Affinage

ELOVL1

Very long chain fatty acid elongase 1 · UniProt Q9BW60

Length
279 aa
Mass
32.7 kDa
Annotated
2026-04-28
33 papers in source corpus 15 papers cited in narrative 14 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

ELOVL1 is a ubiquitously expressed microsomal fatty acid elongase that catalyzes the rate-limiting condensation step in very long-chain fatty acid (VLCFA) synthesis, preferentially elongating saturated and monounsaturated C20–C22-CoA substrates to C24–C26 products that serve as precursors for sphingolipids, acylceramides, and meibum wax esters (PMID:20937905, PMID:20166112). Its activity is coordinated with ceramide synthases CERS2 and CERS3 to match acyl-CoA production with utilization, and is essential for epidermal permeability barrier formation, tear film lipid integrity, and myelin sphingolipid composition, as demonstrated by neonatal lethality from barrier failure in knockout mice and hypomyelination with behavioral deficits in mutant mice (PMID:23689133, PMID:29401594, PMID:32123819). Dominant (p.S165F) and recessive loss-of-function mutations in human ELOVL1 cause ichthyosis, hypomyelination, and spastic paraplegia, with patient fibroblasts and stratum corneum showing severe reductions in ≥C24 ceramides and sphingomyelins (PMID:30487246, PMID:35379526). In CD8+ T cells, ELOVL1 inactivation shifts fatty acid pools to destabilize INSIG1, activate SREBP2-dependent cholesterol biosynthesis, increase membrane cholesterol, and enhance T cell receptor signaling and antitumor function (PMID:40065102).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2002 Medium

    Initial genomic characterization established that Elovl1 encodes a ubiquitously expressed microsomal enzyme involved in VLCFA and sphingolipid synthesis, providing the gene identity needed for subsequent functional studies.

    Evidence Genomic cloning, sequencing, and Northern blot analysis in mouse

    PMID:11891222

    Open questions at the time
    • Single descriptive study without enzymatic characterization
    • No substrate specificity determined
    • No loss-of-function data
  2. 2010 High

    Biochemical comparison of all seven ELOVL family members revealed that ELOVL1 is the primary elongase for saturated and monounsaturated C20–C22-CoAs to C24–C26, resolving which elongase produces the bulk of VLCFA for sphingolipid synthesis and establishing that elevated C26:0 in X-ALD reflects increased substrate availability rather than ELOVL1 overexpression.

    Evidence In vitro elongase activity assays across all ELOVLs; stable isotope elongation assays and siRNA knockdown in X-ALD patient fibroblasts; GC-MS profiling

    PMID:20166112 PMID:20937905

    Open questions at the time
    • No in vivo genetic confirmation yet in mammals
    • Regulation of ELOVL1 expression and activity incompletely defined
    • Precise mechanism of ELOVL1–CERS2 co-regulation unknown
  3. 2013 High

    Genetic knockout in mice demonstrated that Elovl1 is non-redundant and essential for epidermal barrier function: loss of Elovl1 shortened ceramide acyl chains below C26, disrupted lipid lamellae, and caused neonatal lethality, establishing the physiological requirement for ELOVL1 in skin.

    Evidence Elovl1 knockout mice; stratum corneum lipidomics; ultrastructural analysis; CerS2/CerS3 immunofluorescence

    PMID:23689133

    Open questions at the time
    • Contribution to non-epidermal tissues not yet assessed in this model
    • Whether CerS3 can partially compensate in specific skin layers unclear
    • No human genetic confirmation at this time
  4. 2014 High

    Pharmacological studies showed that Lorenzo's oil fatty acids and fibrate-CoA esters inhibit ELOVL1 via mixed inhibition kinetics, identifying ELOVL1 as a druggable target for reducing pathological VLCFA accumulation.

    Evidence Microsomal ELOVL1 activity assays with kinetic analysis; LC-MS/MS cellular sphingomyelin profiling; inhibition studies in X-ALD fibroblasts

    PMID:24489110 PMID:25499606

    Open questions at the time
    • In vivo efficacy of ELOVL1 inhibition for X-ALD not demonstrated
    • No selective small-molecule ELOVL1 inhibitor developed
    • Structural basis for inhibitor binding unknown
  5. 2018 High

    A dominant de novo ELOVL1 mutation (p.S165F) was shown to abolish enzymatic activity and cause ichthyosis, hypomyelination, spastic paraplegia, and optic atrophy in humans, while tissue-specific knockout in mice revealed ELOVL1's essential role in meibum VLCFA synthesis and tear film integrity, together extending the phenotypic spectrum from skin to brain and eye.

    Evidence Patient fibroblast isotope-labelled elongation assays and LC-MS/MS; tissue-specific Elovl1 knockout mice with meibum lipidomics and ocular phenotyping

    PMID:29401594 PMID:29496980 PMID:30487246

    Open questions at the time
    • Genotype–phenotype correlations across multiple mutations not established
    • Whether dominant-negative vs. haploinsufficiency mechanism applies unclear
    • No therapeutic rescue in human disease attempted
  6. 2019 High

    Brain-focused analysis of Elovl1 mutant mice revealed shortened sphingolipid acyl chains, reduced galactosylceramide, modest hypomyelination of large-diameter axons, and behavioral deficits, establishing ELOVL1's specific contribution to CNS myelin lipid composition.

    Evidence Brain lipidomics; corpus callosum electron microscopy; motor coordination and acoustic startle behavioral testing in Elovl1 mutant mice

    PMID:32123819

    Open questions at the time
    • Degree to which other elongases compensate in brain not quantified
    • Impact on peripheral nervous system myelin not assessed
    • Mechanism linking shortened acyl chains to hypomyelination not defined
  7. 2022 Medium

    Identification of a homozygous splice site mutation confirmed autosomal recessive ELOVL1 deficiency as a human disease with severe acylceramide loss in stratum corneum, complementing the earlier dominant mutation and broadening the genetic landscape.

    Evidence Whole exome sequencing; RNA splicing analysis; LC-MS/MS ceramide profiling of patient stratum corneum

    PMID:35379526

    Open questions at the time
    • Single family reported
    • Functional rescue not performed
    • CNS phenotype characterization limited
  8. 2024 Medium

    Simvastatin was shown to downregulate ELOVL1 expression in astrocytes via mTOR inhibition, and astrocytic ELOVL1 overexpression partially reversed neuroprotection, placing ELOVL1 as a mediator of VLCFA-dependent neurotoxicity downstream of mTOR signaling after traumatic brain injury.

    Evidence Cryogenic TBI mouse model; AAV-mediated astrocytic ELOVL1 overexpression; mTOR pathway analysis; cortical VLCFA quantification

    PMID:39243948

    Open questions at the time
    • Causal link between specific VLCFA species and neurotoxicity not fully resolved
    • Single pharmacological agent used to define pathway
    • Not confirmed in human astrocytes
  9. 2025 High

    A CRISPR metabolic screen in CD8+ T cells uncovered a non-canonical role for ELOVL1: its loss shifts fatty acid composition to destabilize INSIG1, activate SREBP2-mediated cholesterol synthesis, increase plasma membrane cholesterol, and amplify TCR signaling, enhancing antitumor T cell function in vivo.

    Evidence Genome-wide CRISPR/Cas9 screen; single-cell RNA-seq; adoptive T cell transfer; INSIG1/SREBP2 pathway analysis; metabolic profiling

    PMID:40065102

    Open questions at the time
    • Specific ELOVL1 substrate(s) responsible for INSIG1 destabilization not identified at lipid species level
    • Impact on other immune cell types unknown
    • Therapeutic window for T cell-directed ELOVL1 inhibition not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for ELOVL1 substrate selectivity and inhibitor binding, the development of selective ELOVL1 inhibitors suitable for clinical use, the full genotype–phenotype spectrum of ELOVL1 deficiency in humans, and the molecular mechanism linking shortened acyl-chain sphingolipids to hypomyelination.
  • No crystal or cryo-EM structure of ELOVL1
  • No selective small-molecule inhibitor advanced to preclinical studies
  • Mechanism by which C24-sphingolipid loss causes myelin instability not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 5
Localization
GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-1430728 Metabolism 7 R-HSA-168256 Immune System 1
Partners
CERS2CERS3INSIG1

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 ELOVL1 exhibits high enzymatic activity toward saturated and monounsaturated C20- and C22-CoAs, catalyzing their elongation to C24-CoA, and is essential for the production of C24 sphingolipids; its activity is co-regulated with ceramide synthase CERS2 to coordinate C24-CoA production with utilization; knockdown of ELOVL1 reduces LYN kinase activity, confirming C24-sphingolipid importance in membrane microdomain function. In vitro elongase activity assay with all seven ELOVL family members; siRNA knockdown; LYN kinase activity measurement Proceedings of the National Academy of Sciences of the United States of America High 20937905
2010 ELOVL1 is the single elongase responsible for synthesizing both saturated VLCFA (C26:0) and monounsaturated VLCFA (C26:1) from C22 substrates; ELOVL1 knockdown reduces C22:0-to-C26:0 elongation and lowers C26:0 levels in X-ALD fibroblasts, demonstrating that elevated C26:0 in X-ALD results from increased substrate availability (cytosolic VLCFA-CoA) rather than increased ELOVL1 expression. Stable isotope elongation assay; siRNA knockdown of ELOVL1 in X-ALD fibroblasts; GC-MS fatty acid profiling EMBO molecular medicine High 20166112
2013 Elovl1 knockout mice die shortly after birth due to epidermal barrier defects; in the epidermis, loss of Elovl1 reduces ceramides with ≥C26 fatty acids and increases ceramides with ≤C24 fatty acids, and reduces C24 sphingomyelin; CerS2 and CerS3, expressed in epidermal-layer-specific manner, regulate Elovl1 to produce acyl-CoAs of different chain lengths, establishing Elovl1 as a key determinant of epidermal ceramide chain length. Elovl1 knockout mouse generation; lipidomics of stratum corneum; ultrastructural analysis of lipid lamellae; immunofluorescence for CerS2/CerS3 Molecular and cellular biology High 23689133
2014 Oleic and erucic acids (components of Lorenzo's oil) inhibit ELOVL1 in a mixed (non-competitive) inhibition kinetics manner; the 4:1 mixture (Lorenzo's oil composition) shows the most potent inhibitory activity and reduces saturated VLCFA-sphingomyelin levels in cells, suggesting ELOVL1 inhibition underlies Lorenzo's oil mechanism of action. ELOVL1 activity assay with kinetic analysis; cellular sphingomyelin profiling by LC-MS/MS Journal of lipid research High 24489110
2014 CoA esters of bezafibrate and gemfibrozil specifically inhibit ELOVL1 enzymatic activity; kinetic characterization using microsomal fractions from ELOVL1-overexpressing HEK293 cells established that fibrates act as inhibitors of ELOVL1-mediated chain elongation. Microsomal elongation assay from ELOVL1-overexpressing HEK293 cells; inhibition kinetics with fibrate CoA esters; X-ALD fibroblast elongation assay Biochimica et biophysica acta High 25499606
2018 A dominant de novo ELOVL1 mutation (p.S165F) abrogates ELOVL1 enzymatic activity, reduces ≥C24 ceramides and sphingomyelins in patient fibroblasts, and causes ichthyosis, hypomyelination, spastic paraplegia, and optic atrophy; loading fibroblasts with C22:0-VLCFAs increased C24:0-ceramides and sphingomyelins, and competitive inhibition between saturated and monounsaturated VLCFAs for ceramide and sphingomyelin synthesis was identified. Stable isotope-labelled [13C]malonyl-CoA elongation assay; LC-MS/MS ceramide/sphingomyelin quantification; patient fibroblast studies; VLCFA loading experiments Journal of medical genetics High 29496980 30487246
2018 Elovl1 gene disruption in mice shortens acyl chain lengths in cholesteryl esters and wax esters in meibum lipids, causing dry eye phenotypes (increased eye-blink frequency, elevated water evaporation from ocular surface); aged Elovl1 mutant mice develop corneal opacity, establishing ELOVL1 as the primary elongase for saturated VLC meibum fatty acids and as essential for tear film lipid barrier function. Tissue-specific Elovl1 knockout mice; meibum lipid profiling; eye-blink frequency measurement; corneal phenotype analysis FASEB journal High 29401594
2019 Elovl1 mutant mice show markedly shortened acyl chain lengths of sphingolipids (galactosylceramides, sulfatides, sphingomyelins, ceramides) in the brain, reduced galactosylceramide levels, modest hypomyelination especially in large-diameter axons, and behavioral deficits including poorer motor coordination and reduced acoustic startle response. Elovl1 mutant mouse analysis; brain lipidomics; electron microscopy of corpus callosum; behavioral testing FASEB bioAdvances High 32123819
2002 Elovl1 encodes a ubiquitously expressed microsomal enzyme involved in very long-chain fatty acid and sphingolipid synthesis; the mouse Elovl1 gene consists of eight exons spanning 5.4 kb and is arranged in a tail-to-tail array with the cell cycle gene p55Cdc, with both genes co-expressed during proliferation-differentiation transitions. Genomic cloning; DNA sequencing; Northern blot mRNA analysis The Journal of biological chemistry Medium 11891222
2016 In zebrafish, Elovl1 knockdown increases long-chain fatty acids (C14–C20) and causes lipid droplet accumulation in the swim bladder; Elovl1a and Elovl1b are required for swim bladder inflation and gene expression in swim bladder development, while Elovl1b is additionally required for kidney development and renal clearance. Morpholino knockdown of elovl1a/b in zebrafish; Oil-Red-O lipid staining; gene expression analysis; renal clearance assay Organogenesis Medium 27078170
2022 A homozygous splice site mutation in ELOVL1 (c.376-2A>G) causes exon skipping, leading to loss of ELOVL1 function with autosomal recessive inheritance; LC-MS/MS analysis of patient stratum corneum showed significant shortening of fatty acid moieties and severe reduction in acylceramide levels. Whole exome sequencing; RNA splicing analysis; LC-MS/MS ceramide profiling of stratum corneum Brain & development Medium 35379526
2025 Elovl1 inactivation in CD8+ T cells leads to accumulation of saturated long-chain fatty acids, which destabilizes INSIG1, activates SREBP2, increases plasma membrane cholesterol, and strengthens T cell receptor signaling; Elovl1-deficient T cells also show increased mitochondrial fitness and fatty acid oxidation. CRISPR/Cas9 metabolic screen; single-cell RNA sequencing; adoptive T cell transfer in vivo; INSIG1/SREBP2 pathway analysis; metabolic profiling Nature metabolism High 40065102
2024 Simvastatin downregulates ELOVL1 expression in astrocytes by inhibiting mTOR signaling after traumatic brain injury; overexpression of ELOVL1 in astrocytes partially attenuates the neuroprotective benefits of simvastatin, establishing that astrocytic ELOVL1 mediates VLCFA-dependent neurotoxicity downstream of mTOR. In vivo cryogenic TBI mouse model; AAV-mediated astrocytic ELOVL1 overexpression; mTOR pathway inhibition; saturated VLCFA quantification in cortex Brain research bulletin Medium 39243948
2025 CRISPRi screening identified ELOVL1 as a key mediator of 1-deoxy-sphingolipid (1-deoxySL) toxicity; pharmacological inhibition of ELOVL1 alleviated cellular, mitochondrial, and neuronal toxicity induced by 1-deoxySLs; mechanistic studies showed that 1-deoxyDHceramide conjugated to nervonic acid (m18:0/24:1, a product requiring ELOVL1 activity) is the principal toxic species, inducing apoptosis through mitochondrial permeability transition pore formation. CRISPRi screen; genetic knockdown; cytotoxicity assays; stable isotope-resolved lipidomics via LC-MS/MS; mPTP inhibition with cyclosporin A; BAX inhibition bioRxivpreprint Medium bio_10.1101_2025.05.13.653734

Source papers

Stage 0 corpus · 33 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingolipid synthesis. Proceedings of the National Academy of Sciences of the United States of America 296 20937905
1989 SSC1, an essential member of the yeast HSP70 multigene family, encodes a mitochondrial protein. Molecular and cellular biology 213 2674677
1987 SSC1, a member of the 70-kDa heat shock protein multigene family of Saccharomyces cerevisiae, is essential for growth. Proceedings of the National Academy of Sciences of the United States of America 168 3035571
2013 Impaired epidermal permeability barrier in mice lacking elovl1, the gene responsible for very-long-chain fatty acid production. Molecular and cellular biology 144 23689133
2010 The role of ELOVL1 in very long-chain fatty acid homeostasis and X-linked adrenoleukodystrophy. EMBO molecular medicine 136 20166112
2000 Mitochondrial Hsp70 Ssc1: role in protein folding. The Journal of biological chemistry 89 11096111
1997 Mge1 functions as a nucleotide release factor for Ssc1, a mitochondrial Hsp70 of Saccharomyces cerevisiae. Journal of molecular biology 81 9048947
2000 Role of the mitochondrial Hsp70s, Ssc1 and Ssq1, in the maturation of Yfh1. Molecular and cellular biology 74 10779357
2010 Cox25 teams up with Mss51, Ssc1, and Cox14 to regulate mitochondrial cytochrome c oxidase subunit 1 expression and assembly in Saccharomyces cerevisiae. The Journal of biological chemistry 68 21068384
2018 De novo mutation in ELOVL1 causes ichthyosis, acanthosis nigricans, hypomyelination, spastic paraplegia, high frequency deafness and optic atrophy. Journal of medical genetics 59 30487246
2018 Very long-chain tear film lipids produced by fatty acid elongase ELOVL1 prevent dry eye disease in mice. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 57 29401594
2018 Dominant ELOVL1 mutation causes neurological disorder with ichthyotic keratoderma, spasticity, hypomyelination and dysmorphic features. Journal of medical genetics 48 29496980
2014 Lorenzo's oil inhibits ELOVL1 and lowers the level of sphingomyelin with a saturated very long-chain fatty acid. Journal of lipid research 47 24489110
2001 The two mitochondrial heat shock proteins 70, Ssc1 and Ssq1, compete for the cochaperone Mge1. Journal of molecular biology 33 11601843
2014 Enzymatic characterization of ELOVL1, a key enzyme in very long-chain fatty acid synthesis. Biochimica et biophysica acta 32 25499606
2019 Reduced chain length in myelin sphingolipids and poorer motor coordination in mice deficient in the fatty acid elongase Elovl1. FASEB bioAdvances 25 32123819
2016 The fatty acid chain elongase, Elovl1, is required for kidney and swim bladder development during zebrafish embryogenesis. Organogenesis 25 27078170
2022 Hypomyelinating spastic dyskinesia and ichthyosis caused by a homozygous splice site mutation leading to exon skipping in ELOVL1. Brain & development 22 35379526
2011 Primary sequence that determines the functional overlap between mitochondrial heat shock protein 70 Ssc1 and Ssc3 of Saccharomyces cerevisiae. The Journal of biological chemistry 13 21474445
2021 Discovery and Optimization of Pyrazole Amides as Inhibitors of ELOVL1. Journal of medicinal chemistry 10 34748351
2021 Discovery of Novel, Orally Bioavailable Pyrimidine Ether-Based Inhibitors of ELOVL1. Journal of medicinal chemistry 10 34871500
2025 A functional single-cell metabolic survey identifies Elovl1 as a target to enhance CD8+ T cell fitness in solid tumours. Nature metabolism 9 40065102
2005 Mapping of 443 porcine EST improves the comparative maps for SSC1 and SSC7 with the human genome. Animal genetics 9 16167980
1999 Interaction between the nucleotide exchange factor Mge1 and the mitochondrial Hsp70 Ssc1. The Journal of biological chemistry 9 10196216
2014 Development of Cotton leaf curl virus resistant transgenic cotton using antisense ßC1 gene. Saudi journal of biological sciences 7 27081361
2002 Elovl1 and p55Cdc genes are localized in a tail-to-tail array and are co-expressed in proliferating cells. The Journal of biological chemistry 7 11891222
2024 ELOVL1 is upregulated and promotes tumor growth in hepatocellular carcinoma through regulating PI3K-AKT-mTOR signaling. Heliyon 4 39144963
2019 Homology modeling and docking analysis of ßC1 protein encoded by Cotton leaf curl Multan betasatellite with different plant flavonoids. Heliyon 3 30899831
2025 Biallelic ELOVL1 Variants Are Linked to Hypomyelinating Leukodystrophy, Movement Disorder, and Ichthyosis. Movement disorders : official journal of the Movement Disorder Society 1 40590574
2026 Time-dependent changes in meibum lipid composition and progression of dry eye following disruption of the fatty acid elongase Elovl1. The Journal of biological chemistry 0 41539567
2025 Elovl1 inhibition reduced very long chain fatty acids in a mouse model of adrenoleukodystrophy. iScience 0 40894896
2024 Delayed simvastatin treatment improves neurological recovery after cryogenic traumatic brain injury through downregulation of ELOVL1 by inhibiting mTOR signaling. Brain research bulletin 0 39243948
2019 Development of Virus Resistance Transgenic Cotton Using Cotton Leaf Curl Virus Antisense ßC1 Gene. Methods in molecular biology (Clifton, N.J.) 0 30543080