{"gene":"ELOVL5","run_date":"2026-06-09T23:54:43","timeline":{"discoveries":[{"year":2008,"finding":"ELOVL5 is required for elongation of gamma-linolenic acid (C18:3 n-6) to dihomo-gamma-linolenic acid (C20:3 n-6) and stearidonic acid (C18:4 n-3) to omega3-arachidonic acid (C20:4 n-3) in mouse liver microsomes. Elovl5 knockout mice accumulate C18 substrates and have reduced arachidonic acid and DHA levels. Reduced ELOVL5 activity leads to activation of SREBP-1c and its target genes, causing hepatic steatosis; dietary supplementation with arachidonic acid and DHA reversed these molecular and metabolic changes.","method":"Elovl5 knockout mouse model; liver microsomal elongation assays; dietary supplementation rescue experiments","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — knockout mouse with microsomal enzyme assay demonstrating substrate specificity, and dietary rescue confirming mechanism; replicated across multiple readouts","pmids":["18838740"],"is_preprint":false},{"year":2012,"finding":"ELOVL5 controls gluconeogenesis through the mTORC2-Akt2-FoxO1 pathway via its product cis-vaccenic acid (18:1 n-7). Adenoviral overexpression of Elovl5 in obese mice and HepG2 cells increased Akt2-S473 phosphorylation (mTORC2 site) and FoxO1-S256 phosphorylation, inducing rictor mRNA/protein and rictor-mTOR interaction. Rictor knockdown attenuated these effects. Palmitoleic acid (16:1 n-7) but not gamma-linolenic acid (18:3 n-6) was identified as the proximal inducer; inhibition of elongation blocked this induction, implicating cis-vaccenic acid (18:1 n-7) as the key product.","method":"Adenoviral overexpression in vivo (diet-induced obese mice) and HepG2 cells; Akt inhibitor treatment; siRNA rictor knockdown; FA analysis; substrate supplementation experiments","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal approaches (genetic overexpression, pharmacological inhibition, siRNA knockdown, substrate supplementation) in a single focused study establishing pathway mechanism","pmids":["23099444"],"is_preprint":false},{"year":2014,"finding":"Increased hepatic Elovl5 activity in obese mice lowered hepatic triglycerides and increased TG catabolism by elevating protein levels of adipocyte TG lipase (ATGL) and CGI58. FA products of Elovl5 activity increased ATGL (but not CGI58) mRNA through PPARbeta-dependent mechanisms in HepG2 cells. Elovl5 activity regulates FA composition controlling PPARbeta activity and ATGL expression.","method":"Adenoviral overexpression of Elovl5 in obese C57BL/6J mice; PPARbeta agonist treatment in mouse AML12 hepatocytes; radiolabeled fatty acid oxidation assays; protein level measurements","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro complementary experiments with gain-of-function and pharmacological validation identifying PPARbeta as mediator","pmids":["24814977"],"is_preprint":false},{"year":2014,"finding":"Missense mutations in ELOVL5 (p.Gly230Val and p.Leu72Val) cause spinocerebellar ataxia 38 (SCA38). Arachidonic acid and DHA, downstream ELOVL5 products, were reduced in serum of affected individuals. In transfection experiments, mutant ELOVL5 (p.G230V) showed aberrant perinuclear distribution with increased Golgi signal, while wild-type ELOVL5 showed widespread endoplasmic reticulum localization. ELOVL5 was highly expressed in Purkinje cells by immunohistochemistry.","method":"Genetic linkage analysis and targeted resequencing; serum fatty acid measurements; transfection-based subcellular localization studies; immunohistochemistry on mouse and human brain","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — disease-causing mutations identified, biochemical consequence (reduced product FA levels in patients) confirmed, subcellular mislocalization demonstrated; independently replicated across multiple families","pmids":["25065913"],"is_preprint":false},{"year":2013,"finding":"A tryptophan residue at the position equivalent to cysteine-217 in Elovl2 within transmembrane domains 6-7 explains why rat Elovl5 cannot elongate omega-3 docosapentaenoic acid (C22:5n-3) to C24:5n-3, whereas Elovl2 can. Chimera and point mutation studies in yeast expression confirmed that Elovl2 C217 is a critical residue for DPA substrate specificity.","method":"Yeast heterologous expression system; Elovl2/Elovl5 chimeric protein construction; site-directed mutagenesis; substrate specificity assays","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution in yeast with systematic mutagenesis and chimera analysis identifying specific residue responsible for substrate selectivity","pmids":["23873268"],"is_preprint":false},{"year":2021,"finding":"ELOVL5 is directly induced by androgen receptor (AR) signaling in prostate cancer cells, xenografts, and clinical tumors. ELOVL5 depletion altered mitochondrial morphology and function, causing excess reactive oxygen species, suppressing cell proliferation, 3D growth, and in vivo tumor growth and metastasis. Supplementation with cis-vaccenic acid (18:1 n-7), a direct ELOVL5 product, reversed oxidative stress and proliferation/migration effects of ELOVL5 knockdown.","method":"Mass spectrometry lipidomics; transcriptomic analysis; siRNA knockdown in cells and xenografts; patient-derived explants; cis-vaccenic acid supplementation rescue","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (lipidomics, KD in vitro and in vivo, product rescue) establishing AR-ELOVL5-mitochondria-ROS-proliferation axis","pmids":["33547161"],"is_preprint":false},{"year":2023,"finding":"The SCA38 missense variant p.G230V does not abolish ELOVL5 enzymatic activity per se, but causes a conformational change (shift in Loop 6 altering a conserved intramolecular disulfide bond between Loop 2 and Loop 6) leading to Golgi complex accumulation, increased proteasomal degradation, unfolded protein response activation, and reduced cell viability in neurons. SCA38-derived fibroblasts showed reduced ELOVL5 expression and Golgi enlargement. The pathogenic mechanism involves combined loss of function by mislocalization and gain of toxic function by ER/Golgi stress.","method":"Biochemical enzyme activity assays; fibroblast analysis; heterologous overexpression; unfolded protein response assays; mouse cortical neuron viability assays; homology modelling of protein structure","journal":"Human genetics","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — multiple orthogonal methods including structural modelling, biochemical activity assays, cell biological studies, and patient-derived cells establishing conformational pathogenic mechanism","pmids":["37199746"],"is_preprint":false},{"year":2017,"finding":"Elovl5 knockout mice recapitulate SCA38 symptoms including motor deficits on beam balance test and hyposmia. Cerebellar cortex showed reduced molecular layer thickness (from 6 months onward), reduced Purkinje cell layer perimeter, and reduced extension of distal Purkinje cell dendritic arborization (by Sholl analysis of biocytin-filled cells), with conserved dendritic spine density.","method":"Elovl5 knockout mouse behavioral testing (beam balance, olfactory tests); cerebellar morphometry; biocytin filling and Sholl analysis of Purkinje cell dendrites","journal":"Frontiers in cellular neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean KO model with defined behavioral and structural phenotypes, complementary quantitative morphological analyses","pmids":["29163054"],"is_preprint":false},{"year":2015,"finding":"SREBP-1 activates human ELOVL5 transcription through two newly identified SRE binding sites: one in the 10 kb upstream region and one in exon 1. These two SRE motifs are conserved among mammals, establishing the mechanism by which SREBP activates ELOVL5 as part of the negative feedback loop of de novo lipogenesis.","method":"Promoter/enhancer deletion analysis; reporter assays; identification and validation of SREBP binding sites","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter reporter assays with deletion analysis identifying specific binding sites, but single lab study","pmids":["26321664"],"is_preprint":false},{"year":2018,"finding":"ELOVL5 is the key elongase responsible for elongation of 18- and 20-carbon PUFAs in human T-cells. ELOVL5 knockdown in proliferating T-cells and Jurkat cells significantly altered cellular MUFA and PUFA profiles and strongly impaired elongation of 18- and 20-carbon PUFAs. Proliferating T-cells showed increased ELOVL5 expression compared to resting T-cells, with no detectable ELOVL2.","method":"siRNA knockdown; fatty acid profiling; ELOVL expression measurement in resting vs. proliferating primary human T-cells and Jurkat cells","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with direct FA profiling readout in primary human cells; single lab study","pmids":["30293059"],"is_preprint":false},{"year":2022,"finding":"ELOVL5 knockout (CRISPR/Cas9) in renal cell carcinoma suppressed lipid droplet formation, induced ER stress-mediated apoptosis, inhibited AKT Ser473 phosphorylation, and suppressed cell invasion via CCL2 downregulation through AKT-mTOR-STAT3 signaling. Supplementation with ELOVL5 end products (arachidonic acid and EPA) partially reversed proliferation and invasion effects.","method":"CRISPR/Cas9 knockout; LC-ESI-MS/MS lipidomics; in vitro and in vivo tumor growth assays; signaling pathway analysis; product supplementation rescue","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with product rescue and signaling pathway analysis; single lab study","pmids":["35670054"],"is_preprint":false},{"year":2021,"finding":"In renal cancer cells, ELOVL5-mediated PUFA elongation enhances lipid raft-associated AKT-mTOR signaling activation, contributing to enzalutamide resistance. Knocking down ELOVL5 in NE-like prostate cancer cells diminished neuroendocrine phenotypes and enzalutamide resistance, while ELOVL5 overexpression augmented resistance both in vitro and in vivo.","method":"siRNA knockdown; ELOVL5 overexpression; in vitro and in vivo tumor models; AKT-mTOR signaling analysis","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function in vitro and in vivo with signaling pathway mechanism proposed; single lab study","pmids":["34439125"],"is_preprint":false},{"year":2022,"finding":"ELOVL5 knockdown in breast cancer cells promoted epithelial-mesenchymal transition (EMT), cell invasion, and lung metastasis via a lipid droplet accumulation-dependent mechanism: loss of ELOVL5 induced lipid droplet accumulation, which triggered Smad2 acetylation and upregulation of TGF-beta receptors. Inhibition of TGF-beta receptors restored proliferation and dampened invasion in low-ELOVL5 cells. Inhibition of diacylglycerol acyltransferase (blocking lipid droplet formation) reversed TGF-beta receptor induction, invasion, and lung metastasis caused by ELOVL5 knockdown.","method":"siRNA knockdown; murine breast cancer in vivo metastasis models; TGF-beta receptor inhibition; DGAT inhibition; Smad2 acetylation analysis","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo metastasis model with mechanistic dissection using pharmacological inhibitors; single lab study","pmids":["36056008"],"is_preprint":false},{"year":2019,"finding":"miR-21-3p directly targets the 3'UTR of Elovl5 in bovine mammary epithelial cells, as demonstrated by luciferase reporter assays. miR-21-3p negatively regulates Elovl5 mRNA and protein levels, and promotes triglyceride production, an effect attributable to targeting Elovl5.","method":"Luciferase reporter assay with wild-type and mutant 3'UTR; qPCR and Western blotting; miR-21-3p mimic/inhibitor transfection","journal":"DNA and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct 3'UTR reporter assay with mutagenesis plus functional miRNA manipulation; single lab study in bovine cells","pmids":["30707627"],"is_preprint":false},{"year":2017,"finding":"Estrogen enhances hepatic LCPUFA synthesis by downregulating miR-218-5p, which directly targets and suppresses ELOVL5 expression. ELOVL5 was validated as a direct target of miR-218-5p (located in intron 14 of SLIT2 gene) in laying hens.","method":"Bioinformatics target prediction; luciferase reporter assay; qPCR/Western blot; estrogen treatment experiments","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct 3'UTR reporter validation plus hormonal regulation assay; single lab study in avian model","pmids":["28665359"],"is_preprint":false},{"year":2024,"finding":"miR-218-5p directly targets the 3'UTR of Elovl5 (validated by dual-luciferase reporter assay), negatively regulating its expression in mouse hepatocytes. miR-218-5p promotes lipogenesis via the SREBP1 signaling pathway by suppressing Elovl5; silencing miR-218-5p upregulated Elovl5 and suppressed SREBP1-mediated lipogenesis, with the effect of miR-218-5p on lipogenesis blocked by si-Elovl5 both in vitro and in vivo.","method":"Dual luciferase reporter assay; miR-218-5p gain/loss-of-function; siRNA Elovl5 knockdown; high-fat diet NAFLD mouse model; in vitro PA-induced model","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic hierarchy established with miRNA-target validation, epistasis experiment (si-Elovl5 blocks miR effect), and in vivo confirmation; single lab study","pmids":["38972428"],"is_preprint":false},{"year":2021,"finding":"ELOVL5 is expressed in the mouse CNS in a region- and cell-type-specific manner. Highest expression is in cerebellum, brainstem, primary and accessory olfactory regions (especially mitral cells), hippocampal CA2/CA3 pyramidal cells, and motor control regions. ELOVL5 is expressed in oligodendroglial cells at various maturation steps and in microglia; astrocytes show heterogeneous expression.","method":"Elovl5-reporter mouse line; immunofluorescence on adult mouse CNS sections; primary glial cell cultures","journal":"Frontiers in neuroanatomy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization using reporter mouse and immunofluorescence; single lab study establishing cell-type and region specificity","pmids":["33994961"],"is_preprint":false},{"year":2025,"finding":"Deletion of Elovl5 in mouse cerebellum caused changes in fatty acid profile (increased 18- and 20-carbon PUFAs, decreased long-chain PUFAs, increased saturated and monounsaturated FAs). In Purkinje cells of Elovl5 KO mice, basal synaptic transmission was preserved, but recovery from depression of the climbing fiber synapse lacked the fast phase (deficit in replenishment of the readily releasable pool of synaptic vesicles). The parallel fiber synapse showed slower replenishment at high but physiological frequencies (50-100 Hz). Endocannabinoid-mediated synaptically induced suppression of excitation (SSE) had shorter duration in KO mice, consistent with reduced endocannabinoid signaling. Synaptosomes from KO showed dramatic changes in lipid length and unsaturation.","method":"Elovl5 knockout mouse; cerebellar fatty acid profiling; electrophysiological recordings in Purkinje cells; synaptosome lipid analysis","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Moderate — clean KO model with electrophysiology and lipidomics in synaptosomes providing mechanistic link between PUFA composition and specific synaptic deficits","pmids":["40789653"],"is_preprint":false},{"year":2022,"finding":"ELOVL5 knockdown in breast cancer cells (MDA-MB-231) increased MMP1 expression (confirmed by zymography and transcriptomics), decreased CDH11 expression, reduced intercellular adhesion (spheroid formation assay), consistent with enhanced invasive/metastatic potential.","method":"Stable ELOVL5 knockdown; transcriptomics; proteomics; RT-PCR; zymography; spheroid formation assay","journal":"Frontiers in genetics","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — stable KD with multiple readouts (zymography, transcriptomics, functional spheroid assay); single lab study","pmids":["34149804"],"is_preprint":false},{"year":2007,"finding":"ELOVL5 mRNA is localized specifically in the basal layer of sebaceous gland cells in pheromone-producing head skin of male goats, but not in rump skin of males or head skin of orchidectomized males (which do not produce pheromone), suggesting ELOVL5 participates in sebaceous gland-derived pheromone synthesis.","method":"In situ hybridization on goat skin sections","journal":"The Journal of reproduction and development","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — in situ hybridization demonstrating cell-type and androgen-dependent localization; single method but with appropriate anatomical controls","pmids":["17827874"],"is_preprint":false},{"year":2021,"finding":"ELOVL5 knockdown in bovine embryos (morpholino-mediated) reduced specific phospholipid and triacylglycerol species (7 lipid species including phosphatidylcholines, phosphatidylethanolamines, and triacylglycerol) and increased cytoplasmic lipid droplet deposition, with increased ELOVL5 protein abundance in ELOVL5-Mo blastocysts, without detrimental effect on blastocyst development or cell number.","method":"Morpholino-mediated knockdown in bovine embryos; mass spectrometry lipid fingerprinting; confocal microscopy for lipid droplets; Western blot","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — morpholino KD with lipid fingerprinting revealing specific ELOVL5-dependent lipid species in embryos; single lab study","pmids":["33525659"],"is_preprint":false},{"year":2023,"finding":"Deletion of Elovl5 leads to dyslipidemia and atherosclerosis in LDLR-deficient mice through activation of SREBP-1, causing increased hepatic triglyceride and cholesterol, elevated plasma VLDL/IDL/LDL triglycerides and cholesterol, and marked aortic atherosclerotic plaques. Elovl5-/- macrophages showed no differences in most M1/M2 polarization markers, except a slight increase in PGE2 secretion linked to elevated Cox-2 expression.","method":"Elovl5-/-;Ldlr-/- double knockout mouse model; lipid analysis; atherosclerotic plaque assessment; bone marrow-derived macrophage polarization assays; PGE2 measurement","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic double-KO model with multiple phenotypic and molecular readouts; single lab study","pmids":["38000296"],"is_preprint":false},{"year":2025,"finding":"ELOVL5 promotes resolution of lung inflammation after influenza virus infection. ELOVL5 physically binds to STING, inhibiting TBK1 interaction and STING translocation to the Golgi, thereby reducing STING-mediated inflammation and promoting AKT1-mediated tissue repair. ELOVL5 also decreased eicosanoid levels in type II alveolar epithelial cells (AECIIs) to promote resolution. Supplementation with ELOVL5 downstream products reversed increased inflammatory cytokines caused by Elovl5 deficiency.","method":"In vivo AAV9-Sleeping Beauty CRISPR screen; AECIIS-specific Cas9 mouse model; Elovl5 deficiency in vitro and in vivo; STING-TBK1 interaction assay; eicosanoid measurements; downstream product supplementation","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR screen with mechanistic follow-up showing STING binding and functional epistasis; preprint, not peer-reviewed","pmids":["bio_10.1101_2025.06.11.659216"],"is_preprint":true},{"year":2022,"finding":"ELOVL5 knockdown in ELOVL5-low breast cancer cells reduced fatty acid content of specific PUFAs and decreased GPX4 activity, increasing sensitivity to ferroptosis (iron-dependent lipid peroxidation-mediated cell death). External PUFAs (especially DHA) caused cell death by activation of ferroptosis in ELOVL5-knockdown cells.","method":"Stable ELOVL5 knockdown (MDA-MB-231 cells); HPLC-MS fatty acid analysis; flow cytometry for apoptosis; fluorescent microscopy for ROS and lipid droplets; GPX4 colorimetric activity assay; ferrostatin-1/deferoxamine ferroptosis inhibitor controls","journal":"Frontiers in molecular biosciences","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — stable KD with ferroptosis inhibitor confirmation and GPX4 activity measurement; single lab study","pmids":["36714261"],"is_preprint":false},{"year":2025,"finding":"Super-enhancer-driven ELOVL5 transcription is regulated by H3K27ac marks in T-ALL. ELOVL5 knockdown suppressed proliferation and induced apoptosis in T-ALL cells in vitro and in vivo (mouse xenograft models), reducing tumor burden. RNA-seq revealed ELOVL5 promotes T-ALL progression by activating MYC signaling and upregulating SERBP1; SERBP1 silencing phenocopied ELOVL5 KD effects.","method":"H3K27ac ChIP-seq; siRNA knockdown; in vitro and in vivo tumor models; RNA-seq; SERBP1 knockdown epistasis","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq for regulatory mechanism plus KD epistasis establishing ELOVL5-SERBP1-MYC pathway; single lab study","pmids":["41016515"],"is_preprint":false},{"year":2025,"finding":"ELOVL5 mediates production of VLC-PUFAs during HCMV infection and reduces the level of erucic acid (EA, C22:1), an endogenous fatty acid with antiviral properties. ELOVL5 aided the increase in phospholipids containing C22:1 plus VLC-PUFA tails following EA treatment and reduced overall C22:1 levels in HCMV-infected cells. ELOVL5 mollified EA inhibition of HCMV replication, suggesting it plays a role in reducing an antiviral fatty acid.","method":"Lipidomics; HCMV infection model; EA treatment; ELOVL5 manipulation in infected cells","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab preprint with mechanistic interpretation based on correlative lipidomics and functional virus replication assay; limited mechanistic dissection","pmids":["bio_10.1101_2025.03.31.646481"],"is_preprint":true}],"current_model":"ELOVL5 is an endoplasmic reticulum-resident fatty acid elongase that catalyzes the elongation of C18 and C20 polyunsaturated fatty acids (PUFAs) to produce downstream products including arachidonic acid, EPA, and cis-vaccenic acid; its activity regulates SREBP-1c-driven lipogenesis, gluconeogenesis via the mTORC2-Akt2-FoxO1 pathway, hepatic triglyceride catabolism via PPARbeta-ATGL, mitochondrial function, lipid raft-associated AKT-mTOR signaling, and synaptic vesicle release kinetics in Purkinje cells, while loss-of-function missense mutations that cause Golgi mislocalization and ER stress underlie spinocerebellar ataxia 38 (SCA38)."},"narrative":{"mechanistic_narrative":"ELOVL5 is an endoplasmic reticulum-resident fatty acid elongase that catalyzes the rate-limiting elongation of C18 and C20 polyunsaturated fatty acids, generating downstream products including arachidonic acid, DHA, EPA, and cis-vaccenic acid (18:1 n-7) [PMID:18838740, PMID:23873268]. Its substrate specificity is determined by defined transmembrane residues, with a tryptophan at the position equivalent to Elovl2 Cys-217 restricting elongation to C18/C20 PUFAs and excluding C22:5 n-3 [PMID:23873268]. Through control of cellular PUFA and MUFA composition, ELOVL5 governs hepatic lipid metabolism: reduced activity derepresses SREBP-1c and its lipogenic targets to cause hepatic steatosis [PMID:18838740], while its cis-vaccenic acid product drives gluconeogenic control via the mTORC2-Akt2-FoxO1 axis [PMID:23099444] and PUFA products promote triglyceride catabolism through PPARbeta-dependent ATGL induction [PMID:24814977]; loss of ELOVL5 in an LDLR-deficient background produces SREBP-1-driven dyslipidemia and atherosclerosis [PMID:38000296]. ELOVL5 transcription is embedded in a lipogenic feedback circuit, being directly activated by SREBP-1 via conserved SRE elements [PMID:26321664] and repressed by microRNAs including miR-218-5p [PMID:38972428]. In the CNS, ELOVL5 is highly expressed in Purkinje cells [PMID:25065913, PMID:33994961], and its loss alters cerebellar PUFA composition and impairs synaptic vesicle pool replenishment and endocannabinoid-mediated synaptic suppression in Purkinje-cell synapses [PMID:40789653]; mouse knockouts recapitulate SCA38-like motor deficits and hyposmia with Purkinje cell dendritic atrophy [PMID:29163054]. Missense mutations (p.Gly230Val, p.Leu72Val) cause spinocerebellar ataxia 38 (SCA38) through a combined mechanism in which a conformational shift disrupts a conserved Loop2-Loop6 disulfide bond, driving Golgi mislocalization, proteasomal degradation, and unfolded protein response activation alongside reduced product fatty acids [PMID:25065913, PMID:37199746]. ELOVL5 also acts as a pro-tumorigenic and inflammation-resolving factor across multiple tissues, supporting mitochondrial function and proliferation in prostate cancer downstream of androgen receptor signaling [PMID:33547161] and constraining lipid-droplet- and ferroptosis-linked invasive phenotypes [PMID:36056008, PMID:36714261].","teleology":[{"year":2008,"claim":"Establishing the core enzymatic identity of ELOVL5 was needed to define which fatty acids it produces and how its loss perturbs lipid homeostasis.","evidence":"Elovl5 knockout mouse with liver microsomal elongation assays and dietary rescue","pmids":["18838740"],"confidence":"High","gaps":["Did not resolve tissue-specific contributions beyond liver","Mechanistic basis of SREBP-1c derepression not structurally defined"]},{"year":2013,"claim":"Determining why ELOVL5 cannot elongate C22:5 n-3 clarified the structural basis of its substrate range relative to ELOVL2.","evidence":"Yeast heterologous expression with Elovl2/Elovl5 chimeras and site-directed mutagenesis","pmids":["23873268"],"confidence":"High","gaps":["No full-length structure of ELOVL5","Catalytic mechanism of elongation not reconstituted"]},{"year":2012,"claim":"Linking a specific ELOVL5 product to a signaling axis explained how the enzyme controls glucose metabolism beyond bulk lipid supply.","evidence":"Adenoviral overexpression in obese mice and HepG2 cells with rictor knockdown and substrate supplementation","pmids":["23099444"],"confidence":"High","gaps":["How cis-vaccenic acid mechanistically activates mTORC2 not defined","Direct lipid-protein interactions not identified"]},{"year":2014,"claim":"Identifying PPARbeta as a mediator showed how ELOVL5-controlled fatty acid composition drives hepatic triglyceride catabolism.","evidence":"Adenoviral Elovl5 overexpression in obese mice plus PPARbeta agonist treatment in hepatocytes","pmids":["24814977"],"confidence":"High","gaps":["Specific FA ligand activating PPARbeta not pinpointed","CGI58 regulation mechanism unresolved"]},{"year":2014,"claim":"Connecting ELOVL5 missense mutations to SCA38 with reduced patient product fatty acids and mutant mislocalization established the gene as a Mendelian ataxia cause.","evidence":"Genetic linkage and resequencing, serum FA measurement, transfection localization, and brain immunohistochemistry","pmids":["25065913"],"confidence":"High","gaps":["Whether mislocalization alone or loss of product drives neurodegeneration not separated at this stage"]},{"year":2015,"claim":"Mapping SRE elements in the ELOVL5 promoter placed the enzyme within the SREBP lipogenic feedback loop at the transcriptional level.","evidence":"Promoter deletion and reporter assays with SREBP binding site validation","pmids":["26321664"],"confidence":"Medium","gaps":["Single-lab reporter study","Endogenous SREBP occupancy not confirmed in vivo"]},{"year":2017,"claim":"Demonstrating that Elovl5 knockout mice reproduce SCA38 motor and olfactory deficits with Purkinje cell atrophy provided an in vivo disease model.","evidence":"Knockout mouse behavioral testing and cerebellar morphometry with Sholl analysis","pmids":["29163054"],"confidence":"High","gaps":["Molecular link between PUFA loss and dendritic atrophy not defined","Cell-autonomy of Purkinje phenotype not tested"]},{"year":2017,"claim":"Identifying miRNA repressors and hormonal inputs revealed post-transcriptional control of ELOVL5 in LCPUFA synthesis.","evidence":"miR-218-5p and miR-21-3p 3'UTR luciferase validation with hormonal and functional manipulation in avian, bovine, and mouse cells","pmids":["28665359","30707627","38972428"],"confidence":"Medium","gaps":["Cross-species relevance to human regulation incomplete","Other regulatory miRNAs not surveyed"]},{"year":2021,"claim":"Defining ELOVL5 as an androgen-receptor-induced enzyme supporting mitochondrial function and proliferation extended its role into cancer biology.","evidence":"Lipidomics, siRNA knockdown in cells and xenografts, patient-derived explants, and cis-vaccenic acid rescue","pmids":["33547161"],"confidence":"High","gaps":["Mechanism linking cis-vaccenic acid to mitochondrial ROS control unresolved","Generalizability across cancer types not addressed here"]},{"year":2022,"claim":"Loss-of-function studies across renal and breast cancers connected ELOVL5 to lipid-droplet-dependent signaling, ER stress, and metastasis suppression or promotion.","evidence":"CRISPR/stable knockdown with lipidomics, signaling analysis, ferroptosis assays, and in vivo metastasis models","pmids":["35670054","36056008","34149804","36714261","34439125"],"confidence":"Medium","gaps":["Context-dependent pro- versus anti-tumor roles not reconciled","Single-lab studies per tumor type","Direct lipid mediators of each pathway not fully identified"]},{"year":2023,"claim":"Resolving the SCA38 p.G230V mechanism showed disease arises not from abolished catalysis but from a disulfide-bond conformational defect causing Golgi accumulation and proteotoxic stress.","evidence":"Enzyme activity assays, patient fibroblasts, UPR assays, neuron viability, and homology modeling","pmids":["37199746"],"confidence":"High","gaps":["No experimental structure of mutant protein","Relative contribution of loss-of-function versus toxic gain-of-function in vivo unquantified"]},{"year":2025,"claim":"Linking cerebellar PUFA composition to specific synaptic vesicle and endocannabinoid deficits provided a mechanistic basis for the ataxia phenotype.","evidence":"Knockout mouse cerebellar lipidomics, Purkinje cell electrophysiology, and synaptosome lipid analysis","pmids":["40789653"],"confidence":"High","gaps":["Which lipid species directly governs vesicle replenishment not isolated","Molecular target of altered endocannabinoid signaling not defined"]},{"year":null,"claim":"How ELOVL5 product lipids are physically read out by the diverse downstream effectors (mTORC2, PPARbeta, STING, synaptic vesicle machinery) to produce tissue-specific outcomes remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying lipid-sensing mechanism identified","No experimental three-dimensional structure of human ELOVL5","Direct versus indirect effects of altered membrane lipid composition not separated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,4]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[3,6]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[3,6]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,2,21]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,5]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[7,17]}],"complexes":[],"partners":["STING"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9NYP7","full_name":"Very long chain fatty acid elongase 5","aliases":["3-keto acyl-CoA synthase ELOVL5","ELOVL fatty acid elongase 5","ELOVL FA elongase 5","Elongation of very long chain fatty acids protein 5","Fatty acid elongase 1","hELO1","Very long chain 3-ketoacyl-CoA synthase 5","Very long chain 3-oxoacyl-CoA synthase 5"],"length_aa":299,"mass_kda":35.3,"function":"Catalyzes the first and rate-limiting reaction of the four reactions that constitute the long-chain fatty acids elongation cycle. 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 acts specifically toward polyunsaturated acyl-CoA with the higher activity toward C18:3(n-6) acyl-CoA. May participate in the production of monounsaturated and of polyunsaturated VLCFAs of different chain lengths that are involved in multiple biological processes as precursors of membrane lipids and lipid mediators (By similarity) (PubMed:10970790, PubMed:20937905). In conditions where the essential linoleic and alpha linoleic fatty acids are lacking it is also involved in the synthesis of Mead acid from oleic acid (By similarity)","subcellular_location":"Endoplasmic reticulum membrane; Cell projection, dendrite","url":"https://www.uniprot.org/uniprotkb/Q9NYP7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ELOVL5","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000012660","cell_line_id":"CID000318","localizations":[{"compartment":"vesicles","grade":3}],"interactors":[{"gene":"CANX","stoichiometry":0.2},{"gene":"CCDC47","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000318","total_profiled":1310},"omim":[{"mim_id":"619798","title":"E74-LIKE ETS TRANSCRIPTION FACTOR 2; ELF2","url":"https://www.omim.org/entry/619798"},{"mim_id":"615957","title":"SPINOCEREBELLAR ATAXIA 38; SCA38","url":"https://www.omim.org/entry/615957"},{"mim_id":"615539","title":"EHLERS-DANLOS SYNDROME, MUSCULOCONTRACTURAL TYPE, 2; EDSMC2","url":"https://www.omim.org/entry/615539"},{"mim_id":"611805","title":"ELONGATION OF VERY LONG CHAIN FATTY ACIDS-LIKE 5; ELOVL5","url":"https://www.omim.org/entry/611805"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Endoplasmic reticulum","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ELOVL5"},"hgnc":{"alias_symbol":["HELO1","dJ483K16.1"],"prev_symbol":["SCA38"]},"alphafold":{"accession":"Q9NYP7","domains":[{"cath_id":"-","chopping":"27-255","consensus_level":"medium","plddt":91.9371,"start":27,"end":255}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NYP7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NYP7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NYP7-F1-predicted_aligned_error_v6.png","plddt_mean":81.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ELOVL5","jax_strain_url":"https://www.jax.org/strain/search?query=ELOVL5"},"sequence":{"accession":"Q9NYP7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NYP7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NYP7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NYP7"}},"corpus_meta":[{"pmid":"18838740","id":"PMC_18838740","title":"Deletion of ELOVL5 leads to fatty liver through activation of SREBP-1c in mice.","date":"2008","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/18838740","citation_count":189,"is_preprint":false},{"pmid":"19184219","id":"PMC_19184219","title":"Highly unsaturated fatty acid synthesis in Atlantic salmon: characterization of ELOVL5- and ELOVL2-like elongases.","date":"2009","source":"Marine biotechnology (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/19184219","citation_count":146,"is_preprint":false},{"pmid":"20363506","id":"PMC_20363506","title":"Genome-wide association study of normal tension glaucoma: common variants in SRBD1 and ELOVL5 contribute to disease susceptibility.","date":"2010","source":"Ophthalmology","url":"https://pubmed.ncbi.nlm.nih.gov/20363506","citation_count":93,"is_preprint":false},{"pmid":"25065913","id":"PMC_25065913","title":"ELOVL5 mutations cause spinocerebellar ataxia 38.","date":"2014","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25065913","citation_count":83,"is_preprint":false},{"pmid":"33547161","id":"PMC_33547161","title":"ELOVL5 Is a Critical and Targetable Fatty Acid Elongase in Prostate Cancer.","date":"2021","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/33547161","citation_count":76,"is_preprint":false},{"pmid":"25329159","id":"PMC_25329159","title":"Supplementation with N-3 long-chain polyunsaturated fatty acids or olive oil in men and women with renal disease induces differential changes in the DNA methylation of FADS2 and ELOVL5 in peripheral blood mononuclear cells.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/25329159","citation_count":71,"is_preprint":false},{"pmid":"25542509","id":"PMC_25542509","title":"The capacity for long-chain polyunsaturated fatty acid synthesis in a carnivorous vertebrate: Functional characterisation and nutritional regulation of a Fads2 fatty acyl desaturase with Δ4 activity and an Elovl5 elongase in striped snakehead (Channa striata).","date":"2014","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/25542509","citation_count":50,"is_preprint":false},{"pmid":"23099444","id":"PMC_23099444","title":"Elovl5 regulates the mTORC2-Akt-FOXO1 pathway by controlling hepatic cis-vaccenic acid synthesis in diet-induced obese mice.","date":"2012","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/23099444","citation_count":49,"is_preprint":false},{"pmid":"24814977","id":"PMC_24814977","title":"Fatty acid elongase-5 (Elovl5) regulates hepatic triglyceride catabolism in obese C57BL/6J mice.","date":"2014","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/24814977","citation_count":47,"is_preprint":false},{"pmid":"23873268","id":"PMC_23873268","title":"Molecular basis for differential elongation of omega-3 docosapentaenoic acid by the rat Elovl5 and Elovl2.","date":"2013","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/23873268","citation_count":47,"is_preprint":false},{"pmid":"26112824","id":"PMC_26112824","title":"Polyunsaturated fatty acid metabolism in a marine teleost, Nibe croaker Nibea mitsukurii: Functional characterization of Fads2 desaturase and Elovl5 and Elovl4 elongases.","date":"2015","source":"Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/26112824","citation_count":43,"is_preprint":false},{"pmid":"21508110","id":"PMC_21508110","title":"Association between SRBD1 and ELOVL5 gene polymorphisms and primary open-angle glaucoma.","date":"2011","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/21508110","citation_count":37,"is_preprint":false},{"pmid":"23597093","id":"PMC_23597093","title":"An evolutionary perspective on Elovl5 fatty acid elongase: comparison of Northern pike and duplicated paralogs from Atlantic salmon.","date":"2013","source":"BMC evolutionary biology","url":"https://pubmed.ncbi.nlm.nih.gov/23597093","citation_count":34,"is_preprint":false},{"pmid":"29163054","id":"PMC_29163054","title":"Motor Deficits and Cerebellar Atrophy in Elovl5 Knock Out Mice.","date":"2017","source":"Frontiers in cellular neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/29163054","citation_count":29,"is_preprint":false},{"pmid":"36056008","id":"PMC_36056008","title":"Downregulation of Elovl5 promotes breast cancer metastasis through a lipid-droplet accumulation-mediated induction of TGF-β receptors.","date":"2022","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/36056008","citation_count":29,"is_preprint":false},{"pmid":"28665359","id":"PMC_28665359","title":"Estrogen Promotes Hepatic Synthesis of Long-Chain Polyunsaturated Fatty Acids by Regulating ELOVL5 at Post-Transcriptional Level in Laying Hens.","date":"2017","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/28665359","citation_count":29,"is_preprint":false},{"pmid":"27143115","id":"PMC_27143115","title":"Clinical and neuroradiological features of spinocerebellar ataxia 38 (SCA38).","date":"2016","source":"Parkinsonism & related disorders","url":"https://pubmed.ncbi.nlm.nih.gov/27143115","citation_count":28,"is_preprint":false},{"pmid":"30293059","id":"PMC_30293059","title":"Polyunsaturated fatty acid elongation and desaturation in activated human T-cells: ELOVL5 is the key elongase.","date":"2018","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/30293059","citation_count":27,"is_preprint":false},{"pmid":"32883522","id":"PMC_32883522","title":"Polyunsaturated fatty acids synthesized by freshwater fish: A new insight to the roles of elovl2 and elovl5 in vivo.","date":"2020","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/32883522","citation_count":26,"is_preprint":false},{"pmid":"35670054","id":"PMC_35670054","title":"ELOVL5-mediated fatty acid elongation promotes cellular proliferation and invasion in renal cell carcinoma.","date":"2022","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/35670054","citation_count":24,"is_preprint":false},{"pmid":"26321664","id":"PMC_26321664","title":"Identification of human ELOVL5 enhancer regions controlled by SREBP.","date":"2015","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/26321664","citation_count":22,"is_preprint":false},{"pmid":"24919687","id":"PMC_24919687","title":"Functional characterization of the duck and turkey fatty acyl elongase enzymes ELOVL5 and ELOVL2.","date":"2014","source":"The Journal of nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/24919687","citation_count":21,"is_preprint":false},{"pmid":"32880080","id":"PMC_32880080","title":"Elovl2 But Not Elovl5 Is Essential for the Biosynthesis of Docosahexaenoic Acid (DHA) in Zebrafish: Insight from a Comparative Gene Knockout Study.","date":"2020","source":"Marine biotechnology (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/32880080","citation_count":21,"is_preprint":false},{"pmid":"34439125","id":"PMC_34439125","title":"ELOVL5-Mediated Long Chain Fatty Acid Elongation Contributes to Enzalutamide Resistance of Prostate Cancer.","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/34439125","citation_count":20,"is_preprint":false},{"pmid":"36714261","id":"PMC_36714261","title":"ELOVL5 and IGFBP6 genes modulate sensitivity of breast cancer cells to ferroptosis.","date":"2023","source":"Frontiers in molecular biosciences","url":"https://pubmed.ncbi.nlm.nih.gov/36714261","citation_count":18,"is_preprint":false},{"pmid":"30862453","id":"PMC_30862453","title":"Long-term efficacy of docosahexaenoic acid (DHA) for Spinocerebellar Ataxia 38 (SCA38) treatment: An open label extension study.","date":"2019","source":"Parkinsonism & related disorders","url":"https://pubmed.ncbi.nlm.nih.gov/30862453","citation_count":18,"is_preprint":false},{"pmid":"30914501","id":"PMC_30914501","title":"DHA intake interacts with ELOVL2 and ELOVL5 genetic variants to influence polyunsaturated fatty acids in human milk.","date":"2019","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/30914501","citation_count":18,"is_preprint":false},{"pmid":"31244960","id":"PMC_31244960","title":"Effect of gestational oily fish intake on the risk of allergy in children may be influenced by FADS1/2, ELOVL5 expression and DNA methylation.","date":"2019","source":"Genes & nutrition","url":"https://pubmed.ncbi.nlm.nih.gov/31244960","citation_count":18,"is_preprint":false},{"pmid":"16273301","id":"PMC_16273301","title":"Mutation screening of three candidate genes, ELOVL5, SMAP1 and GLULD1 in autosomal recessive retinitis pigmentosa.","date":"2005","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/16273301","citation_count":17,"is_preprint":false},{"pmid":"30707627","id":"PMC_30707627","title":"miR-21-3p Targets Elovl5 and Regulates Triglyceride Production in Mammary Epithelial Cells of Cow.","date":"2019","source":"DNA and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/30707627","citation_count":17,"is_preprint":false},{"pmid":"30291282","id":"PMC_30291282","title":"Genome-wide methylation analysis identifies ELOVL5 as an epigenetic biomarker for the risk of type 2 diabetes mellitus.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30291282","citation_count":17,"is_preprint":false},{"pmid":"34500050","id":"PMC_34500050","title":"Ovine ELOVL5 and FASN genes polymorphisms and their correlations with sheep tail fat deposition.","date":"2021","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/34500050","citation_count":16,"is_preprint":false},{"pmid":"34149804","id":"PMC_34149804","title":"Effect of the Expression of ELOVL5 and IGFBP6 Genes on the Metastatic Potential of Breast Cancer Cells.","date":"2021","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34149804","citation_count":15,"is_preprint":false},{"pmid":"29454701","id":"PMC_29454701","title":"Fatty acid elongase 5 (ELOVL5) alters the synthesis of long-chain unsaturated fatty acids in goat mammary epithelial cells.","date":"2018","source":"Journal of dairy science","url":"https://pubmed.ncbi.nlm.nih.gov/29454701","citation_count":15,"is_preprint":false},{"pmid":"23269620","id":"PMC_23269620","title":"The SNP in the promoter region of the bovine ELOVL5 gene influences economic traits including subcutaneous fat thickness.","date":"2012","source":"Molecular biology reports","url":"https://pubmed.ncbi.nlm.nih.gov/23269620","citation_count":15,"is_preprint":false},{"pmid":"37939591","id":"PMC_37939591","title":"miR-19b-3p regulated by estrogen controls lipid synthesis through targeting MSMO1 and ELOVL5 in LMH cells.","date":"2023","source":"Poultry science","url":"https://pubmed.ncbi.nlm.nih.gov/37939591","citation_count":14,"is_preprint":false},{"pmid":"29555199","id":"PMC_29555199","title":"Cloning, tissue distribution, functional characterization and nutritional regulation of a fatty acyl Elovl5 elongase in chu's croaker Nibea coibor.","date":"2018","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/29555199","citation_count":14,"is_preprint":false},{"pmid":"30145362","id":"PMC_30145362","title":"miR-146a is involved in the regulation of vertebrate LC-PUFA biosynthesis by targeting elovl5 as demonstrated in rabbitfish Siganus canaliculatus.","date":"2018","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/30145362","citation_count":14,"is_preprint":false},{"pmid":"28943298","id":"PMC_28943298","title":"Cloning and functional characterization of fads2 desaturase and elovl5 elongase from Japanese flounder Paralichthys olivaceus.","date":"2017","source":"Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/28943298","citation_count":13,"is_preprint":false},{"pmid":"27538705","id":"PMC_27538705","title":"Cloning, expression and functional characterization of the polyunsaturated fatty acid elongase (ELOVL5) gene from sea cucumber (Apostichopus japonicus).","date":"2016","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/27538705","citation_count":13,"is_preprint":false},{"pmid":"28931069","id":"PMC_28931069","title":"Methylation associated transcriptional repression of ELOVL5 in novel colorectal cancer cell lines.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28931069","citation_count":12,"is_preprint":false},{"pmid":"30319448","id":"PMC_30319448","title":"The Transcriptional Factor PPARαb Positively Regulates Elovl5 Elongase in Golden Pompano Trachinotus ovatus (Linnaeus 1758).","date":"2018","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/30319448","citation_count":12,"is_preprint":false},{"pmid":"26950699","id":"PMC_26950699","title":"Molecular Cloning, Functional Characterization and Nutritional Regulation of the Putative Elongase Elovl5 in the Orange-Spotted Grouper (Epinephelus coioides).","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26950699","citation_count":12,"is_preprint":false},{"pmid":"35120941","id":"PMC_35120941","title":"Environmental adaptation in fish induced changes in the regulatory region of fatty acid elongase gene, elovl5, involved in long-chain polyunsaturated fatty acid biosynthesis.","date":"2022","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/35120941","citation_count":11,"is_preprint":false},{"pmid":"27169705","id":"PMC_27169705","title":"Dietary Oil Source and Selenium Supplementation Modulate Fads2 and Elovl5 Transcriptional Levels in Liver and Brain of Meagre (Argyrosomus regius).","date":"2016","source":"Lipids","url":"https://pubmed.ncbi.nlm.nih.gov/27169705","citation_count":11,"is_preprint":false},{"pmid":"36291290","id":"PMC_36291290","title":"Glioblastoma Multiforme Tumors in Women Have a Lower Expression of Fatty Acid Elongases ELOVL2, ELOVL5, ELOVL6, and ELOVL7 than in Men.","date":"2022","source":"Brain sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36291290","citation_count":9,"is_preprint":false},{"pmid":"27374149","id":"PMC_27374149","title":"Regulatory divergence of homeologous Atlantic salmon elovl5 genes following the salmonid-specific whole-genome duplication.","date":"2016","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/27374149","citation_count":9,"is_preprint":false},{"pmid":"17827874","id":"PMC_17827874","title":"Localization of the candidate genes ELOVL5 and SCD1 for 'male effect' pheromone synthesis in goats (Capra hircus).","date":"2007","source":"The Journal of reproduction and development","url":"https://pubmed.ncbi.nlm.nih.gov/17827874","citation_count":9,"is_preprint":false},{"pmid":"37199746","id":"PMC_37199746","title":"Spinocerebellar ataxia 38: structure-function analysis shows ELOVL5 G230V is proteotoxic, conformationally altered and a mutational hotspot.","date":"2023","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37199746","citation_count":8,"is_preprint":false},{"pmid":"33525659","id":"PMC_33525659","title":"ELOVL5 Participates in Embryonic Lipid Determination of Cellular Membranes and Cytoplasmic Droplets.","date":"2021","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33525659","citation_count":8,"is_preprint":false},{"pmid":"33994961","id":"PMC_33994961","title":"Elovl5 Expression in the Central Nervous System of the Adult Mouse.","date":"2021","source":"Frontiers in neuroanatomy","url":"https://pubmed.ncbi.nlm.nih.gov/33994961","citation_count":7,"is_preprint":false},{"pmid":"32222967","id":"PMC_32222967","title":"Functional characterisation of fatty acyl desaturase, Fads2, and elongase, Elovl5, in the Boddart's goggle-eyed goby Boleophthalmus boddarti (Gobiidae) suggests an incapacity for long-chain polyunsaturated fatty acid biosynthesis.","date":"2020","source":"Journal of fish biology","url":"https://pubmed.ncbi.nlm.nih.gov/32222967","citation_count":7,"is_preprint":false},{"pmid":"28245901","id":"PMC_28245901","title":"Genetic Variants in the ELOVL5 but not ELOVL2 Gene Associated with Polyunsaturated Fatty Acids in Han Chinese Breast Milk.","date":"2017","source":"Biomedical and environmental sciences : BES","url":"https://pubmed.ncbi.nlm.nih.gov/28245901","citation_count":7,"is_preprint":false},{"pmid":"32957627","id":"PMC_32957627","title":"Seawater Culture Increases Omega-3 Long-Chain Polyunsaturated Fatty Acids (N-3 LC-PUFA) Levels in Japanese Sea Bass (Lateolabrax japonicus), Probably by Upregulating Elovl5.","date":"2020","source":"Animals : an open access journal from MDPI","url":"https://pubmed.ncbi.nlm.nih.gov/32957627","citation_count":7,"is_preprint":false},{"pmid":"29233754","id":"PMC_29233754","title":"Molecular characterization, tissue distribution and differential nutritional regulation of putative Elovl5 elongase in silver barb (Puntius gonionotus).","date":"2017","source":"Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/29233754","citation_count":5,"is_preprint":false},{"pmid":"35933444","id":"PMC_35933444","title":"Effects of the administration of Elovl5-dependent fatty acids on a spino-cerebellar ataxia 38 mouse model.","date":"2022","source":"Behavioral and brain functions : BBF","url":"https://pubmed.ncbi.nlm.nih.gov/35933444","citation_count":4,"is_preprint":false},{"pmid":"39018654","id":"PMC_39018654","title":"ELOVL5 and VLDLR synergistically affect n-3 PUFA deposition in eggs of different chicken breeds.","date":"2024","source":"Poultry science","url":"https://pubmed.ncbi.nlm.nih.gov/39018654","citation_count":4,"is_preprint":false},{"pmid":"38972428","id":"PMC_38972428","title":"miR-218-5p promotes hepatic lipogenesis through targeting Elovl5 in non-alcoholic fatty liver disease.","date":"2024","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/38972428","citation_count":4,"is_preprint":false},{"pmid":"32239337","id":"PMC_32239337","title":"The requirements for sterol regulatory element-binding protein (Srebp) and stimulatory protein 1 (Sp1)-binding elements in the transcriptional activation of two freshwater fish Channa striata and Danio rerio elovl5 elongase.","date":"2020","source":"Fish physiology and biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32239337","citation_count":4,"is_preprint":false},{"pmid":"26299859","id":"PMC_26299859","title":"[Two Elovl5-like elongase genes in Cyprinus carpio var. Jian: Gene characterization, mRNA expression, and nutritional regulation].","date":"2015","source":"Molekuliarnaia biologiia","url":"https://pubmed.ncbi.nlm.nih.gov/26299859","citation_count":4,"is_preprint":false},{"pmid":"37080058","id":"PMC_37080058","title":"Hepatic transcriptome analysis reveals that elovl5 deletion promotes PUFA biosynthesis and deposition.","date":"2023","source":"Comparative biochemistry and physiology. Part D, Genomics & proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/37080058","citation_count":3,"is_preprint":false},{"pmid":"26505436","id":"PMC_26505436","title":"Single nucleotide polymorphisms of Δ6-desaturase and Elovl5 segments and their associations with common carp (Cyprinus carpio) growth traits.","date":"2015","source":"Genetics and molecular research : GMR","url":"https://pubmed.ncbi.nlm.nih.gov/26505436","citation_count":3,"is_preprint":false},{"pmid":"38000296","id":"PMC_38000296","title":"Deletion of Elovl5 leads to dyslipidemia and atherosclerosis in LDLR-deficient mice.","date":"2023","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/38000296","citation_count":2,"is_preprint":false},{"pmid":"31765035","id":"PMC_31765035","title":"Immunolocalization of c-Fos, ELOVL5 and oestradiol in the ewe vulva in relation to oestrus behaviour after treatment with lipopolysaccharide.","date":"2019","source":"Reproduction in domestic animals = Zuchthygiene","url":"https://pubmed.ncbi.nlm.nih.gov/31765035","citation_count":2,"is_preprint":false},{"pmid":"26433464","id":"PMC_26433464","title":"SCA38 is rare in Mainland China.","date":"2015","source":"Journal of the neurological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/26433464","citation_count":1,"is_preprint":false},{"pmid":"41016515","id":"PMC_41016515","title":"Super-enhancer-driven ELOVL5 promotes T-ALL progression through the MYC-SERBP1 pathway.","date":"2025","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/41016515","citation_count":0,"is_preprint":false},{"pmid":"40789653","id":"PMC_40789653","title":"Impact of Elovl5 Deficiency on Cerebellar Excitatory Synaptic Transmission in Mice.","date":"2025","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/40789653","citation_count":0,"is_preprint":false},{"pmid":"41329269","id":"PMC_41329269","title":"ELOVL5 Regulates Ferroptosis in Breast Cancer Cells.","date":"2025","source":"Doklady. Biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/41329269","citation_count":0,"is_preprint":false},{"pmid":"42225919","id":"PMC_42225919","title":"Co-overexpression of ELOVL2 and ELOVL5 promotes clear cell renal cell carcinoma progression through LIMK1-mediated cytoskeletal reorganization.","date":"2026","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/42225919","citation_count":0,"is_preprint":false},{"pmid":"33169581","id":"PMC_33169581","title":"[Transgenesis of Drosophila melanogaster with an Elovl5 gene enables the production of longer-chain fatty acids].","date":"2020","source":"Sheng wu gong cheng xue bao = Chinese journal of biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/33169581","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.06.11.659216","title":"<i>In vivo</i>  AAV9-SB-CRISPR screen identifies fatty acid elongase ELOVL5 as a pro-resolving mediator in lung inflammation","date":"2025-06-16","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.11.659216","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.03.31.646481","title":"Human Cytomegalovirus Infection Reduces an Endogenous Antiviral Fatty Acid by Promoting Host Metabolism","date":"2025-03-31","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.31.646481","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.10.16.617081","title":"Voluntary Exercise Attenuates Tumor Growth in a Preclinical Model of Castration-Resistant Prostate Cancer","date":"2024-10-18","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.16.617081","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":41298,"output_tokens":7546,"usd":0.118542,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16831,"output_tokens":3965,"usd":0.09164,"stage2_stop_reason":"end_turn"},"total_usd":0.210182,"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\": 2008,\n      \"finding\": \"ELOVL5 is required for elongation of gamma-linolenic acid (C18:3 n-6) to dihomo-gamma-linolenic acid (C20:3 n-6) and stearidonic acid (C18:4 n-3) to omega3-arachidonic acid (C20:4 n-3) in mouse liver microsomes. Elovl5 knockout mice accumulate C18 substrates and have reduced arachidonic acid and DHA levels. Reduced ELOVL5 activity leads to activation of SREBP-1c and its target genes, causing hepatic steatosis; dietary supplementation with arachidonic acid and DHA reversed these molecular and metabolic changes.\",\n      \"method\": \"Elovl5 knockout mouse model; liver microsomal elongation assays; dietary supplementation rescue experiments\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — knockout mouse with microsomal enzyme assay demonstrating substrate specificity, and dietary rescue confirming mechanism; replicated across multiple readouts\",\n      \"pmids\": [\"18838740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ELOVL5 controls gluconeogenesis through the mTORC2-Akt2-FoxO1 pathway via its product cis-vaccenic acid (18:1 n-7). Adenoviral overexpression of Elovl5 in obese mice and HepG2 cells increased Akt2-S473 phosphorylation (mTORC2 site) and FoxO1-S256 phosphorylation, inducing rictor mRNA/protein and rictor-mTOR interaction. Rictor knockdown attenuated these effects. Palmitoleic acid (16:1 n-7) but not gamma-linolenic acid (18:3 n-6) was identified as the proximal inducer; inhibition of elongation blocked this induction, implicating cis-vaccenic acid (18:1 n-7) as the key product.\",\n      \"method\": \"Adenoviral overexpression in vivo (diet-induced obese mice) and HepG2 cells; Akt inhibitor treatment; siRNA rictor knockdown; FA analysis; substrate supplementation experiments\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal approaches (genetic overexpression, pharmacological inhibition, siRNA knockdown, substrate supplementation) in a single focused study establishing pathway mechanism\",\n      \"pmids\": [\"23099444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Increased hepatic Elovl5 activity in obese mice lowered hepatic triglycerides and increased TG catabolism by elevating protein levels of adipocyte TG lipase (ATGL) and CGI58. FA products of Elovl5 activity increased ATGL (but not CGI58) mRNA through PPARbeta-dependent mechanisms in HepG2 cells. Elovl5 activity regulates FA composition controlling PPARbeta activity and ATGL expression.\",\n      \"method\": \"Adenoviral overexpression of Elovl5 in obese C57BL/6J mice; PPARbeta agonist treatment in mouse AML12 hepatocytes; radiolabeled fatty acid oxidation assays; protein level measurements\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro complementary experiments with gain-of-function and pharmacological validation identifying PPARbeta as mediator\",\n      \"pmids\": [\"24814977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Missense mutations in ELOVL5 (p.Gly230Val and p.Leu72Val) cause spinocerebellar ataxia 38 (SCA38). Arachidonic acid and DHA, downstream ELOVL5 products, were reduced in serum of affected individuals. In transfection experiments, mutant ELOVL5 (p.G230V) showed aberrant perinuclear distribution with increased Golgi signal, while wild-type ELOVL5 showed widespread endoplasmic reticulum localization. ELOVL5 was highly expressed in Purkinje cells by immunohistochemistry.\",\n      \"method\": \"Genetic linkage analysis and targeted resequencing; serum fatty acid measurements; transfection-based subcellular localization studies; immunohistochemistry on mouse and human brain\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — disease-causing mutations identified, biochemical consequence (reduced product FA levels in patients) confirmed, subcellular mislocalization demonstrated; independently replicated across multiple families\",\n      \"pmids\": [\"25065913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A tryptophan residue at the position equivalent to cysteine-217 in Elovl2 within transmembrane domains 6-7 explains why rat Elovl5 cannot elongate omega-3 docosapentaenoic acid (C22:5n-3) to C24:5n-3, whereas Elovl2 can. Chimera and point mutation studies in yeast expression confirmed that Elovl2 C217 is a critical residue for DPA substrate specificity.\",\n      \"method\": \"Yeast heterologous expression system; Elovl2/Elovl5 chimeric protein construction; site-directed mutagenesis; substrate specificity assays\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution in yeast with systematic mutagenesis and chimera analysis identifying specific residue responsible for substrate selectivity\",\n      \"pmids\": [\"23873268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ELOVL5 is directly induced by androgen receptor (AR) signaling in prostate cancer cells, xenografts, and clinical tumors. ELOVL5 depletion altered mitochondrial morphology and function, causing excess reactive oxygen species, suppressing cell proliferation, 3D growth, and in vivo tumor growth and metastasis. Supplementation with cis-vaccenic acid (18:1 n-7), a direct ELOVL5 product, reversed oxidative stress and proliferation/migration effects of ELOVL5 knockdown.\",\n      \"method\": \"Mass spectrometry lipidomics; transcriptomic analysis; siRNA knockdown in cells and xenografts; patient-derived explants; cis-vaccenic acid supplementation rescue\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (lipidomics, KD in vitro and in vivo, product rescue) establishing AR-ELOVL5-mitochondria-ROS-proliferation axis\",\n      \"pmids\": [\"33547161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The SCA38 missense variant p.G230V does not abolish ELOVL5 enzymatic activity per se, but causes a conformational change (shift in Loop 6 altering a conserved intramolecular disulfide bond between Loop 2 and Loop 6) leading to Golgi complex accumulation, increased proteasomal degradation, unfolded protein response activation, and reduced cell viability in neurons. SCA38-derived fibroblasts showed reduced ELOVL5 expression and Golgi enlargement. The pathogenic mechanism involves combined loss of function by mislocalization and gain of toxic function by ER/Golgi stress.\",\n      \"method\": \"Biochemical enzyme activity assays; fibroblast analysis; heterologous overexpression; unfolded protein response assays; mouse cortical neuron viability assays; homology modelling of protein structure\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — multiple orthogonal methods including structural modelling, biochemical activity assays, cell biological studies, and patient-derived cells establishing conformational pathogenic mechanism\",\n      \"pmids\": [\"37199746\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Elovl5 knockout mice recapitulate SCA38 symptoms including motor deficits on beam balance test and hyposmia. Cerebellar cortex showed reduced molecular layer thickness (from 6 months onward), reduced Purkinje cell layer perimeter, and reduced extension of distal Purkinje cell dendritic arborization (by Sholl analysis of biocytin-filled cells), with conserved dendritic spine density.\",\n      \"method\": \"Elovl5 knockout mouse behavioral testing (beam balance, olfactory tests); cerebellar morphometry; biocytin filling and Sholl analysis of Purkinje cell dendrites\",\n      \"journal\": \"Frontiers in cellular neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO model with defined behavioral and structural phenotypes, complementary quantitative morphological analyses\",\n      \"pmids\": [\"29163054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SREBP-1 activates human ELOVL5 transcription through two newly identified SRE binding sites: one in the 10 kb upstream region and one in exon 1. These two SRE motifs are conserved among mammals, establishing the mechanism by which SREBP activates ELOVL5 as part of the negative feedback loop of de novo lipogenesis.\",\n      \"method\": \"Promoter/enhancer deletion analysis; reporter assays; identification and validation of SREBP binding sites\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter reporter assays with deletion analysis identifying specific binding sites, but single lab study\",\n      \"pmids\": [\"26321664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ELOVL5 is the key elongase responsible for elongation of 18- and 20-carbon PUFAs in human T-cells. ELOVL5 knockdown in proliferating T-cells and Jurkat cells significantly altered cellular MUFA and PUFA profiles and strongly impaired elongation of 18- and 20-carbon PUFAs. Proliferating T-cells showed increased ELOVL5 expression compared to resting T-cells, with no detectable ELOVL2.\",\n      \"method\": \"siRNA knockdown; fatty acid profiling; ELOVL expression measurement in resting vs. proliferating primary human T-cells and Jurkat cells\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with direct FA profiling readout in primary human cells; single lab study\",\n      \"pmids\": [\"30293059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ELOVL5 knockout (CRISPR/Cas9) in renal cell carcinoma suppressed lipid droplet formation, induced ER stress-mediated apoptosis, inhibited AKT Ser473 phosphorylation, and suppressed cell invasion via CCL2 downregulation through AKT-mTOR-STAT3 signaling. Supplementation with ELOVL5 end products (arachidonic acid and EPA) partially reversed proliferation and invasion effects.\",\n      \"method\": \"CRISPR/Cas9 knockout; LC-ESI-MS/MS lipidomics; in vitro and in vivo tumor growth assays; signaling pathway analysis; product supplementation rescue\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with product rescue and signaling pathway analysis; single lab study\",\n      \"pmids\": [\"35670054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In renal cancer cells, ELOVL5-mediated PUFA elongation enhances lipid raft-associated AKT-mTOR signaling activation, contributing to enzalutamide resistance. Knocking down ELOVL5 in NE-like prostate cancer cells diminished neuroendocrine phenotypes and enzalutamide resistance, while ELOVL5 overexpression augmented resistance both in vitro and in vivo.\",\n      \"method\": \"siRNA knockdown; ELOVL5 overexpression; in vitro and in vivo tumor models; AKT-mTOR signaling analysis\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function in vitro and in vivo with signaling pathway mechanism proposed; single lab study\",\n      \"pmids\": [\"34439125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ELOVL5 knockdown in breast cancer cells promoted epithelial-mesenchymal transition (EMT), cell invasion, and lung metastasis via a lipid droplet accumulation-dependent mechanism: loss of ELOVL5 induced lipid droplet accumulation, which triggered Smad2 acetylation and upregulation of TGF-beta receptors. Inhibition of TGF-beta receptors restored proliferation and dampened invasion in low-ELOVL5 cells. Inhibition of diacylglycerol acyltransferase (blocking lipid droplet formation) reversed TGF-beta receptor induction, invasion, and lung metastasis caused by ELOVL5 knockdown.\",\n      \"method\": \"siRNA knockdown; murine breast cancer in vivo metastasis models; TGF-beta receptor inhibition; DGAT inhibition; Smad2 acetylation analysis\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo metastasis model with mechanistic dissection using pharmacological inhibitors; single lab study\",\n      \"pmids\": [\"36056008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"miR-21-3p directly targets the 3'UTR of Elovl5 in bovine mammary epithelial cells, as demonstrated by luciferase reporter assays. miR-21-3p negatively regulates Elovl5 mRNA and protein levels, and promotes triglyceride production, an effect attributable to targeting Elovl5.\",\n      \"method\": \"Luciferase reporter assay with wild-type and mutant 3'UTR; qPCR and Western blotting; miR-21-3p mimic/inhibitor transfection\",\n      \"journal\": \"DNA and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct 3'UTR reporter assay with mutagenesis plus functional miRNA manipulation; single lab study in bovine cells\",\n      \"pmids\": [\"30707627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Estrogen enhances hepatic LCPUFA synthesis by downregulating miR-218-5p, which directly targets and suppresses ELOVL5 expression. ELOVL5 was validated as a direct target of miR-218-5p (located in intron 14 of SLIT2 gene) in laying hens.\",\n      \"method\": \"Bioinformatics target prediction; luciferase reporter assay; qPCR/Western blot; estrogen treatment experiments\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct 3'UTR reporter validation plus hormonal regulation assay; single lab study in avian model\",\n      \"pmids\": [\"28665359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"miR-218-5p directly targets the 3'UTR of Elovl5 (validated by dual-luciferase reporter assay), negatively regulating its expression in mouse hepatocytes. miR-218-5p promotes lipogenesis via the SREBP1 signaling pathway by suppressing Elovl5; silencing miR-218-5p upregulated Elovl5 and suppressed SREBP1-mediated lipogenesis, with the effect of miR-218-5p on lipogenesis blocked by si-Elovl5 both in vitro and in vivo.\",\n      \"method\": \"Dual luciferase reporter assay; miR-218-5p gain/loss-of-function; siRNA Elovl5 knockdown; high-fat diet NAFLD mouse model; in vitro PA-induced model\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic hierarchy established with miRNA-target validation, epistasis experiment (si-Elovl5 blocks miR effect), and in vivo confirmation; single lab study\",\n      \"pmids\": [\"38972428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ELOVL5 is expressed in the mouse CNS in a region- and cell-type-specific manner. Highest expression is in cerebellum, brainstem, primary and accessory olfactory regions (especially mitral cells), hippocampal CA2/CA3 pyramidal cells, and motor control regions. ELOVL5 is expressed in oligodendroglial cells at various maturation steps and in microglia; astrocytes show heterogeneous expression.\",\n      \"method\": \"Elovl5-reporter mouse line; immunofluorescence on adult mouse CNS sections; primary glial cell cultures\",\n      \"journal\": \"Frontiers in neuroanatomy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization using reporter mouse and immunofluorescence; single lab study establishing cell-type and region specificity\",\n      \"pmids\": [\"33994961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Deletion of Elovl5 in mouse cerebellum caused changes in fatty acid profile (increased 18- and 20-carbon PUFAs, decreased long-chain PUFAs, increased saturated and monounsaturated FAs). In Purkinje cells of Elovl5 KO mice, basal synaptic transmission was preserved, but recovery from depression of the climbing fiber synapse lacked the fast phase (deficit in replenishment of the readily releasable pool of synaptic vesicles). The parallel fiber synapse showed slower replenishment at high but physiological frequencies (50-100 Hz). Endocannabinoid-mediated synaptically induced suppression of excitation (SSE) had shorter duration in KO mice, consistent with reduced endocannabinoid signaling. Synaptosomes from KO showed dramatic changes in lipid length and unsaturation.\",\n      \"method\": \"Elovl5 knockout mouse; cerebellar fatty acid profiling; electrophysiological recordings in Purkinje cells; synaptosome lipid analysis\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO model with electrophysiology and lipidomics in synaptosomes providing mechanistic link between PUFA composition and specific synaptic deficits\",\n      \"pmids\": [\"40789653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ELOVL5 knockdown in breast cancer cells (MDA-MB-231) increased MMP1 expression (confirmed by zymography and transcriptomics), decreased CDH11 expression, reduced intercellular adhesion (spheroid formation assay), consistent with enhanced invasive/metastatic potential.\",\n      \"method\": \"Stable ELOVL5 knockdown; transcriptomics; proteomics; RT-PCR; zymography; spheroid formation assay\",\n      \"journal\": \"Frontiers in genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — stable KD with multiple readouts (zymography, transcriptomics, functional spheroid assay); single lab study\",\n      \"pmids\": [\"34149804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ELOVL5 mRNA is localized specifically in the basal layer of sebaceous gland cells in pheromone-producing head skin of male goats, but not in rump skin of males or head skin of orchidectomized males (which do not produce pheromone), suggesting ELOVL5 participates in sebaceous gland-derived pheromone synthesis.\",\n      \"method\": \"In situ hybridization on goat skin sections\",\n      \"journal\": \"The Journal of reproduction and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — in situ hybridization demonstrating cell-type and androgen-dependent localization; single method but with appropriate anatomical controls\",\n      \"pmids\": [\"17827874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ELOVL5 knockdown in bovine embryos (morpholino-mediated) reduced specific phospholipid and triacylglycerol species (7 lipid species including phosphatidylcholines, phosphatidylethanolamines, and triacylglycerol) and increased cytoplasmic lipid droplet deposition, with increased ELOVL5 protein abundance in ELOVL5-Mo blastocysts, without detrimental effect on blastocyst development or cell number.\",\n      \"method\": \"Morpholino-mediated knockdown in bovine embryos; mass spectrometry lipid fingerprinting; confocal microscopy for lipid droplets; Western blot\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — morpholino KD with lipid fingerprinting revealing specific ELOVL5-dependent lipid species in embryos; single lab study\",\n      \"pmids\": [\"33525659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Deletion of Elovl5 leads to dyslipidemia and atherosclerosis in LDLR-deficient mice through activation of SREBP-1, causing increased hepatic triglyceride and cholesterol, elevated plasma VLDL/IDL/LDL triglycerides and cholesterol, and marked aortic atherosclerotic plaques. Elovl5-/- macrophages showed no differences in most M1/M2 polarization markers, except a slight increase in PGE2 secretion linked to elevated Cox-2 expression.\",\n      \"method\": \"Elovl5-/-;Ldlr-/- double knockout mouse model; lipid analysis; atherosclerotic plaque assessment; bone marrow-derived macrophage polarization assays; PGE2 measurement\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic double-KO model with multiple phenotypic and molecular readouts; single lab study\",\n      \"pmids\": [\"38000296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ELOVL5 promotes resolution of lung inflammation after influenza virus infection. ELOVL5 physically binds to STING, inhibiting TBK1 interaction and STING translocation to the Golgi, thereby reducing STING-mediated inflammation and promoting AKT1-mediated tissue repair. ELOVL5 also decreased eicosanoid levels in type II alveolar epithelial cells (AECIIs) to promote resolution. Supplementation with ELOVL5 downstream products reversed increased inflammatory cytokines caused by Elovl5 deficiency.\",\n      \"method\": \"In vivo AAV9-Sleeping Beauty CRISPR screen; AECIIS-specific Cas9 mouse model; Elovl5 deficiency in vitro and in vivo; STING-TBK1 interaction assay; eicosanoid measurements; downstream product supplementation\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR screen with mechanistic follow-up showing STING binding and functional epistasis; preprint, not peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.06.11.659216\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ELOVL5 knockdown in ELOVL5-low breast cancer cells reduced fatty acid content of specific PUFAs and decreased GPX4 activity, increasing sensitivity to ferroptosis (iron-dependent lipid peroxidation-mediated cell death). External PUFAs (especially DHA) caused cell death by activation of ferroptosis in ELOVL5-knockdown cells.\",\n      \"method\": \"Stable ELOVL5 knockdown (MDA-MB-231 cells); HPLC-MS fatty acid analysis; flow cytometry for apoptosis; fluorescent microscopy for ROS and lipid droplets; GPX4 colorimetric activity assay; ferrostatin-1/deferoxamine ferroptosis inhibitor controls\",\n      \"journal\": \"Frontiers in molecular biosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — stable KD with ferroptosis inhibitor confirmation and GPX4 activity measurement; single lab study\",\n      \"pmids\": [\"36714261\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Super-enhancer-driven ELOVL5 transcription is regulated by H3K27ac marks in T-ALL. ELOVL5 knockdown suppressed proliferation and induced apoptosis in T-ALL cells in vitro and in vivo (mouse xenograft models), reducing tumor burden. RNA-seq revealed ELOVL5 promotes T-ALL progression by activating MYC signaling and upregulating SERBP1; SERBP1 silencing phenocopied ELOVL5 KD effects.\",\n      \"method\": \"H3K27ac ChIP-seq; siRNA knockdown; in vitro and in vivo tumor models; RNA-seq; SERBP1 knockdown epistasis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq for regulatory mechanism plus KD epistasis establishing ELOVL5-SERBP1-MYC pathway; single lab study\",\n      \"pmids\": [\"41016515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ELOVL5 mediates production of VLC-PUFAs during HCMV infection and reduces the level of erucic acid (EA, C22:1), an endogenous fatty acid with antiviral properties. ELOVL5 aided the increase in phospholipids containing C22:1 plus VLC-PUFA tails following EA treatment and reduced overall C22:1 levels in HCMV-infected cells. ELOVL5 mollified EA inhibition of HCMV replication, suggesting it plays a role in reducing an antiviral fatty acid.\",\n      \"method\": \"Lipidomics; HCMV infection model; EA treatment; ELOVL5 manipulation in infected cells\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab preprint with mechanistic interpretation based on correlative lipidomics and functional virus replication assay; limited mechanistic dissection\",\n      \"pmids\": [\"bio_10.1101_2025.03.31.646481\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"ELOVL5 is an endoplasmic reticulum-resident fatty acid elongase that catalyzes the elongation of C18 and C20 polyunsaturated fatty acids (PUFAs) to produce downstream products including arachidonic acid, EPA, and cis-vaccenic acid; its activity regulates SREBP-1c-driven lipogenesis, gluconeogenesis via the mTORC2-Akt2-FoxO1 pathway, hepatic triglyceride catabolism via PPARbeta-ATGL, mitochondrial function, lipid raft-associated AKT-mTOR signaling, and synaptic vesicle release kinetics in Purkinje cells, while loss-of-function missense mutations that cause Golgi mislocalization and ER stress underlie spinocerebellar ataxia 38 (SCA38).\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ELOVL5 is an endoplasmic reticulum-resident fatty acid elongase that catalyzes the rate-limiting elongation of C18 and C20 polyunsaturated fatty acids, generating downstream products including arachidonic acid, DHA, EPA, and cis-vaccenic acid (18:1 n-7) [#0, #4]. Its substrate specificity is determined by defined transmembrane residues, with a tryptophan at the position equivalent to Elovl2 Cys-217 restricting elongation to C18/C20 PUFAs and excluding C22:5 n-3 [#4]. Through control of cellular PUFA and MUFA composition, ELOVL5 governs hepatic lipid metabolism: reduced activity derepresses SREBP-1c and its lipogenic targets to cause hepatic steatosis [#0], while its cis-vaccenic acid product drives gluconeogenic control via the mTORC2-Akt2-FoxO1 axis [#1] and PUFA products promote triglyceride catabolism through PPARbeta-dependent ATGL induction [#2]; loss of ELOVL5 in an LDLR-deficient background produces SREBP-1-driven dyslipidemia and atherosclerosis [#21]. ELOVL5 transcription is embedded in a lipogenic feedback circuit, being directly activated by SREBP-1 via conserved SRE elements [#8] and repressed by microRNAs including miR-218-5p [#15]. In the CNS, ELOVL5 is highly expressed in Purkinje cells [#3, #16], and its loss alters cerebellar PUFA composition and impairs synaptic vesicle pool replenishment and endocannabinoid-mediated synaptic suppression in Purkinje-cell synapses [#17]; mouse knockouts recapitulate SCA38-like motor deficits and hyposmia with Purkinje cell dendritic atrophy [#7]. Missense mutations (p.Gly230Val, p.Leu72Val) cause spinocerebellar ataxia 38 (SCA38) through a combined mechanism in which a conformational shift disrupts a conserved Loop2-Loop6 disulfide bond, driving Golgi mislocalization, proteasomal degradation, and unfolded protein response activation alongside reduced product fatty acids [#3, #6]. ELOVL5 also acts as a pro-tumorigenic and inflammation-resolving factor across multiple tissues, supporting mitochondrial function and proliferation in prostate cancer downstream of androgen receptor signaling [#5] and constraining lipid-droplet- and ferroptosis-linked invasive phenotypes [#12, #23].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Establishing the core enzymatic identity of ELOVL5 was needed to define which fatty acids it produces and how its loss perturbs lipid homeostasis.\",\n      \"evidence\": \"Elovl5 knockout mouse with liver microsomal elongation assays and dietary rescue\",\n      \"pmids\": [\"18838740\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve tissue-specific contributions beyond liver\", \"Mechanistic basis of SREBP-1c derepression not structurally defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Determining why ELOVL5 cannot elongate C22:5 n-3 clarified the structural basis of its substrate range relative to ELOVL2.\",\n      \"evidence\": \"Yeast heterologous expression with Elovl2/Elovl5 chimeras and site-directed mutagenesis\",\n      \"pmids\": [\"23873268\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No full-length structure of ELOVL5\", \"Catalytic mechanism of elongation not reconstituted\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Linking a specific ELOVL5 product to a signaling axis explained how the enzyme controls glucose metabolism beyond bulk lipid supply.\",\n      \"evidence\": \"Adenoviral overexpression in obese mice and HepG2 cells with rictor knockdown and substrate supplementation\",\n      \"pmids\": [\"23099444\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How cis-vaccenic acid mechanistically activates mTORC2 not defined\", \"Direct lipid-protein interactions not identified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identifying PPARbeta as a mediator showed how ELOVL5-controlled fatty acid composition drives hepatic triglyceride catabolism.\",\n      \"evidence\": \"Adenoviral Elovl5 overexpression in obese mice plus PPARbeta agonist treatment in hepatocytes\",\n      \"pmids\": [\"24814977\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific FA ligand activating PPARbeta not pinpointed\", \"CGI58 regulation mechanism unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connecting ELOVL5 missense mutations to SCA38 with reduced patient product fatty acids and mutant mislocalization established the gene as a Mendelian ataxia cause.\",\n      \"evidence\": \"Genetic linkage and resequencing, serum FA measurement, transfection localization, and brain immunohistochemistry\",\n      \"pmids\": [\"25065913\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether mislocalization alone or loss of product drives neurodegeneration not separated at this stage\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Mapping SRE elements in the ELOVL5 promoter placed the enzyme within the SREBP lipogenic feedback loop at the transcriptional level.\",\n      \"evidence\": \"Promoter deletion and reporter assays with SREBP binding site validation\",\n      \"pmids\": [\"26321664\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab reporter study\", \"Endogenous SREBP occupancy not confirmed in vivo\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrating that Elovl5 knockout mice reproduce SCA38 motor and olfactory deficits with Purkinje cell atrophy provided an in vivo disease model.\",\n      \"evidence\": \"Knockout mouse behavioral testing and cerebellar morphometry with Sholl analysis\",\n      \"pmids\": [\"29163054\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between PUFA loss and dendritic atrophy not defined\", \"Cell-autonomy of Purkinje phenotype not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identifying miRNA repressors and hormonal inputs revealed post-transcriptional control of ELOVL5 in LCPUFA synthesis.\",\n      \"evidence\": \"miR-218-5p and miR-21-3p 3'UTR luciferase validation with hormonal and functional manipulation in avian, bovine, and mouse cells\",\n      \"pmids\": [\"28665359\", \"30707627\", \"38972428\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cross-species relevance to human regulation incomplete\", \"Other regulatory miRNAs not surveyed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defining ELOVL5 as an androgen-receptor-induced enzyme supporting mitochondrial function and proliferation extended its role into cancer biology.\",\n      \"evidence\": \"Lipidomics, siRNA knockdown in cells and xenografts, patient-derived explants, and cis-vaccenic acid rescue\",\n      \"pmids\": [\"33547161\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking cis-vaccenic acid to mitochondrial ROS control unresolved\", \"Generalizability across cancer types not addressed here\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Loss-of-function studies across renal and breast cancers connected ELOVL5 to lipid-droplet-dependent signaling, ER stress, and metastasis suppression or promotion.\",\n      \"evidence\": \"CRISPR/stable knockdown with lipidomics, signaling analysis, ferroptosis assays, and in vivo metastasis models\",\n      \"pmids\": [\"35670054\", \"36056008\", \"34149804\", \"36714261\", \"34439125\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Context-dependent pro- versus anti-tumor roles not reconciled\", \"Single-lab studies per tumor type\", \"Direct lipid mediators of each pathway not fully identified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Resolving the SCA38 p.G230V mechanism showed disease arises not from abolished catalysis but from a disulfide-bond conformational defect causing Golgi accumulation and proteotoxic stress.\",\n      \"evidence\": \"Enzyme activity assays, patient fibroblasts, UPR assays, neuron viability, and homology modeling\",\n      \"pmids\": [\"37199746\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No experimental structure of mutant protein\", \"Relative contribution of loss-of-function versus toxic gain-of-function in vivo unquantified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linking cerebellar PUFA composition to specific synaptic vesicle and endocannabinoid deficits provided a mechanistic basis for the ataxia phenotype.\",\n      \"evidence\": \"Knockout mouse cerebellar lipidomics, Purkinje cell electrophysiology, and synaptosome lipid analysis\",\n      \"pmids\": [\"40789653\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which lipid species directly governs vesicle replenishment not isolated\", \"Molecular target of altered endocannabinoid signaling not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ELOVL5 product lipids are physically read out by the diverse downstream effectors (mTORC2, PPARbeta, STING, synaptic vesicle machinery) to produce tissue-specific outcomes remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying lipid-sensing mechanism identified\", \"No experimental three-dimensional structure of human ELOVL5\", \"Direct versus indirect effects of altered membrane lipid composition not separated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0016746\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [3, 6]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [3, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 2, 21]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [7, 17]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"STING\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}