":[{"pmid":"20937905","id":"PMC_20937905","title":"ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid synthesis.","date":"2010","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/20937905","citation_count":299,"is_preprint":false},{"pmid":"23689133","id":"PMC_23689133","title":"Impaired epidermal permeability barrier in mice lacking elovl1, the gene responsible for very-long-chain fatty acid production.","date":"2013","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/23689133","citation_count":145,"is_preprint":false},{"pmid":"20166112","id":"PMC_20166112","title":"The role of ELOVL1 in very long-chain fatty acid homeostasis and X-linked adrenoleukodystrophy.","date":"2010","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/20166112","citation_count":137,"is_preprint":false},{"pmid":"30487246","id":"PMC_30487246","title":"De novo mutation in ELOVL1 causes ichthyosis, acanthosis nigricans, hypomyelination, spastic paraplegia, high frequency deafness and optic atrophy.","date":"2018","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30487246","citation_count":61,"is_preprint":false},{"pmid":"29401594","id":"PMC_29401594","title":"Very long-chain tear film lipids produced by fatty acid elongase ELOVL1 prevent dry eye disease in mice.","date":"2018","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/29401594","citation_count":57,"is_preprint":false},{"pmid":"29496980","id":"PMC_29496980","title":"Dominant ELOVL1 mutation causes neurological disorder with ichthyotic keratoderma, spasticity, hypomyelination and dysmorphic features.","date":"2018","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29496980","citation_count":49,"is_preprint":false},{"pmid":"24489110","id":"PMC_24489110","title":"Lorenzo's oil inhibits ELOVL1 and lowers the level of sphingomyelin with a saturated very long-chain fatty acid.","date":"2014","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/24489110","citation_count":48,"is_preprint":false},{"pmid":"25499606","id":"PMC_25499606","title":"Enzymatic characterization of ELOVL1, a key enzyme in very long-chain fatty acid synthesis.","date":"2014","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/25499606","citation_count":32,"is_preprint":false},{"pmid":"32123819","id":"PMC_32123819","title":"Reduced chain length in myelin sphingolipids and poorer motor coordination in mice deficient in the fatty acid elongase Elovl1.","date":"2019","source":"FASEB bioAdvances","url":"https://pubmed.ncbi.nlm.nih.gov/32123819","citation_count":25,"is_preprint":false},{"pmid":"27078170","id":"PMC_27078170","title":"The fatty acid chain elongase, Elovl1, is required for kidney and swim bladder development during zebrafish embryogenesis.","date":"2016","source":"Organogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/27078170","citation_count":25,"is_preprint":false},{"pmid":"35379526","id":"PMC_35379526","title":"Hypomyelinating spastic dyskinesia and ichthyosis caused by a homozygous splice site mutation leading to exon skipping in ELOVL1.","date":"2022","source":"Brain & development","url":"https://pubmed.ncbi.nlm.nih.gov/35379526","citation_count":23,"is_preprint":false},{"pmid":"34871500","id":"PMC_34871500","title":"Discovery of Novel, Orally Bioavailable Pyrimidine Ether-Based Inhibitors of ELOVL1.","date":"2021","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34871500","citation_count":12,"is_preprint":false},{"pmid":"40065102","id":"PMC_40065102","title":"A functional single-cell metabolic survey identifies Elovl1 as a target to enhance CD8+ T cell fitness in solid tumours.","date":"2025","source":"Nature metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/40065102","citation_count":11,"is_preprint":false},{"pmid":"34748351","id":"PMC_34748351","title":"Discovery and Optimization of Pyrazole Amides as Inhibitors of ELOVL1.","date":"2021","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34748351","citation_count":10,"is_preprint":false},{"pmid":"11891222","id":"PMC_11891222","title":"Elovl1 and p55Cdc genes are localized in a tail-to-tail array and are co-expressed in proliferating cells.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11891222","citation_count":7,"is_preprint":false},{"pmid":"39144963","id":"PMC_39144963","title":"ELOVL1 is upregulated and promotes tumor growth in hepatocellular carcinoma through regulating PI3K-AKT-mTOR signaling.","date":"2024","source":"Heliyon","url":"https://pubmed.ncbi.nlm.nih.gov/39144963","citation_count":4,"is_preprint":false},{"pmid":"40590574","id":"PMC_40590574","title":"Biallelic ELOVL1 Variants Are Linked to Hypomyelinating Leukodystrophy, Movement Disorder, and Ichthyosis.","date":"2025","source":"Movement disorders : official journal of the Movement Disorder Society","url":"https://pubmed.ncbi.nlm.nih.gov/40590574","citation_count":2,"is_preprint":false},{"pmid":"40894896","id":"PMC_40894896","title":"Elovl1 inhibition reduced very long chain fatty acids in a mouse model of adrenoleukodystrophy.","date":"2025","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/40894896","citation_count":2,"is_preprint":false},{"pmid":"39243948","id":"PMC_39243948","title":"Delayed simvastatin treatment improves neurological recovery after cryogenic traumatic brain injury through downregulation of ELOVL1 by inhibiting mTOR signaling.","date":"2024","source":"Brain research bulletin","url":"https://pubmed.ncbi.nlm.nih.gov/39243948","citation_count":1,"is_preprint":false},{"pmid":"42104482","id":"PMC_42104482","title":"ELOVL1 promotes the progression of intrahepatic cholangiocarcinoma by enhancing endoplasmic reticulum stress and the PI3K/AKT/mTOR signaling pathway.","date":"2026","source":"Biology direct","url":"https://pubmed.ncbi.nlm.nih.gov/42104482","citation_count":0,"is_preprint":false},{"pmid":"42218992","id":"PMC_42218992","title":"Molecular cloning, phylogenetic analysis and functional characterization of an Elovl1/7-like elongase from the freshwater crayfish (Procambarus clarkii).","date":"2026","source":"Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/42218992","citation_count":0,"is_preprint":false},{"pmid":"42103229","id":"PMC_42103229","title":"A comprehensive discovery platform for ELOVL1 small-molecule inhibitors targeting very long-chain fatty acid synthesis in adrenoleukodystrophy.","date":"2026","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/42103229","citation_count":0,"is_preprint":false},{"pmid":"41539567","id":"PMC_41539567","title":"Time-dependent changes in meibum lipid composition and progression of dry eye following disruption of the fatty acid elongase Elovl1.","date":"2026","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/41539567","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.05.13.653734","title":"Very long chain fatty acids drive 1-deoxy-Sphingolipid toxicity","date":"2025-05-16","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.13.653734","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":14587,"output_tokens":4501,"usd":0.055638,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12554,"output_tokens":3548,"usd":0.075735,"stage2_stop_reason":"end_turn"},"total_usd":0.131373,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2010,\n      \"finding\": \"ELOVL1 was identified as the elongase with high activity toward saturated and monounsaturated C20- and C22-CoAs, producing C24-CoAs, and shown to be essential for C24 sphingolipid synthesis; in vitro substrate specificity assays across all seven mammalian ELOVLs established this selectivity\",\n      \"method\": \"In vitro elongation assays determining substrate specificities of all mammalian ELOVL enzymes; ELOVL1 knockdown in cells\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzymatic assay with defined substrates, replicated across multiple ELOVL family members for comparison, plus cellular knockdown confirmation\",\n      \"pmids\": [\"20937905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ELOVL1 activity is regulated together with ceramide synthase CERS2 to coordinate C24-CoA production with its utilization in C24 sphingolipid synthesis\",\n      \"method\": \"Biochemical co-regulation analysis; knockdown experiments linking ELOVL1 and CERS2 activity\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single lab, cellular knockdown showing coordinated regulation with CERS2, but mechanistic detail is limited in the abstract\",\n      \"pmids\": [\"20937905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Knockdown of ELOVL1 caused a reduction in the activity of Src kinase LYN, establishing that C24-sphingolipids produced by ELOVL1 are important for membrane microdomain (lipid raft) function\",\n      \"method\": \"ELOVL1 siRNA knockdown followed by measurement of LYN kinase activity\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, single method (knockdown + kinase activity assay), no rescue experiment described\",\n      \"pmids\": [\"20937905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"ELOVL1 is the single elongase responsible for synthesis of both saturated VLCFA (C26:0) and monounsaturated VLCFA (C26:1); ELOVL1 knockdown in X-ALD fibroblasts reduced elongation of C22:0 to C26:0 and lowered C26:0 levels\",\n      \"method\": \"ELOVL1 siRNA knockdown in X-ALD patient fibroblasts with VLCFA quantification; elongation assays\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional knockdown in disease-relevant cells, independently replicated by multiple labs (PMID 20937905, 20166112, 25499606)\",\n      \"pmids\": [\"20166112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ELOVL1 is the fatty acid elongase responsible for producing C20–C28 fatty acids in the epidermis; Elovl1 knockout mice showed decreased ceramides with ≥C26 fatty acids and increased ceramides with ≤C24, with severely disrupted lipid lamellae in the stratum corneum and lethal epidermal permeability barrier defects\",\n      \"method\": \"Elovl1 knockout mouse generation; lipidomic analysis of epidermal ceramides; electron microscopy of stratum corneum\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout with defined biochemical and structural phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"23689133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Ceramide synthases CerS2 and CerS3, expressed in epidermis layer-specific manner, regulate ELOVL1 to produce acyl-CoAs of different chain lengths in the epidermis\",\n      \"method\": \"Elovl1 KO mouse analysis with CerS2/CerS3 expression profiling and lipidomic comparison\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single lab, genetic model with lipidomics, but CerS regulatory mechanism on ELOVL1 is inferred rather than directly tested\",\n      \"pmids\": [\"23689133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Oleic and erucic acids (constituents of Lorenzo's oil) inhibit ELOVL1 via mixed (non-competitive) inhibition kinetics; the 4:1 oleate/erucate mixture (matching Lorenzo's oil composition) exhibits the most potent inhibitory activity and reduces saturated VLCFA-sphingomyelin levels in cells\",\n      \"method\": \"In vitro ELOVL1 enzyme inhibition kinetics assay; cellular sphingomyelin profiling after Lorenzo's oil treatment\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — kinetic characterization with mode-of-inhibition analysis plus cellular validation, single lab but two orthogonal methods\",\n      \"pmids\": [\"24489110\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The CoA esters of bezafibrate and gemfibrozil specifically inhibit ELOVL1 chain elongation activity; kinetic characterization of ELOVL1 was performed using X-ALD fibroblasts and microsomal fractions from ELOVL1-overexpressing HEK293 cells\",\n      \"method\": \"ELOVL1 overexpression in HEK293 cells, microsomal fraction preparation, in vitro elongation assay, fibrate inhibition kinetics\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstituted enzyme assay with kinetic analysis, use of both patient fibroblasts and overexpression system\",\n      \"pmids\": [\"25499606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"A de novo dominant ELOVL1 mutation (p.S165F) abrogates ELOVL1 enzymatic activity and reduces ≥C24 ceramides and sphingomyelins in patient fibroblasts; fibroblast loading with C22:0 VLCFAs increased C24:0-ceramides and sphingomyelins, and competitive inhibition between saturated and monounsaturated VLCFAs for ceramide/sphingomyelin synthesis was demonstrated\",\n      \"method\": \"Stable isotope-labelled [13C]malonyl-CoA elongation assay; LC-MS/MS ceramide and sphingomyelin profiling; VLCFA loading experiments in patient fibroblasts\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct enzymatic activity assay with patient mutation, multiple orthogonal methods including isotope labeling and lipidomics, single lab\",\n      \"pmids\": [\"30487246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The p.Ser165Phe ELOVL1 mutation reduces levels of C24:0–C28:0 and C26:1 fatty acids while increasing C20:0 and C22:0 in transfected HEK293 cells and patient fibroblasts, confirming loss of elongase function for C22→C26+ substrates\",\n      \"method\": \"Stable transfection of HEK293 cells with wild-type or p.S165F ELOVL1; gas chromatography-mass spectrometry VLCFA profiling; patient fibroblast VLCFA profiling\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — functional activity assay in transfected cells corroborated by patient fibroblast data, two independent groups identified same mutation and same biochemical effect\",\n      \"pmids\": [\"29496980\", \"30487246\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ELOVL1 is primarily responsible for synthesis of saturated VLCFAs in meibomian gland (meibum), while ELOVL1, ELOVL3, and ELOVL4 redundantly participate in monounsaturated VLCFA synthesis; Elovl1 gene disruption in mice shortened acyl chains in cholesteryl esters and wax esters of meibum, causing dry eye phenotype\",\n      \"method\": \"Elovl1 conditional knockout mice; lipidomic analysis of meibum; measurement of ocular water evaporation and eye-blink frequency\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with defined biochemical phenotype (lipidomics) and functional readouts, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"29401594\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ELOVL1 deficiency in mice markedly shortened acyl chain length of myelin sphingolipids (galactosylceramides, sulfatides, sphingomyelins, ceramides) in the brain, reduced galactosylceramide levels, caused modest hypomyelination of large-diameter axons, and produced motor coordination deficits and reduced acoustic startle response\",\n      \"method\": \"Elovl1 mutant mice; lipidomic analysis of brain sphingolipids; electron microscopy of corpus callosum; behavioral testing\",\n      \"journal\": \"FASEB bioAdvances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic model with multiple orthogonal methods including lipidomics, ultrastructural analysis, and behavioral phenotyping\",\n      \"pmids\": [\"32123819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Elovl1 knockdown in zebrafish embryos increased levels of long-chain fatty acids (C14–C20) relative to controls, demonstrating that Elovl1 function in elongating these substrates is conserved in zebrafish; knockdown impaired swim bladder inflation and affected kidney development\",\n      \"method\": \"Morpholino knockdown of elovl1a and elovl1b in zebrafish; fatty acid profiling; gene expression analysis\",\n      \"journal\": \"Organogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — morpholino knockdown with biochemical (fatty acid profiling) and developmental phenotype readouts in zebrafish ortholog model\",\n      \"pmids\": [\"27078170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"ELOVL1 encodes a microsomal enzyme belonging to a conserved family involved in very long-chain fatty acid and sphingolipid formation; the mouse Elovl1 gene consists of 8 exons spanning 5.4 kb and is arranged in a tail-to-tail array with cell cycle gene p55Cdc, with both co-expressed during proliferation-differentiation transitions\",\n      \"method\": \"Genomic lambda phage clone isolation and sequencing; mRNA expression analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — genomic structure determination and expression analysis, no direct enzymatic or functional assay for ELOVL1 protein mechanism\",\n      \"pmids\": [\"11891222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Elovl1 inactivation in CD8+ T cells leads to accumulation of saturated long-chain fatty acids, which destabilizes INSIG1, leading to SREBP2 activation, increased plasma membrane cholesterol, and stronger T cell receptor signaling; Elovl1-deficient T cells also exhibit increased mitochondrial fitness and fatty acid oxidation\",\n      \"method\": \"CRISPR/Cas9 screen in CD8+ T cells; single-cell RNA sequencing; INSIG1/SREBP2 pathway analysis; adoptive transfer experiments; membrane cholesterol measurement\",\n      \"journal\": \"Nature metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR-based functional screen with multiple mechanistic follow-up assays (SREBP2/INSIG1 pathway, cholesterol measurement, metabolic assays), single lab\",\n      \"pmids\": [\"40065102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Simvastatin downregulates ELOVL1 expression in astrocytes via inhibition of mTOR signaling; overexpression of ELOVL1 specifically in astrocytes using AAV partially reversed the neuroprotective effects of simvastatin after traumatic brain injury, linking astrocytic ELOVL1 and mTOR signaling to VLCFA-mediated neurotoxicity\",\n      \"method\": \"Mouse cryogenic TBI model; AAV-mediated astrocyte-specific ELOVL1 overexpression; simvastatin treatment; saturated VLCFA quantification in cortex\",\n      \"journal\": \"Brain research bulletin\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — genetic gain-of-function with functional readout in vivo, single lab, single study\",\n      \"pmids\": [\"39243948\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CRISPRi screen identified ELOVL1 as a key mediator of 1-deoxy-sphingolipid-induced toxicity; pharmacological inhibition of ELOVL1 alleviated cellular, mitochondrial, and neuronal toxicity induced by 1-deoxy-sphingolipids; the principal toxic species was identified as 1-deoxyDHceramide conjugated to nervonic acid (m18:0/24:1), a VLC ceramide whose synthesis depends on ELOVL1\",\n      \"method\": \"CRISPRi genetic screen; siRNA knockdown validation; cytotoxicity assays; stable isotope-resolved lipidomics by LC-MS/MS; pharmacological ELOVL1 inhibition\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPRi screen with genetic and pharmacological validation, isotope-resolved lipidomics, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.05.13.653734\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"ELOVL1 disruption in mice (both epidermis-specific transgene-containing KO and tamoxifen-inducible conditional KO) causes time-dependent shortening of acyl chains in meibum cholesteryl esters, wax monoesters, and type 1ω wax diesters, and reduction in type 2ω wax diesters; dry eye phenotypes appear later than lipid composition changes, establishing a causal link between ELOVL1-dependent meibum VLCFA production and tear film barrier function\",\n      \"method\": \"Two conditional/inducible Elovl1 KO mouse models; lipidomic analysis of meibum lipid classes over time; dry eye phenotype assessment (eye blink frequency, water evaporation, meibomian gland orifice plugging)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two independent genetic mouse models, time-resolved lipidomics plus multiple functional dry eye readouts, single lab\",\n      \"pmids\": [\"41539567\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ELOVL1 is a microsomal fatty acid elongase that catalyzes the rate-limiting condensation step of the VLCFA elongation cycle, acting preferentially on saturated and monounsaturated C20–C24 acyl-CoA substrates to produce C22–C28+ VLCFAs; these products are essential precursors for C24/C26 ceramides and sphingomyelins in myelin, epidermis, and meibum, where they maintain membrane structure and barrier function, and ELOVL1 activity is coordinated with ceramide synthases CerS2/CerS3, is inhibited in mixed fashion by oleic and erucic acids (Lorenzo's oil), and controls membrane cholesterol homeostasis via the INSIG1/SREBP2 axis in T cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ELOVL1 is the microsomal fatty acid elongase that catalyzes the rate-limiting condensation step of very-long-chain fatty acid (VLCFA) synthesis, acting preferentially on saturated and monounsaturated C20- and C22-acyl-CoAs to generate C24-C28 VLCFAs essential for sphingolipid production [#0, #3]. Its activity is functionally coupled to the ceramide synthases CerS2 and CerS3, which channel ELOVL1-derived acyl-CoAs of defined chain length into C24/C26 ceramides and sphingomyelins [#1, #5]. The resulting VLCFA-sphingolipids underpin membrane microdomain function, supporting LYN/Src-family kinase activity [#2], and are structurally required across multiple tissues: Elovl1 loss in mice shortens epidermal ceramide chains and disrupts stratum corneum lipid lamellae, producing a lethal skin permeability barrier defect [#4]; shortens meibum cholesteryl/wax ester acyl chains, causing a dry-eye phenotype [#10, #17]; and shortens myelin sphingolipid chains, causing hypomyelination and motor and sensory deficits [#11]. A de novo dominant p.S165F mutation that abrogates elongase activity and lowers \\u2265C24 ceramides/sphingomyelins establishes ELOVL1 as the human disease gene for this loss-of-function condition [#8, #9]. ELOVL1 is inhibited in mixed (non-competitive) fashion by oleic and erucic acids, the constituents of Lorenzo's oil, and by the CoA esters of bezafibrate and gemfibrozil [#6, #7]. Beyond fatty acid metabolism, ELOVL1 controls plasma-membrane cholesterol homeostasis in CD8+ T cells through the INSIG1/SREBP2 axis, tuning T cell receptor signaling [#14], and its products contribute to 1-deoxy-sphingolipid neurotoxicity [#16].\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established which of the seven mammalian elongases produces C24 VLCFAs, defining ELOVL1's substrate niche and its essentiality for C24 sphingolipid synthesis.\",\n      \"evidence\": \"In vitro elongation assays of all mammalian ELOVLs with defined acyl-CoA substrates plus cellular knockdown\",\n      \"pmids\": [\"20937905\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural basis for substrate-length selectivity\", \"Catalytic mechanism of condensation not resolved at residue level\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Linked ELOVL1 output to downstream utilization by showing its co-regulation with CerS2 and a functional consequence for lipid-raft-dependent kinase signaling.\",\n      \"evidence\": \"Knockdown of ELOVL1 with CERS2 co-regulation analysis and LYN kinase activity measurement\",\n      \"pmids\": [\"20937905\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of ELOVL1-CerS2 coordination not directly tested\", \"No rescue experiment for the LYN activity phenotype\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated in disease-relevant cells that ELOVL1 is the single elongase generating both saturated and monounsaturated C26 VLCFAs, implicating it in X-ALD lipid biology.\",\n      \"evidence\": \"ELOVL1 siRNA knockdown in X-ALD patient fibroblasts with VLCFA quantification\",\n      \"pmids\": [\"20166112\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not address regulation of ELOVL1 in X-ALD\", \"Therapeutic modulation not tested here\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Genetic knockout established ELOVL1 as physiologically required for epidermal VLCFA/ceramide production and an intact skin permeability barrier.\",\n      \"evidence\": \"Elovl1 knockout mice with epidermal ceramide lipidomics and stratum corneum electron microscopy\",\n      \"pmids\": [\"23689133\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"CerS2/CerS3 regulation of ELOVL1 inferred rather than directly demonstrated\", \"Layer-specific control mechanism unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined the pharmacology of ELOVL1, showing Lorenzo's oil components and fibrate-CoAs inhibit the enzyme, providing a mechanistic basis for VLCFA-lowering therapy.\",\n      \"evidence\": \"In vitro inhibition kinetics with mode-of-inhibition analysis and cellular sphingomyelin profiling\",\n      \"pmids\": [\"24489110\", \"25499606\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No co-structure of ELOVL1 with inhibitors\", \"In vivo efficacy of inhibition not established here\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified ELOVL1 as a human disease gene by showing a de novo dominant p.S165F mutation abolishes elongase activity and shifts ceramide/sphingomyelin chain lengths.\",\n      \"evidence\": \"Isotope-labelled malonyl-CoA elongation assay, transfected HEK293 and patient-fibroblast VLCFA/ceramide lipidomics; mutation found by two groups\",\n      \"pmids\": [\"29496980\", \"30487246\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dominant-negative versus haploinsufficient mechanism not resolved\", \"Full clinical spectrum and genotype-phenotype not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended ELOVL1's tissue roles to the ocular surface, showing it supplies VLCFAs for meibum lipids required for tear film stability.\",\n      \"evidence\": \"Elovl1 conditional knockout mice with meibum lipidomics and dry-eye functional readouts\",\n      \"pmids\": [\"29401594\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Redundancy with ELOVL3/ELOVL4 for monounsaturated species incompletely mapped\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established that ELOVL1 sets myelin sphingolipid chain length and that its loss causes hypomyelination and neurological deficits.\",\n      \"evidence\": \"Elovl1 mutant mice with brain sphingolipid lipidomics, corpus callosum EM, and behavioral testing\",\n      \"pmids\": [\"32123819\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-autonomous oligodendrocyte requirement not isolated\", \"Link to human neurological disease phenotype not directly tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed a signaling role beyond bulk lipid structure: ELOVL1 controls membrane cholesterol via INSIG1/SREBP2 and tunes CD8+ T cell receptor signaling and metabolism.\",\n      \"evidence\": \"CRISPR/Cas9 screen in CD8+ T cells, scRNA-seq, INSIG1/SREBP2 pathway analysis, cholesterol measurement, adoptive transfer\",\n      \"pmids\": [\"40065102\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, not independently replicated\", \"Direct biochemical link between saturated LCFA accumulation and INSIG1 destabilization not fully resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Implicated ELOVL1 in sphingolipid-driven cytotoxicity by identifying it as required for synthesis of a toxic VLC 1-deoxy-ceramide species.\",\n      \"evidence\": \"CRISPRi screen, siRNA and pharmacological validation, isotope-resolved lipidomics (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.05.13.653734\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"In vivo relevance of the toxic species not established\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Two independent KO models resolved the temporal order of meibum lipid remodeling, establishing that ELOVL1-dependent VLCFA shortening causally precedes dry-eye pathology.\",\n      \"evidence\": \"Epidermis-specific transgene KO and tamoxifen-inducible conditional KO mice with time-resolved meibum lipidomics and dry-eye phenotyping\",\n      \"pmids\": [\"41539567\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular trigger converting altered meibum to barrier failure not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ELOVL1 substrate-length selectivity and catalysis are encoded structurally, and how its activity is coordinately regulated with ceramide synthases across tissues, remains unresolved.\",\n      \"evidence\": \"No structural or reconstituted regulatory mechanism in the timeline\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No experimental structure of ELOVL1\", \"Mechanism of CerS2/CerS3 coupling unproven\", \"Tissue-specific regulatory inputs uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 3, 8, 9]},\n      {\"term_id\": \"GO:0016746\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [7, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 3, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CERS2\", \"CERS3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}