{"gene":"ELOVL5","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2008,"finding":"ELOVL5 is required in vivo 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); deletion of Elovl5 in mice reduces arachidonic acid and DHA levels, which activates SREBP-1c and its target genes, leading to hepatic steatosis reversible by dietary arachidonic acid and DHA supplementation.","method":"Elovl5 knockout mouse model, liver microsomal enzyme assay, dietary supplementation rescue","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 1-2 — in vivo knockout with biochemical substrate/product profiling, mechanistic pathway placement, and dietary rescue confirming causality; replicated in multiple follow-up studies","pmids":["18838740"],"is_preprint":false},{"year":2012,"finding":"Elovl5 controls gluconeogenesis through the mTORC2-Akt2-FoxO1 pathway: elevated Elovl5 activity increases cis-vaccenic acid (18:1 n-7) synthesis, induces rictor mRNA and protein, promotes rictor-mTOR interaction, and selectively phosphorylates Akt2-S473 (mTORC2 site) but not Akt2-T308, leading to FoxO1-S256 phosphorylation and reduced nuclear FoxO1; rictor knockdown blocks these effects.","method":"Adenoviral overexpression of Elovl5 in obese mice and HepG2 cells, Akt inhibitor treatment, rictor siRNA knockdown, fatty acid analysis, phospho-specific Western blotting","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (gain-of-function, inhibitor, siRNA knockdown, fatty acid supplementation) in both in vivo and in vitro systems by same lab","pmids":["23099444"],"is_preprint":false},{"year":2014,"finding":"Elovl5 activity regulates hepatic triglyceride catabolism in obese mice by producing fatty acid products (including cis-vaccenic acid) that activate PPARβ-dependent induction of ATGL (adipocyte triglyceride lipase) mRNA and protein, thereby promoting TG catabolism without affecting β-oxidation capacity; Elovl5 also reduces ER stress markers.","method":"Adenoviral Elovl5 overexpression in obese C57BL/6J mice, PPARβ agonist treatment, siRNA knockdown, fatty acyl carnitine profiling, Western blotting","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 2 — in vivo and in vitro complementary approaches with pharmacological and genetic dissection of pathway","pmids":["24814977"],"is_preprint":false},{"year":2013,"finding":"The differential ability of rat Elovl5 vs Elovl2 to elongate C22 omega-3 docosapentaenoic acid (DPA, 22:5n-3) to 24:5n-3 is determined by a single residue: cysteine at position 217 in Elovl2 (critical for DPA elongation) vs tryptophan at the equivalent position in Elovl5 (which cannot elongate DPA); this was established by chimeric protein and point mutation analysis in a yeast expression system.","method":"Yeast heterologous expression, Elovl2/Elovl5 chimeras, site-directed mutagenesis, fatty acid profiling","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 1 — reconstitution with point mutagenesis identifying specific catalytic residue differences","pmids":["23873268"],"is_preprint":false},{"year":2014,"finding":"ELOVL5 missense mutations (p.Gly230Val and p.Leu72Val) cause spinocerebellar ataxia type 38 (SCA38); mutant ELOVL5 shows aberrant perinuclear/Golgi accumulation rather than the normal widespread ER distribution, and affected individuals have reduced serum arachidonic acid and DHA.","method":"Linkage analysis, targeted resequencing, Sanger sequencing in families, transfection with subcellular localization imaging (immunofluorescence), serum fatty acid profiling","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 — genetic identification plus functional subcellular localization experiments in transfected cells with clinical biochemical correlation","pmids":["25065913"],"is_preprint":false},{"year":2017,"finding":"Elovl5 knockout mice develop progressive motor deficits (beam balance test), hyposmia, and cerebellar atrophy with reduced molecular layer thickness and decreased distal Purkinje cell dendritic arborization (by Sholl analysis of biocytin-filled PCs), recapitulating SCA38 symptoms; dendritic spine density is preserved.","method":"Elovl5 knockout mouse model, behavioral testing, morphometric cerebellar analysis, biocytin filling with Sholl dendritic analysis","journal":"Frontiers in cellular neuroscience","confidence":"High","confidence_rationale":"Tier 2 — clean knockout with defined cellular and behavioral phenotypes, multiple quantitative morphological readouts","pmids":["29163054"],"is_preprint":false},{"year":2021,"finding":"ELOVL5 is directly transcriptionally induced by the androgen receptor (AR) in prostate cancer; ELOVL5 depletion alters mitochondrial morphology and function, increases reactive oxygen species, and suppresses prostate cancer cell proliferation, 3D growth, and in vivo tumor growth and metastasis; supplementation with cis-vaccenic acid (a direct ELOVL5 elongation product) reverses oxidative stress and proliferation/migration defects of ELOVL5 knockdown.","method":"Transcriptomics, ChIP, ELOVL5 siRNA/shRNA knockdown, mass spectrometry lipidomics, ROS assays, mitochondrial function assays, xenograft mouse models, cis-vaccenic acid supplementation rescue","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods including in vitro and in vivo models with substrate rescue experiment confirming mechanistic specificity","pmids":["33547161"],"is_preprint":false},{"year":2015,"finding":"Two SREBP binding sites in the human ELOVL5 gene (one ~10 kb upstream, one in exon 1) are identified as functional enhancer elements conserved among mammals; SREBP activates ELOVL5 transcription through these SRE motifs, establishing ELOVL5 as a direct SREBP-1 target gene within a negative feedback loop of de novo lipogenesis.","method":"Promoter/enhancer deletion analysis, luciferase reporter assays, electrophoretic mobility shift assay (EMSA)","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — reporter assays and EMSA in a single study identify functional cis-regulatory elements","pmids":["26321664"],"is_preprint":false},{"year":2021,"finding":"ELOVL5-mediated fatty acid elongation in renal cell carcinoma promotes AKT Ser473 phosphorylation and AKT-mTOR-STAT3 signaling, supporting cell invasion via CCL2 upregulation; ELOVL5 knockout suppresses lipid droplet formation and induces apoptosis via ER stress; supplementation with arachidonic acid and EPA partially reverses proliferation and invasion defects.","method":"CRISPR/Cas9 ELOVL5 knockout, LC-MS lipidomics, Western blotting for AKT/mTOR/STAT3 signaling, fatty acid supplementation rescue, in vivo xenograft","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 — genetic knockout with signaling pathway analysis and substrate rescue in single study","pmids":["35670054"],"is_preprint":false},{"year":2021,"finding":"ELOVL5-mediated PUFA elongation enhances lipid raft-associated AKT-mTOR signaling, contributing to enzalutamide resistance in neuroendocrine-like prostate cancer cells; ELOVL5 knockdown reduces neuroendocrine phenotype and resistance, while overexpression augments resistance in vitro and in vivo.","method":"shRNA knockdown, ELOVL5 overexpression, enzalutamide resistance assays, lipid raft isolation, AKT-mTOR signaling Western blotting, xenograft models","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 2 — gain- and loss-of-function with signaling pathway analysis in single lab study","pmids":["34439125"],"is_preprint":false},{"year":2022,"finding":"Downregulation of ELOVL5 in breast cancer promotes EMT, cell invasion, and lung metastasis through lipid-droplet accumulation-dependent Smad2 acetylation, which upregulates TGF-β receptors; inhibition of TGF-β receptors or diacylglycerol acyltransferase (blocking lipid droplet formation) reverses invasion and metastasis caused by ELOVL5 loss.","method":"shRNA knockdown, lipid droplet imaging, TGF-β receptor inhibitor treatment, DGAT inhibitor treatment, Smad2 acetylation assay, murine breast cancer metastasis models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — multiple pharmacological and genetic interventions establishing pathway sequence in single study","pmids":["36056008"],"is_preprint":false},{"year":2023,"finding":"The SCA38-causing ELOVL5 p.G230V variant has normal enzymatic activity but is proteotoxic: it is mislocalized to the Golgi (instead of ER), undergoes increased proteasomal degradation, triggers unfolded protein response more strongly than wild-type, and decreases neuronal viability; homology modelling reveals p.G230V shifts Loop 6 and alters a conserved disulfide bond connecting Loop 2 and Loop 6 that is elongase-specific.","method":"Biochemical elongase activity assay in SCA38 fibroblasts, proteasome inhibitor treatment, UPR reporter assays in cortical neurons, immunofluorescence localization, homology structural modelling","journal":"Human genetics","confidence":"High","confidence_rationale":"Tier 1-2 — biochemical activity measurement, structural modelling, UPR/viability assays, and localization studies in a single study providing mechanistic model of pathogenesis","pmids":["37199746"],"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 expression is significantly upregulated upon T-cell activation/proliferation, and ELOVL5 knockdown markedly impairs elongation of these substrates and alters cellular PUFA profiles; no functional ELOVL2 was detected in these cells.","method":"siRNA knockdown of ELOVL5 in primary human T-cells and Jurkat cells, exogenous PUFA incorporation assays, RT-qPCR, fatty acid profiling","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with substrate incorporation assays in primary human cells, single study","pmids":["30293059"],"is_preprint":false},{"year":2021,"finding":"ELOVL5 knockdown in bovine embryos reduces the content of specific phospholipid species (phosphatidylcholines, phosphatidylethanolamines) and triacylglycerol, while increasing cytoplasmic lipid droplet deposition, demonstrating that ELOVL5 participates in embryonic lipid composition of cellular membranes.","method":"Morpholino-mediated knockdown in bovine embryos, mass spectrometry-based lipid fingerprinting, lipid droplet imaging","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with lipidomics in a clean embryo model, single study","pmids":["33525659"],"is_preprint":false},{"year":2025,"finding":"In Elovl5 knockout mouse cerebellum, deletion increases 18- and 20-carbon PUFAs, decreases long-chain PUFAs, and increases saturated/monounsaturated fatty acids in synaptosomes; loss of Elovl5 impairs replenishment of the readily releasable pool of synaptic vesicles at climbing fiber and parallel fiber synapses, and shortens endocannabinoid-mediated suppression of excitation (SSE) in Purkinje cells, linking ELOVL5-dependent lipid composition to synaptic transmission and plasticity.","method":"Elovl5 knockout mice, electrophysiological recordings in Purkinje cells (paired-pulse and high-frequency stimulation protocols), synaptosome lipid analysis, SSE assays","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 1-2 — clean knockout with direct electrophysiological readouts and matched lipidomics in synaptosomes, multiple synaptic measurements","pmids":["40789653"],"is_preprint":false},{"year":2021,"finding":"Elovl5 expression in the adult mouse CNS is region- and cell-type-specific: highest in cerebellar Purkinje cells, mitral cells of olfactory regions, brainstem, and motor-related telencephalic regions; Elovl5 is expressed in oligodendroglial cells at various maturation stages and in microglia, with heterogeneous expression in astrocytes.","method":"Elovl5-reporter mouse line, immunofluorescence on CNS sections, primary glial cell cultures","journal":"Frontiers in neuroanatomy","confidence":"Medium","confidence_rationale":"Tier 2 — direct reporter/immunofluorescence localization with cellular resolution, providing functional context for SCA38 pathology","pmids":["33994961"],"is_preprint":false},{"year":2007,"finding":"ELOVL5 mRNA is specifically localized to the basal layer of sebaceous gland cells in the pheromone-producing head skin of male goats but absent in non-pheromone-producing rump skin and orchidectomized goat head skin, implicating ELOVL5 in pheromone fatty acid synthesis in sebaceous glands.","method":"In situ hybridization on goat skin sections","journal":"The Journal of reproduction and development","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization by in situ hybridization with appropriate negative controls (rump skin, orchidectomized animals)","pmids":["17827874"],"is_preprint":false},{"year":2017,"finding":"Estrogen promotes hepatic LCPUFA synthesis by downregulating miR-218-5p, which directly targets and represses ELOVL5; miR-218-5p binds the 3'UTR of ELOVL5 (validated by luciferase reporter assay) and negatively regulates ELOVL5 mRNA and protein levels, thereby modulating PUFA biosynthesis at the post-transcriptional level.","method":"Luciferase 3'UTR reporter assay, miRNA mimic/inhibitor transfection, Western blotting, qPCR in chicken hepatocytes","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 — 3'UTR reporter validation plus gain/loss-of-function miRNA experiments in single study","pmids":["28665359"],"is_preprint":false},{"year":2019,"finding":"miR-21-3p directly targets the 3'UTR of Elovl5 in bovine mammary epithelial cells (validated by luciferase reporter assay) and negatively regulates Elovl5 mRNA and protein; miR-21-3p mimics promote triglyceride production, an effect attributed to Elovl5 suppression.","method":"Luciferase 3'UTR reporter assay, miRNA mimic/inhibitor transfection, qPCR, Western blotting","journal":"DNA and cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — direct 3'UTR reporter validation plus functional miRNA experiments, single lab","pmids":["30707627"],"is_preprint":false},{"year":2024,"finding":"miR-218-5p directly targets and suppresses Elovl5 expression in mouse hepatocytes (validated by dual luciferase reporter assay); miR-218-5p inhibition upregulates Elovl5 and suppresses SREBP1-mediated lipogenesis signaling, reducing lipid accumulation in a palmitic acid-induced NAFLD model; the pro-lipogenic effect of miR-218-5p is blocked by si-Elovl5, confirming Elovl5 as the functional target.","method":"Dual luciferase reporter assay, gain/loss-of-function miRNA experiments in AML12 cells and HFD mouse model, SREBP1 pathway Western blotting","journal":"Biochemical pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 — 3'UTR reporter plus in vivo/in vitro functional validation with epistasis (si-Elovl5 blocks miR-218-5p effect)","pmids":["38972428"],"is_preprint":false},{"year":2023,"finding":"Deletion of Elovl5 in LDLR-deficient mice activates SREBP-1, increases hepatic triglyceride and cholesterol, elevates VLDL/IDL/LDL plasma lipids, and results in marked aortic atherosclerotic plaques; Elovl5-deficient macrophages show slightly elevated PGE2 secretion (likely due to Cox-2) but no major differences in M1/M2 polarization markers.","method":"Elovl5-/-;Ldlr-/- double knockout mice, lipoprotein profiling, hepatic lipid analysis, aortic plaque quantification, bone marrow-derived macrophage polarization assays","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — double knockout model with multiple metabolic readouts and mechanistic link to SREBP-1 activation","pmids":["38000296"],"is_preprint":false},{"year":2025,"finding":"ELOVL5 physically binds to STING and inhibits TBK1 interaction with STING and its translocation to the Golgi, thereby reducing STING-mediated inflammatory signaling in lung epithelial cells; Elovl5 deficiency impairs lung inflammation resolution after influenza infection and reduces AKT1-mediated tissue repair; ELOVL5 also decreases eicosanoid levels in alveolar epithelial cells.","method":"In vivo CRISPR screen (AAV9-Sleeping Beauty), Elovl5 conditional knockout in lung epithelial cells, co-immunoprecipitation of ELOVL5 with STING, STING-TBK1 interaction assay, Golgi trafficking assay, eicosanoid profiling","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP identifying novel STING binding partner plus functional in vivo screen and KO phenotype; preprint, not yet peer-reviewed","pmids":[],"is_preprint":true},{"year":2025,"finding":"ELOVL5 promotes VLC-PUFA production in HCMV-infected cells and aids removal of erucic acid (C22:1, an endogenous antiviral fatty acid) by elongation; ELOVL5 activity is stimulated by HCMV infection and reduces C22:1 levels, thereby mollifying the antiviral effect of erucic acid on virus replication.","method":"Lipidomics, erucic acid supplementation, ELOVL5 functional assay in HCMV-infected cells","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 — lipidomics-based inference in single preprint; ELOVL5-specific mechanistic evidence is indirect","pmids":[],"is_preprint":true},{"year":2025,"finding":"ELOVL5 is a super-enhancer-driven oncogene in T-ALL; ELOVL5 knockdown suppresses T-ALL cell proliferation and induces apoptosis in vitro and reduces tumor burden in xenograft models; RNA-seq shows ELOVL5 promotes T-ALL progression by activating MYC signaling and upregulating SERBP1.","method":"H3K27ac ChIP-seq, shRNA knockdown, RNA-seq, xenograft mouse models, SERBP1 silencing","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP-seq confirming super-enhancer regulation, loss-of-function in vivo and in vitro, transcriptomic pathway analysis identifying MYC-SERBP1 axis","pmids":["41016515"],"is_preprint":false}],"current_model":"ELOVL5 is an endoplasmic reticulum-resident, multipass transmembrane fatty acid elongase that catalyzes the rate-limiting elongation of C18 and C20 polyunsaturated fatty acids (including gamma-linolenic, stearidonic, arachidonic acid precursors, and EPA series substrates) to longer-chain PUFAs; its products—particularly arachidonic acid, DHA, EPA, and cis-vaccenic acid—act as feedback regulators of SREBP-1c-mediated lipogenesis, activate PPARβ to induce ATGL-dependent TG catabolism, and modulate the mTORC2-Akt2-FoxO1 gluconeogenic axis; SCA38-causing missense mutations (e.g., p.G230V) misfold ELOVL5, causing Golgi mislocalization, proteasomal degradation, and ER/Golgi stress-mediated proteotoxicity in Purkinje cells; loss of Elovl5 in cerebellar neurons alters synaptosomal PUFA composition and impairs synaptic vesicle replenishment and endocannabinoid-mediated plasticity; in cancer contexts, ELOVL5-dependent lipid elongation sustains phospholipid acyl-chain length in membranes, supports mitochondrial function, activates AKT-mTOR signaling, and drives proliferation and metastasis, while ELOVL5 also physically interacts with STING to restrain innate inflammatory signaling."},"narrative":{"teleology":[{"year":2007,"claim":"Establishing that ELOVL5 expression is tissue- and hormone-regulated: ELOVL5 mRNA was detected specifically in the basal layer of androgen-dependent sebaceous glands, linking the elongase to specialized lipid production in a defined secretory cell type.","evidence":"In situ hybridization on goat head vs. rump skin and orchidectomized controls","pmids":["17827874"],"confidence":"Medium","gaps":["No direct functional assay of ELOVL5 enzymatic activity in these cells","Relevance to human sebaceous biology not tested"]},{"year":2008,"claim":"The first loss-of-function model established ELOVL5 as the in vivo enzyme required for elongating C18:3 n-6 → C20:3 n-6 and C18:4 n-3 → C20:4 n-3, and revealed that the resulting arachidonic acid and DHA depletion derepresses SREBP-1c, causing hepatic steatosis—thereby placing ELOVL5 products as feedback regulators of lipogenic transcription.","evidence":"Elovl5 knockout mouse with hepatic microsomal assays and dietary AA/DHA rescue","pmids":["18838740"],"confidence":"High","gaps":["Structural basis for substrate specificity unknown","Whether ELOVL5 is rate-limiting in all tissues not addressed"]},{"year":2012,"claim":"Beyond lipogenesis, ELOVL5 was linked to glucose metabolism: its product cis-vaccenic acid induces rictor expression, enhances mTORC2-dependent Akt2 S473 phosphorylation, and promotes FoxO1 phosphorylation to suppress gluconeogenesis, establishing a lipid-to-glucose regulatory circuit.","evidence":"Adenoviral Elovl5 overexpression in obese mice and HepG2 cells with rictor siRNA epistasis and phospho-specific Western blotting","pmids":["23099444"],"confidence":"High","gaps":["Whether cis-vaccenic acid acts directly on rictor transcription or through an intermediate is unclear","Physiological relevance in lean animals not shown"]},{"year":2013,"claim":"The molecular determinant distinguishing ELOVL5 from ELOVL2 substrate range was identified: a tryptophan at the position equivalent to Cys-217 of ELOVL2 prevents ELOVL5 from elongating C22 PUFAs, providing the first structural-level insight into elongase substrate selectivity.","evidence":"Chimeric Elovl2/Elovl5 proteins and point mutagenesis in yeast heterologous expression","pmids":["23873268"],"confidence":"High","gaps":["No crystal or cryo-EM structure of either elongase","Mechanism by which this residue excludes C22 substrates not resolved at atomic level"]},{"year":2014,"claim":"Two advances refined ELOVL5 biology: (1) ELOVL5 missense mutations were identified as the cause of SCA38 via linkage analysis and shown to mislocalize the protein from ER to Golgi, establishing a neurodegenerative disease mechanism; (2) ELOVL5-derived fatty acids were shown to activate PPARβ-dependent ATGL induction, adding triglyceride catabolism to ELOVL5's metabolic repertoire.","evidence":"Family-based linkage/sequencing with subcellular localization imaging (SCA38); adenoviral overexpression in obese mice with PPARβ agonist and siRNA epistasis (TG catabolism)","pmids":["25065913","24814977"],"confidence":"High","gaps":["Whether SCA38 mutations impair enzymatic activity or act purely by proteotoxicity was unresolved at this point","PPARβ activation mechanism by cis-vaccenic acid not defined"]},{"year":2015,"claim":"Identification of two functional SREBP binding sites in the ELOVL5 gene confirmed that SREBP-1 directly activates ELOVL5 transcription, closing a negative-feedback loop in which ELOVL5 products suppress SREBP-1c and SREBP-1c induces ELOVL5.","evidence":"Promoter deletion and luciferase reporter assays plus EMSA for SRE motifs","pmids":["26321664"],"confidence":"Medium","gaps":["ChIP-seq confirmation in endogenous chromatin not performed","Relative contribution of each SRE not quantified in vivo"]},{"year":2017,"claim":"Two studies expanded ELOVL5 regulation and disease modeling: miR-218-5p was validated as a direct post-transcriptional repressor of ELOVL5 linking estrogen signaling to PUFA synthesis, and Elovl5 knockout mice were shown to recapitulate SCA38 with progressive motor deficits, cerebellar atrophy, and reduced Purkinje cell dendritic arborization.","evidence":"Luciferase 3'UTR reporter assay and miRNA gain/loss-of-function in chicken hepatocytes (miR-218-5p); Elovl5 KO mice with behavioral and morphometric cerebellar analysis (SCA38 model)","pmids":["28665359","29163054"],"confidence":"Medium","gaps":["Synaptic and electrophysiological consequences of Elovl5 loss not yet examined","Whether miR-218-5p regulates ELOVL5 in mammalian hepatocytes not shown"]},{"year":2018,"claim":"ELOVL5 was established as the dominant elongase for C18–C20 PUFA elongation in human T cells, with expression upregulated upon T-cell activation, extending its physiological relevance to adaptive immunity.","evidence":"siRNA knockdown in primary human T cells and Jurkat cells with exogenous PUFA incorporation assays","pmids":["30293059"],"confidence":"Medium","gaps":["Functional consequences for T-cell effector function not tested","Whether other elongases compensate during prolonged activation unknown"]},{"year":2021,"claim":"Multiple cancer studies converged to establish ELOVL5 as a driver of oncogenic lipid metabolism: in prostate cancer it is an AR target gene whose product cis-vaccenic acid sustains mitochondrial function and suppresses ROS; in renal cell carcinoma ELOVL5 promotes AKT-mTOR-STAT3 signaling and invasion; and its elongation products enhance lipid-raft AKT-mTOR signaling to drive enzalutamide resistance in neuroendocrine prostate cancer.","evidence":"ChIP, siRNA/shRNA/CRISPR KO, xenografts, lipidomics, and cis-vaccenic acid/AA/EPA rescue across multiple cancer cell models","pmids":["33547161","35670054","34439125"],"confidence":"Medium","gaps":["Whether ELOVL5 inhibition has therapeutic selectivity over normal tissues is untested","Direct lipid species mediating AKT activation not identified","Contribution of specific PUFA products vs. total elongation flux unclear"]},{"year":2021,"claim":"Regional mapping in the CNS revealed that Elovl5 is most highly expressed in cerebellar Purkinje cells and olfactory mitral cells, directly explaining the selective vulnerability of these neurons in SCA38.","evidence":"Elovl5-reporter mouse line with immunofluorescence across CNS regions and glial cultures","pmids":["33994961"],"confidence":"Medium","gaps":["Functional consequence of Elovl5 in oligodendrocytes and microglia not explored","Whether regional expression differences translate to differing lipid profiles not shown"]},{"year":2022,"claim":"An unexpected tumor-suppressive role was demonstrated: ELOVL5 loss in breast cancer promotes EMT and metastasis through lipid droplet accumulation, Smad2 acetylation, and TGFβ receptor upregulation, contrasting with its oncogenic role in other cancers and revealing context-dependent functions.","evidence":"shRNA knockdown, lipid droplet imaging, TGFβR and DGAT inhibitor epistasis, murine metastasis models","pmids":["36056008"],"confidence":"Medium","gaps":["Mechanism by which lipid droplet accumulation drives Smad2 acetylation not defined","Reconciliation of tumor-suppressive vs. oncogenic roles across cancer types lacking"]},{"year":2023,"claim":"The SCA38 pathomechanism was refined: the p.G230V mutant retains normal catalytic activity but is proteotoxic, undergoing Golgi mislocalization, accelerated proteasomal degradation, and augmented UPR activation that reduces neuronal viability; structural modeling implicated disruption of a conserved disulfide bond linking Loop 2 and Loop 6.","evidence":"Enzymatic activity assays in patient fibroblasts, proteasome inhibitor treatment, UPR reporter assays in cortical neurons, homology modeling","pmids":["37199746"],"confidence":"High","gaps":["No experimental structure of ELOVL5 to validate the Loop 2–Loop 6 disulfide model","Whether other SCA38 mutations share the same proteotoxic mechanism untested"]},{"year":2023,"claim":"Elovl5 loss on an LDLR-deficient background activated SREBP-1, increased hepatic and plasma lipids, and caused atherosclerosis, demonstrating that ELOVL5 deficiency drives cardiovascular disease through the same SREBP-1 derepression mechanism identified in 2008.","evidence":"Elovl5−/−;Ldlr−/− double knockout mice with lipoprotein profiling and aortic plaque quantification","pmids":["38000296"],"confidence":"Medium","gaps":["Contribution of macrophage-intrinsic vs. hepatic Elovl5 loss to atherosclerosis not dissected","Whether ELOVL5 products directly influence vascular wall lipid metabolism unknown"]},{"year":2024,"claim":"miR-218-5p was validated as a direct ELOVL5 repressor in mammalian hepatocytes, with epistasis (si-Elovl5 blocking miR-218-5p inhibitor effects) confirming ELOVL5 as the functional target mediating miR-218-5p's pro-lipogenic action via SREBP1 in NAFLD.","evidence":"Dual luciferase reporter, miR gain/loss-of-function with si-Elovl5 epistasis in AML12 cells and HFD mouse model","pmids":["38972428"],"confidence":"Medium","gaps":["Whether miR-218-5p regulation of ELOVL5 is relevant beyond the liver not tested","Upstream signals controlling miR-218-5p in NAFLD not identified"]},{"year":2025,"claim":"Direct electrophysiological evidence linked ELOVL5-dependent synaptosomal lipid composition to synaptic function: Elovl5 loss impairs readily releasable pool replenishment at climbing fiber and parallel fiber synapses and shortens endocannabinoid-mediated suppression of excitation in Purkinje cells, providing a synaptic mechanism for SCA38 cerebellar dysfunction.","evidence":"Elovl5 KO mice with paired-pulse and high-frequency stimulation electrophysiology in Purkinje cells plus synaptosome lipidomics","pmids":["40789653"],"confidence":"High","gaps":["Specific lipid species responsible for vesicle replenishment deficit not identified","Whether exogenous PUFA supplementation rescues synaptic phenotypes not tested"]},{"year":2025,"claim":"A novel non-enzymatic function was uncovered: ELOVL5 physically interacts with STING and prevents TBK1 recruitment and STING translocation to the Golgi, restraining innate inflammatory signaling and facilitating lung tissue repair after influenza infection.","evidence":"In vivo CRISPR screen, conditional KO in lung epithelial cells, ELOVL5–STING co-immunoprecipitation, STING–TBK1 interaction and Golgi trafficking assays (preprint)","pmids":[],"confidence":"Medium","gaps":["Preprint; not yet peer-reviewed","Whether STING binding depends on ELOVL5 enzymatic activity or is independent not determined","Reciprocal IP and domain mapping not reported"]},{"year":null,"claim":"Major unresolved questions include the atomic structure of ELOVL5, the identity of specific PUFA species mediating AKT-mTOR activation versus synaptic function, reconciliation of oncogenic versus tumor-suppressive roles across cancer types, and whether the STING-binding function is enzymatic-activity-independent.","evidence":"","pmids":[],"confidence":"Low","gaps":["No experimental structure (X-ray or cryo-EM) of any mammalian ELOVL family member","Specific lipid mediators linking ELOVL5 products to AKT phosphorylation unidentified","Therapeutic window for ELOVL5 modulation in cancer or neurodegeneration unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,3,12,14]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,2,21]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[4,11]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[4,11]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,2,3,12,14]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,8,9]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,5,11]},{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[14]}],"complexes":[],"partners":["STING","SREBF1","RICTOR"],"other_free_text":[]},"mechanistic_narrative":"ELOVL5 is an endoplasmic reticulum-resident fatty acid elongase that catalyzes the condensation step in elongation of C18 and C20 polyunsaturated fatty acids—including gamma-linolenic acid, stearidonic acid, and eicosapentaenoic acid—to longer-chain PUFAs such as arachidonic acid, DHA, and cis-vaccenic acid, but cannot elongate C22 PUFAs owing to a tryptophan residue at the position equivalent to Cys-217 of ELOVL2 [PMID:18838740, PMID:23873268]. The PUFA products of ELOVL5 feed back to suppress SREBP-1c-driven lipogenesis, activate PPARβ-dependent triglyceride catabolism via ATGL induction, and stimulate the mTORC2–Akt2–FoxO1 axis to restrain gluconeogenesis [PMID:18838740, PMID:23099444, PMID:24814977]. Missense mutations (e.g., p.G230V) cause spinocerebellar ataxia type 38 (SCA38) not through loss of catalytic activity but via protein misfolding, Golgi mislocalization, proteasomal degradation, and ER-stress-mediated Purkinje cell toxicity, while complete Elovl5 loss alters synaptosomal PUFA composition and impairs synaptic vesicle replenishment and endocannabinoid-mediated plasticity in cerebellar circuits [PMID:25065913, PMID:37199746, PMID:40789653]. In multiple cancer types, ELOVL5-dependent elongation sustains membrane phospholipid acyl-chain composition, supports mitochondrial function, and activates AKT–mTOR signaling to drive proliferation, survival, and metastasis [PMID:33547161, PMID:35670054, PMID:34439125]."},"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). 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Biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/41329269","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":40070,"output_tokens":6504,"usd":0.108885},"stage2":{"model":"claude-opus-4-6","input_tokens":10089,"output_tokens":4437,"usd":0.242055},"total_usd":0.35094,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2008,\n      \"finding\": \"ELOVL5 is required in vivo 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); deletion of Elovl5 in mice reduces arachidonic acid and DHA levels, which activates SREBP-1c and its target genes, leading to hepatic steatosis reversible by dietary arachidonic acid and DHA supplementation.\",\n      \"method\": \"Elovl5 knockout mouse model, liver microsomal enzyme assay, dietary supplementation rescue\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vivo knockout with biochemical substrate/product profiling, mechanistic pathway placement, and dietary rescue confirming causality; replicated in multiple follow-up studies\",\n      \"pmids\": [\"18838740\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Elovl5 controls gluconeogenesis through the mTORC2-Akt2-FoxO1 pathway: elevated Elovl5 activity increases cis-vaccenic acid (18:1 n-7) synthesis, induces rictor mRNA and protein, promotes rictor-mTOR interaction, and selectively phosphorylates Akt2-S473 (mTORC2 site) but not Akt2-T308, leading to FoxO1-S256 phosphorylation and reduced nuclear FoxO1; rictor knockdown blocks these effects.\",\n      \"method\": \"Adenoviral overexpression of Elovl5 in obese mice and HepG2 cells, Akt inhibitor treatment, rictor siRNA knockdown, fatty acid analysis, phospho-specific Western blotting\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (gain-of-function, inhibitor, siRNA knockdown, fatty acid supplementation) in both in vivo and in vitro systems by same lab\",\n      \"pmids\": [\"23099444\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Elovl5 activity regulates hepatic triglyceride catabolism in obese mice by producing fatty acid products (including cis-vaccenic acid) that activate PPARβ-dependent induction of ATGL (adipocyte triglyceride lipase) mRNA and protein, thereby promoting TG catabolism without affecting β-oxidation capacity; Elovl5 also reduces ER stress markers.\",\n      \"method\": \"Adenoviral Elovl5 overexpression in obese C57BL/6J mice, PPARβ agonist treatment, siRNA knockdown, fatty acyl carnitine profiling, Western blotting\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo and in vitro complementary approaches with pharmacological and genetic dissection of pathway\",\n      \"pmids\": [\"24814977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The differential ability of rat Elovl5 vs Elovl2 to elongate C22 omega-3 docosapentaenoic acid (DPA, 22:5n-3) to 24:5n-3 is determined by a single residue: cysteine at position 217 in Elovl2 (critical for DPA elongation) vs tryptophan at the equivalent position in Elovl5 (which cannot elongate DPA); this was established by chimeric protein and point mutation analysis in a yeast expression system.\",\n      \"method\": \"Yeast heterologous expression, Elovl2/Elovl5 chimeras, site-directed mutagenesis, fatty acid profiling\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution with point mutagenesis identifying specific catalytic residue differences\",\n      \"pmids\": [\"23873268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ELOVL5 missense mutations (p.Gly230Val and p.Leu72Val) cause spinocerebellar ataxia type 38 (SCA38); mutant ELOVL5 shows aberrant perinuclear/Golgi accumulation rather than the normal widespread ER distribution, and affected individuals have reduced serum arachidonic acid and DHA.\",\n      \"method\": \"Linkage analysis, targeted resequencing, Sanger sequencing in families, transfection with subcellular localization imaging (immunofluorescence), serum fatty acid profiling\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic identification plus functional subcellular localization experiments in transfected cells with clinical biochemical correlation\",\n      \"pmids\": [\"25065913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Elovl5 knockout mice develop progressive motor deficits (beam balance test), hyposmia, and cerebellar atrophy with reduced molecular layer thickness and decreased distal Purkinje cell dendritic arborization (by Sholl analysis of biocytin-filled PCs), recapitulating SCA38 symptoms; dendritic spine density is preserved.\",\n      \"method\": \"Elovl5 knockout mouse model, behavioral testing, morphometric cerebellar analysis, biocytin filling with Sholl dendritic analysis\",\n      \"journal\": \"Frontiers in cellular neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean knockout with defined cellular and behavioral phenotypes, multiple quantitative morphological readouts\",\n      \"pmids\": [\"29163054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ELOVL5 is directly transcriptionally induced by the androgen receptor (AR) in prostate cancer; ELOVL5 depletion alters mitochondrial morphology and function, increases reactive oxygen species, and suppresses prostate cancer cell proliferation, 3D growth, and in vivo tumor growth and metastasis; supplementation with cis-vaccenic acid (a direct ELOVL5 elongation product) reverses oxidative stress and proliferation/migration defects of ELOVL5 knockdown.\",\n      \"method\": \"Transcriptomics, ChIP, ELOVL5 siRNA/shRNA knockdown, mass spectrometry lipidomics, ROS assays, mitochondrial function assays, xenograft mouse models, cis-vaccenic acid supplementation rescue\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods including in vitro and in vivo models with substrate rescue experiment confirming mechanistic specificity\",\n      \"pmids\": [\"33547161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Two SREBP binding sites in the human ELOVL5 gene (one ~10 kb upstream, one in exon 1) are identified as functional enhancer elements conserved among mammals; SREBP activates ELOVL5 transcription through these SRE motifs, establishing ELOVL5 as a direct SREBP-1 target gene within a negative feedback loop of de novo lipogenesis.\",\n      \"method\": \"Promoter/enhancer deletion analysis, luciferase reporter assays, electrophoretic mobility shift assay (EMSA)\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reporter assays and EMSA in a single study identify functional cis-regulatory elements\",\n      \"pmids\": [\"26321664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ELOVL5-mediated fatty acid elongation in renal cell carcinoma promotes AKT Ser473 phosphorylation and AKT-mTOR-STAT3 signaling, supporting cell invasion via CCL2 upregulation; ELOVL5 knockout suppresses lipid droplet formation and induces apoptosis via ER stress; supplementation with arachidonic acid and EPA partially reverses proliferation and invasion defects.\",\n      \"method\": \"CRISPR/Cas9 ELOVL5 knockout, LC-MS lipidomics, Western blotting for AKT/mTOR/STAT3 signaling, fatty acid supplementation rescue, in vivo xenograft\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic knockout with signaling pathway analysis and substrate rescue in single study\",\n      \"pmids\": [\"35670054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ELOVL5-mediated PUFA elongation enhances lipid raft-associated AKT-mTOR signaling, contributing to enzalutamide resistance in neuroendocrine-like prostate cancer cells; ELOVL5 knockdown reduces neuroendocrine phenotype and resistance, while overexpression augments resistance in vitro and in vivo.\",\n      \"method\": \"shRNA knockdown, ELOVL5 overexpression, enzalutamide resistance assays, lipid raft isolation, AKT-mTOR signaling Western blotting, xenograft models\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — gain- and loss-of-function with signaling pathway analysis in single lab study\",\n      \"pmids\": [\"34439125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Downregulation of ELOVL5 in breast cancer promotes EMT, cell invasion, and lung metastasis through lipid-droplet accumulation-dependent Smad2 acetylation, which upregulates TGF-β receptors; inhibition of TGF-β receptors or diacylglycerol acyltransferase (blocking lipid droplet formation) reverses invasion and metastasis caused by ELOVL5 loss.\",\n      \"method\": \"shRNA knockdown, lipid droplet imaging, TGF-β receptor inhibitor treatment, DGAT inhibitor treatment, Smad2 acetylation assay, murine breast cancer metastasis models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple pharmacological and genetic interventions establishing pathway sequence in single study\",\n      \"pmids\": [\"36056008\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The SCA38-causing ELOVL5 p.G230V variant has normal enzymatic activity but is proteotoxic: it is mislocalized to the Golgi (instead of ER), undergoes increased proteasomal degradation, triggers unfolded protein response more strongly than wild-type, and decreases neuronal viability; homology modelling reveals p.G230V shifts Loop 6 and alters a conserved disulfide bond connecting Loop 2 and Loop 6 that is elongase-specific.\",\n      \"method\": \"Biochemical elongase activity assay in SCA38 fibroblasts, proteasome inhibitor treatment, UPR reporter assays in cortical neurons, immunofluorescence localization, homology structural modelling\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical activity measurement, structural modelling, UPR/viability assays, and localization studies in a single study providing mechanistic model of pathogenesis\",\n      \"pmids\": [\"37199746\"],\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 expression is significantly upregulated upon T-cell activation/proliferation, and ELOVL5 knockdown markedly impairs elongation of these substrates and alters cellular PUFA profiles; no functional ELOVL2 was detected in these cells.\",\n      \"method\": \"siRNA knockdown of ELOVL5 in primary human T-cells and Jurkat cells, exogenous PUFA incorporation assays, RT-qPCR, fatty acid profiling\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with substrate incorporation assays in primary human cells, single study\",\n      \"pmids\": [\"30293059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ELOVL5 knockdown in bovine embryos reduces the content of specific phospholipid species (phosphatidylcholines, phosphatidylethanolamines) and triacylglycerol, while increasing cytoplasmic lipid droplet deposition, demonstrating that ELOVL5 participates in embryonic lipid composition of cellular membranes.\",\n      \"method\": \"Morpholino-mediated knockdown in bovine embryos, mass spectrometry-based lipid fingerprinting, lipid droplet imaging\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with lipidomics in a clean embryo model, single study\",\n      \"pmids\": [\"33525659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In Elovl5 knockout mouse cerebellum, deletion increases 18- and 20-carbon PUFAs, decreases long-chain PUFAs, and increases saturated/monounsaturated fatty acids in synaptosomes; loss of Elovl5 impairs replenishment of the readily releasable pool of synaptic vesicles at climbing fiber and parallel fiber synapses, and shortens endocannabinoid-mediated suppression of excitation (SSE) in Purkinje cells, linking ELOVL5-dependent lipid composition to synaptic transmission and plasticity.\",\n      \"method\": \"Elovl5 knockout mice, electrophysiological recordings in Purkinje cells (paired-pulse and high-frequency stimulation protocols), synaptosome lipid analysis, SSE assays\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — clean knockout with direct electrophysiological readouts and matched lipidomics in synaptosomes, multiple synaptic measurements\",\n      \"pmids\": [\"40789653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Elovl5 expression in the adult mouse CNS is region- and cell-type-specific: highest in cerebellar Purkinje cells, mitral cells of olfactory regions, brainstem, and motor-related telencephalic regions; Elovl5 is expressed in oligodendroglial cells at various maturation stages and in microglia, with heterogeneous expression in astrocytes.\",\n      \"method\": \"Elovl5-reporter mouse line, immunofluorescence on CNS sections, primary glial cell cultures\",\n      \"journal\": \"Frontiers in neuroanatomy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct reporter/immunofluorescence localization with cellular resolution, providing functional context for SCA38 pathology\",\n      \"pmids\": [\"33994961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"ELOVL5 mRNA is specifically localized to the basal layer of sebaceous gland cells in the pheromone-producing head skin of male goats but absent in non-pheromone-producing rump skin and orchidectomized goat head skin, implicating ELOVL5 in pheromone fatty acid synthesis in sebaceous glands.\",\n      \"method\": \"In situ hybridization on goat skin sections\",\n      \"journal\": \"The Journal of reproduction and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization by in situ hybridization with appropriate negative controls (rump skin, orchidectomized animals)\",\n      \"pmids\": [\"17827874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Estrogen promotes hepatic LCPUFA synthesis by downregulating miR-218-5p, which directly targets and represses ELOVL5; miR-218-5p binds the 3'UTR of ELOVL5 (validated by luciferase reporter assay) and negatively regulates ELOVL5 mRNA and protein levels, thereby modulating PUFA biosynthesis at the post-transcriptional level.\",\n      \"method\": \"Luciferase 3'UTR reporter assay, miRNA mimic/inhibitor transfection, Western blotting, qPCR in chicken hepatocytes\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — 3'UTR reporter validation plus gain/loss-of-function miRNA experiments in single study\",\n      \"pmids\": [\"28665359\"],\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 (validated by luciferase reporter assay) and negatively regulates Elovl5 mRNA and protein; miR-21-3p mimics promote triglyceride production, an effect attributed to Elovl5 suppression.\",\n      \"method\": \"Luciferase 3'UTR reporter assay, miRNA mimic/inhibitor transfection, qPCR, Western blotting\",\n      \"journal\": \"DNA and cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct 3'UTR reporter validation plus functional miRNA experiments, single lab\",\n      \"pmids\": [\"30707627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"miR-218-5p directly targets and suppresses Elovl5 expression in mouse hepatocytes (validated by dual luciferase reporter assay); miR-218-5p inhibition upregulates Elovl5 and suppresses SREBP1-mediated lipogenesis signaling, reducing lipid accumulation in a palmitic acid-induced NAFLD model; the pro-lipogenic effect of miR-218-5p is blocked by si-Elovl5, confirming Elovl5 as the functional target.\",\n      \"method\": \"Dual luciferase reporter assay, gain/loss-of-function miRNA experiments in AML12 cells and HFD mouse model, SREBP1 pathway Western blotting\",\n      \"journal\": \"Biochemical pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — 3'UTR reporter plus in vivo/in vitro functional validation with epistasis (si-Elovl5 blocks miR-218-5p effect)\",\n      \"pmids\": [\"38972428\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Deletion of Elovl5 in LDLR-deficient mice activates SREBP-1, increases hepatic triglyceride and cholesterol, elevates VLDL/IDL/LDL plasma lipids, and results in marked aortic atherosclerotic plaques; Elovl5-deficient macrophages show slightly elevated PGE2 secretion (likely due to Cox-2) but no major differences in M1/M2 polarization markers.\",\n      \"method\": \"Elovl5-/-;Ldlr-/- double knockout mice, lipoprotein profiling, hepatic lipid analysis, aortic plaque quantification, bone marrow-derived macrophage polarization assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — double knockout model with multiple metabolic readouts and mechanistic link to SREBP-1 activation\",\n      \"pmids\": [\"38000296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ELOVL5 physically binds to STING and inhibits TBK1 interaction with STING and its translocation to the Golgi, thereby reducing STING-mediated inflammatory signaling in lung epithelial cells; Elovl5 deficiency impairs lung inflammation resolution after influenza infection and reduces AKT1-mediated tissue repair; ELOVL5 also decreases eicosanoid levels in alveolar epithelial cells.\",\n      \"method\": \"In vivo CRISPR screen (AAV9-Sleeping Beauty), Elovl5 conditional knockout in lung epithelial cells, co-immunoprecipitation of ELOVL5 with STING, STING-TBK1 interaction assay, Golgi trafficking assay, eicosanoid profiling\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP identifying novel STING binding partner plus functional in vivo screen and KO phenotype; preprint, not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ELOVL5 promotes VLC-PUFA production in HCMV-infected cells and aids removal of erucic acid (C22:1, an endogenous antiviral fatty acid) by elongation; ELOVL5 activity is stimulated by HCMV infection and reduces C22:1 levels, thereby mollifying the antiviral effect of erucic acid on virus replication.\",\n      \"method\": \"Lipidomics, erucic acid supplementation, ELOVL5 functional assay in HCMV-infected cells\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — lipidomics-based inference in single preprint; ELOVL5-specific mechanistic evidence is indirect\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ELOVL5 is a super-enhancer-driven oncogene in T-ALL; ELOVL5 knockdown suppresses T-ALL cell proliferation and induces apoptosis in vitro and reduces tumor burden in xenograft models; RNA-seq shows ELOVL5 promotes T-ALL progression by activating MYC signaling and upregulating SERBP1.\",\n      \"method\": \"H3K27ac ChIP-seq, shRNA knockdown, RNA-seq, xenograft mouse models, SERBP1 silencing\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP-seq confirming super-enhancer regulation, loss-of-function in vivo and in vitro, transcriptomic pathway analysis identifying MYC-SERBP1 axis\",\n      \"pmids\": [\"41016515\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ELOVL5 is an endoplasmic reticulum-resident, multipass transmembrane fatty acid elongase that catalyzes the rate-limiting elongation of C18 and C20 polyunsaturated fatty acids (including gamma-linolenic, stearidonic, arachidonic acid precursors, and EPA series substrates) to longer-chain PUFAs; its products—particularly arachidonic acid, DHA, EPA, and cis-vaccenic acid—act as feedback regulators of SREBP-1c-mediated lipogenesis, activate PPARβ to induce ATGL-dependent TG catabolism, and modulate the mTORC2-Akt2-FoxO1 gluconeogenic axis; SCA38-causing missense mutations (e.g., p.G230V) misfold ELOVL5, causing Golgi mislocalization, proteasomal degradation, and ER/Golgi stress-mediated proteotoxicity in Purkinje cells; loss of Elovl5 in cerebellar neurons alters synaptosomal PUFA composition and impairs synaptic vesicle replenishment and endocannabinoid-mediated plasticity; in cancer contexts, ELOVL5-dependent lipid elongation sustains phospholipid acyl-chain length in membranes, supports mitochondrial function, activates AKT-mTOR signaling, and drives proliferation and metastasis, while ELOVL5 also physically interacts with STING to restrain innate inflammatory signaling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ELOVL5 is an endoplasmic reticulum-resident fatty acid elongase that catalyzes the condensation step in elongation of C18 and C20 polyunsaturated fatty acids—including gamma-linolenic acid, stearidonic acid, and eicosapentaenoic acid—to longer-chain PUFAs such as arachidonic acid, DHA, and cis-vaccenic acid, but cannot elongate C22 PUFAs owing to a tryptophan residue at the position equivalent to Cys-217 of ELOVL2 [PMID:18838740, PMID:23873268]. The PUFA products of ELOVL5 feed back to suppress SREBP-1c-driven lipogenesis, activate PPARβ-dependent triglyceride catabolism via ATGL induction, and stimulate the mTORC2–Akt2–FoxO1 axis to restrain gluconeogenesis [PMID:18838740, PMID:23099444, PMID:24814977]. Missense mutations (e.g., p.G230V) cause spinocerebellar ataxia type 38 (SCA38) not through loss of catalytic activity but via protein misfolding, Golgi mislocalization, proteasomal degradation, and ER-stress-mediated Purkinje cell toxicity, while complete Elovl5 loss alters synaptosomal PUFA composition and impairs synaptic vesicle replenishment and endocannabinoid-mediated plasticity in cerebellar circuits [PMID:25065913, PMID:37199746, PMID:40789653]. In multiple cancer types, ELOVL5-dependent elongation sustains membrane phospholipid acyl-chain composition, supports mitochondrial function, and activates AKT–mTOR signaling to drive proliferation, survival, and metastasis [PMID:33547161, PMID:35670054, PMID:34439125].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Establishing that ELOVL5 expression is tissue- and hormone-regulated: ELOVL5 mRNA was detected specifically in the basal layer of androgen-dependent sebaceous glands, linking the elongase to specialized lipid production in a defined secretory cell type.\",\n      \"evidence\": \"In situ hybridization on goat head vs. rump skin and orchidectomized controls\",\n      \"pmids\": [\"17827874\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct functional assay of ELOVL5 enzymatic activity in these cells\", \"Relevance to human sebaceous biology not tested\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"The first loss-of-function model established ELOVL5 as the in vivo enzyme required for elongating C18:3 n-6 → C20:3 n-6 and C18:4 n-3 → C20:4 n-3, and revealed that the resulting arachidonic acid and DHA depletion derepresses SREBP-1c, causing hepatic steatosis—thereby placing ELOVL5 products as feedback regulators of lipogenic transcription.\",\n      \"evidence\": \"Elovl5 knockout mouse with hepatic microsomal assays and dietary AA/DHA rescue\",\n      \"pmids\": [\"18838740\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for substrate specificity unknown\", \"Whether ELOVL5 is rate-limiting in all tissues not addressed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Beyond lipogenesis, ELOVL5 was linked to glucose metabolism: its product cis-vaccenic acid induces rictor expression, enhances mTORC2-dependent Akt2 S473 phosphorylation, and promotes FoxO1 phosphorylation to suppress gluconeogenesis, establishing a lipid-to-glucose regulatory circuit.\",\n      \"evidence\": \"Adenoviral Elovl5 overexpression in obese mice and HepG2 cells with rictor siRNA epistasis and phospho-specific Western blotting\",\n      \"pmids\": [\"23099444\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether cis-vaccenic acid acts directly on rictor transcription or through an intermediate is unclear\", \"Physiological relevance in lean animals not shown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"The molecular determinant distinguishing ELOVL5 from ELOVL2 substrate range was identified: a tryptophan at the position equivalent to Cys-217 of ELOVL2 prevents ELOVL5 from elongating C22 PUFAs, providing the first structural-level insight into elongase substrate selectivity.\",\n      \"evidence\": \"Chimeric Elovl2/Elovl5 proteins and point mutagenesis in yeast heterologous expression\",\n      \"pmids\": [\"23873268\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal or cryo-EM structure of either elongase\", \"Mechanism by which this residue excludes C22 substrates not resolved at atomic level\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Two advances refined ELOVL5 biology: (1) ELOVL5 missense mutations were identified as the cause of SCA38 via linkage analysis and shown to mislocalize the protein from ER to Golgi, establishing a neurodegenerative disease mechanism; (2) ELOVL5-derived fatty acids were shown to activate PPARβ-dependent ATGL induction, adding triglyceride catabolism to ELOVL5's metabolic repertoire.\",\n      \"evidence\": \"Family-based linkage/sequencing with subcellular localization imaging (SCA38); adenoviral overexpression in obese mice with PPARβ agonist and siRNA epistasis (TG catabolism)\",\n      \"pmids\": [\"25065913\", \"24814977\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SCA38 mutations impair enzymatic activity or act purely by proteotoxicity was unresolved at this point\", \"PPARβ activation mechanism by cis-vaccenic acid not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identification of two functional SREBP binding sites in the ELOVL5 gene confirmed that SREBP-1 directly activates ELOVL5 transcription, closing a negative-feedback loop in which ELOVL5 products suppress SREBP-1c and SREBP-1c induces ELOVL5.\",\n      \"evidence\": \"Promoter deletion and luciferase reporter assays plus EMSA for SRE motifs\",\n      \"pmids\": [\"26321664\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ChIP-seq confirmation in endogenous chromatin not performed\", \"Relative contribution of each SRE not quantified in vivo\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Two studies expanded ELOVL5 regulation and disease modeling: miR-218-5p was validated as a direct post-transcriptional repressor of ELOVL5 linking estrogen signaling to PUFA synthesis, and Elovl5 knockout mice were shown to recapitulate SCA38 with progressive motor deficits, cerebellar atrophy, and reduced Purkinje cell dendritic arborization.\",\n      \"evidence\": \"Luciferase 3'UTR reporter assay and miRNA gain/loss-of-function in chicken hepatocytes (miR-218-5p); Elovl5 KO mice with behavioral and morphometric cerebellar analysis (SCA38 model)\",\n      \"pmids\": [\"28665359\", \"29163054\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Synaptic and electrophysiological consequences of Elovl5 loss not yet examined\", \"Whether miR-218-5p regulates ELOVL5 in mammalian hepatocytes not shown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"ELOVL5 was established as the dominant elongase for C18–C20 PUFA elongation in human T cells, with expression upregulated upon T-cell activation, extending its physiological relevance to adaptive immunity.\",\n      \"evidence\": \"siRNA knockdown in primary human T cells and Jurkat cells with exogenous PUFA incorporation assays\",\n      \"pmids\": [\"30293059\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequences for T-cell effector function not tested\", \"Whether other elongases compensate during prolonged activation unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Multiple cancer studies converged to establish ELOVL5 as a driver of oncogenic lipid metabolism: in prostate cancer it is an AR target gene whose product cis-vaccenic acid sustains mitochondrial function and suppresses ROS; in renal cell carcinoma ELOVL5 promotes AKT-mTOR-STAT3 signaling and invasion; and its elongation products enhance lipid-raft AKT-mTOR signaling to drive enzalutamide resistance in neuroendocrine prostate cancer.\",\n      \"evidence\": \"ChIP, siRNA/shRNA/CRISPR KO, xenografts, lipidomics, and cis-vaccenic acid/AA/EPA rescue across multiple cancer cell models\",\n      \"pmids\": [\"33547161\", \"35670054\", \"34439125\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ELOVL5 inhibition has therapeutic selectivity over normal tissues is untested\", \"Direct lipid species mediating AKT activation not identified\", \"Contribution of specific PUFA products vs. total elongation flux unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Regional mapping in the CNS revealed that Elovl5 is most highly expressed in cerebellar Purkinje cells and olfactory mitral cells, directly explaining the selective vulnerability of these neurons in SCA38.\",\n      \"evidence\": \"Elovl5-reporter mouse line with immunofluorescence across CNS regions and glial cultures\",\n      \"pmids\": [\"33994961\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of Elovl5 in oligodendrocytes and microglia not explored\", \"Whether regional expression differences translate to differing lipid profiles not shown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"An unexpected tumor-suppressive role was demonstrated: ELOVL5 loss in breast cancer promotes EMT and metastasis through lipid droplet accumulation, Smad2 acetylation, and TGFβ receptor upregulation, contrasting with its oncogenic role in other cancers and revealing context-dependent functions.\",\n      \"evidence\": \"shRNA knockdown, lipid droplet imaging, TGFβR and DGAT inhibitor epistasis, murine metastasis models\",\n      \"pmids\": [\"36056008\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which lipid droplet accumulation drives Smad2 acetylation not defined\", \"Reconciliation of tumor-suppressive vs. oncogenic roles across cancer types lacking\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"The SCA38 pathomechanism was refined: the p.G230V mutant retains normal catalytic activity but is proteotoxic, undergoing Golgi mislocalization, accelerated proteasomal degradation, and augmented UPR activation that reduces neuronal viability; structural modeling implicated disruption of a conserved disulfide bond linking Loop 2 and Loop 6.\",\n      \"evidence\": \"Enzymatic activity assays in patient fibroblasts, proteasome inhibitor treatment, UPR reporter assays in cortical neurons, homology modeling\",\n      \"pmids\": [\"37199746\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No experimental structure of ELOVL5 to validate the Loop 2–Loop 6 disulfide model\", \"Whether other SCA38 mutations share the same proteotoxic mechanism untested\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Elovl5 loss on an LDLR-deficient background activated SREBP-1, increased hepatic and plasma lipids, and caused atherosclerosis, demonstrating that ELOVL5 deficiency drives cardiovascular disease through the same SREBP-1 derepression mechanism identified in 2008.\",\n      \"evidence\": \"Elovl5−/−;Ldlr−/− double knockout mice with lipoprotein profiling and aortic plaque quantification\",\n      \"pmids\": [\"38000296\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Contribution of macrophage-intrinsic vs. hepatic Elovl5 loss to atherosclerosis not dissected\", \"Whether ELOVL5 products directly influence vascular wall lipid metabolism unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"miR-218-5p was validated as a direct ELOVL5 repressor in mammalian hepatocytes, with epistasis (si-Elovl5 blocking miR-218-5p inhibitor effects) confirming ELOVL5 as the functional target mediating miR-218-5p's pro-lipogenic action via SREBP1 in NAFLD.\",\n      \"evidence\": \"Dual luciferase reporter, miR gain/loss-of-function with si-Elovl5 epistasis in AML12 cells and HFD mouse model\",\n      \"pmids\": [\"38972428\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether miR-218-5p regulation of ELOVL5 is relevant beyond the liver not tested\", \"Upstream signals controlling miR-218-5p in NAFLD not identified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Direct electrophysiological evidence linked ELOVL5-dependent synaptosomal lipid composition to synaptic function: Elovl5 loss impairs readily releasable pool replenishment at climbing fiber and parallel fiber synapses and shortens endocannabinoid-mediated suppression of excitation in Purkinje cells, providing a synaptic mechanism for SCA38 cerebellar dysfunction.\",\n      \"evidence\": \"Elovl5 KO mice with paired-pulse and high-frequency stimulation electrophysiology in Purkinje cells plus synaptosome lipidomics\",\n      \"pmids\": [\"40789653\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific lipid species responsible for vesicle replenishment deficit not identified\", \"Whether exogenous PUFA supplementation rescues synaptic phenotypes not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A novel non-enzymatic function was uncovered: ELOVL5 physically interacts with STING and prevents TBK1 recruitment and STING translocation to the Golgi, restraining innate inflammatory signaling and facilitating lung tissue repair after influenza infection.\",\n      \"evidence\": \"In vivo CRISPR screen, conditional KO in lung epithelial cells, ELOVL5–STING co-immunoprecipitation, STING–TBK1 interaction and Golgi trafficking assays (preprint)\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint; not yet peer-reviewed\", \"Whether STING binding depends on ELOVL5 enzymatic activity or is independent not determined\", \"Reciprocal IP and domain mapping not reported\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major unresolved questions include the atomic structure of ELOVL5, the identity of specific PUFA species mediating AKT-mTOR activation versus synaptic function, reconciliation of oncogenic versus tumor-suppressive roles across cancer types, and whether the STING-binding function is enzymatic-activity-independent.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No experimental structure (X-ray or cryo-EM) of any mammalian ELOVL family member\", \"Specific lipid mediators linking ELOVL5 products to AKT phosphorylation unidentified\", \"Therapeutic window for ELOVL5 modulation in cancer or neurodegeneration unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 3, 12, 14]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 2, 21]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [4, 11]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [4, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 2, 3, 12, 14]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 8, 9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 5, 11]},\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [14]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"STING\",\n      \"SREBF1\",\n      \"RICTOR\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}