Elovl1 inhibition reduced very long chain fatty acids in a mouse model of adrenoleukodystrophy
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE281510 | GEO | 2025/06/27
REPOSITORIES: GEO
Similar Datasets
Project description:X-Adrenoleukodystrophy (X-Ald) disease progression was studied by comparing expression patterns of Abcd1 -/- mouse spinal cords from 3.5, 12 and 22 months of age compared to healthy littermates spinal cords at the same time points.
2011-01-12 | E-MTAB-79 | biostudies-arrayexpress
Project description:Saturated very long-chain fatty acids (VLCFA, ≥ C22), enriched in brain myelin and innate immune cells, accumulate in X-linked adrenoleukodystrophy (X-ALD). The severest form, inherited dysfunction of the VLCFA transporter ABCD1, underlying X-ALD, causes brain myelin destruction with infiltration of pro-inflammatory skewed monocytes/macrophages. How VLCFA levels relate to macrophage activation is unclear. Using whole transcriptome sequencing of X-ALD macrophages, we revealed that VLCFAs prime human macrophage membranes for inflammation and increase factors involved in chemotaxis and invasion. When applied externally, mimicking lipid destruction in X-ALD lesions, VLCFAs did not activate toll-like receptors in healthy cells but provoked pro-inflammatory responses through scavenger receptor CD36-mediated uptake, cumulating in JNK signalling and expression of matrix degrading enzymes and chemokine release. Following pro-inflammatory LPS-activation, VLCFA accumulated in healthy macrophages but were rapidly cleared with onset of resolution by increasing VLCFA degradation through liver-X-receptor mediated upregulation of ABCD1. ABCD1 deficiency impaired VLCFA homeostasis and prolonged pro-inflammatory gene expression. Our study uncovers a pivotal role for ABCD1, a protein linked to neuroinflammation, and associated peroxisomal VLCFA degradation in regulating macrophage plasticity.
2022-11-09 | GSE217140 | GEO
Project description:Adrenoleukodystrophy (ALD) is a rare X-linked neurogenetic disease caused by mutations in the ABCD1 gene. Currently, the molecular mechanisms underlying the onset and severity of ALD still remain unclear. For mining information on candidate genes associated with onset and severity of ALD, RNA-seq had been executed via using whole blood samples from monozygotic twin families with ALD disease. The information on candidate genes of this research had been considered as the crucial for preliminarily exploring the molecular mechanisms relating to the onset and severity of ALD, which offered novel insights and research directions for mitigating and treating the development of ALD.
2024-09-06 | GSE276153 | GEO
Project description:X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene encoding the peroxisomal ABC transporter adrenoleukodystrophy protein (ALDP). X-ALD is characterized by the accumulation of very long-chain fatty acids (VLCFA; > or =C24) in plasma and tissues. In this manuscript we provide insight into the pathway underlying the elevated levels of C26:0 in X-ALD. ALDP transports VLCFacyl-CoA across the peroxisomal membrane. A deficiency in ALDP impairs peroxisomal beta-oxidation of VLCFA but also raises cytosolic levels of VLCFacyl-CoA which are substrate for further elongation. We identify ELOVL1 (elongation of very-long-chain-fatty acids) as the single elongase catalysing the synthesis of both saturated VLCFA (C26:0) and mono-unsaturated VLCFA (C26:1). ELOVL1 expression is not increased in X-ALD fibroblasts suggesting that increased levels of C26:0 result from increased substrate availability due to the primary deficiency in ALDP. Importantly, ELOVL1 knockdown reduces elongation of C22:0 to C26:0 and lowers C26:0 levels in X-ALD fibroblasts. Given the likely pathogenic effects of high C26:0 levels, our findings highlight the potential of modulating ELOVL1 activity in the treatment of X-ALD.
| S-EPMC3377275 | biostudies-literature
Project description:Although not an affected cell type, skin fibroblasts from individuals with childhood cerebral adrenoleukodystrophy (CCALD), an early onset X-linked neurological disorder, show defects in very long chain fatty acid (VLCFA) metabolism that provide the basis for clinical diagnostic tests. We report the gene expression profiles of fibroblasts from childhood cerebral adrenoleukodystrophy patients and healthy controls Primary dermal fibroblast cultures from 5 CC-ALD patients and 5 healthy controls were cultured in DMEM medium supplemented with 10% FBS at 37°C with 5% CO2 until confluence for RNA extraction. The overall goal was to identify genes that are differentially expressed between CCALD patients and healthy controls
2012-03-01 | E-GEOD-34308 | biostudies-arrayexpress
Project description:Although not an affected cell type, skin fibroblasts from individuals with CC-ALD, an early onset X-linked neurological disorder, show defects in very long chain fatty acid (VLCFA) metabolism that provide the basis for clinical diagnostic tests. Skin fibroblasts from CC-ALD patients can be reprogrammed into iPS cells with all the hallmark properties of pluripotency. The iPS cell phenotypes may reflect the tissue-specificity of the lipid metabolic defects found in CC-ALD patients. We report the gene expression profiles of fibroblasts and fibroblast-reprogrammed iPSCs from childhood cerebral adrenoleukodystrophy patients and healthy controls
2012-03-01 | GSE34309 | GEO
Project description:Although not an affected cell type, skin fibroblasts from individuals with CC-ALD, an early onset X-linked neurological disorder, show defects in very long chain fatty acid (VLCFA) metabolism that provide the basis for clinical diagnostic tests. Skin fibroblasts from CC-ALD patients can be reprogrammed into iPS cells with all the hallmark properties of pluripotency. The iPS cell phenotypes may reflect the tissue-specificity of the lipid metabolic defects found in CC-ALD patients. We report the gene expression profiles of fibroblasts and fibroblast-reprogrammed iPSCs from childhood cerebral adrenoleukodystrophy patients and healthy controls Dermal fibroblast cultures from 2 CCALD patients and 3 healthy controls were reprogrammed into iPSCs by transfection with retroviruses desinged to express the human OCT4, SOX2, KLF4 and c-MYC cDNA. Fibroblasts and iPSCs were cultured in 1:1 ratio of DMEM/F12 medium supplemented with 20% KSR at 37°C with 5% CO2 until confluence for RNA extraction. The overall goal was to identify genes that are differentially expressed between CCALD patients and healthy controls.
2012-03-01 | E-GEOD-34309 | biostudies-arrayexpress
Project description:X-linked adrenoleukodystrophy (X-ALD) is an inherited disorder characterized by axonopathy and demyelination in the central nervous system and adrenal insufficiency. Main X-ALD phenotypes are: (i) an adult adrenomyeloneuropathy (AMN) with axonopathy in spinal cords, (ii) cerebral AMN with brain demyelination (cAMN) and (iii) a childhood variant, cALD, characterized by severe cerebral demyelination. Loss of function of the ABCD1 peroxisomal fatty acid transporter and subsequent accumulation of very-long-chain fatty acids (VLCFAs) are the common culprits to all forms of X-ALD, an aberrant microglial activation accounts for the cerebral forms. How same mutation in the ABCD1 gene can lead to clinically very distinct phenotypes and what factors account for the dissimilar clinical outcomes and prognosis of X-ALD variants remain elusive. We wonder whether epigenetics mechanisms could answer the lack of genotype-phenotype correlation. We employed Illumina state of the art technology to analyze the differential methylation of over 485,000 CpG sites throughout the entire human genome and used stringent statistical criteria to define differential methylation patterns between brains of cALD, cAMN and age-matched controls. We identified a common X-ALD methylation signature comprising the hypermethylation in genes harboring the trimethylated histone H3K27me3 mark in their promoters, the hypermethylation for genes driven the oligodendrocyte lineage, and the hypomethylation for immune-associated genes. We also examined the methylated differences between cALD and cAMN resulting with differential immune response pathways and concordance methylation levels with phenotype severity. The detected methylation differences correlated with transcriptional and translational consequences, as supported by Affymetrix expression arrays, quantitative PCR and WB changes. The reliability of these changes was further demonstrated by validating DNA methylation by an independent pyrosequencing assay. From these evidences, we propose the altered transcriptional programs in oligodendrocyte differentiation in X-ALD patients. These observations may provide new therapeutic epigenetic agents.
2019-02-01 | GSE78218 | GEO
Project description:Adrenoleukodystrophy (ALD) is an X-linked inherited peroxisomal disorder due to mutations in the ALD protein and characterized by accumulation of very long-chain fatty acids (VLCFA), specifically hexacosanoic acid (C26:0). This can trigger other pathological processes such as mitochondrial dysfunction, oxidative stress, and inflammation, which if involves the brain tissues can result in a lethal form of the disease called childhood cerebral ALD. With the recent addition of ALD to the Recommended Uniform Screening Panel, there is an increase in the number of individuals who are identified with ALD. However, currently, there is no approved treatment for pre-symptomatic individuals that can arrest or delay symptom development. Here, we report our observations investigating nervonic acid, a monounsaturated fatty acid as a potential therapy for ALD. Using ALD patient-derived fibroblasts, we examined whether nervonic acid can reverse VLCFA accumulation similar to erucic acid, the active ingredient in Lorenzo's oil, a dietary intervention believed to alter disease course. We have shown that nervonic acid can reverse total lipid C26:0 accumulation in a concentration-dependent manner in ALD cell lines. Further, we show that nervonic acid can protect ALD fibroblasts from oxidative insults, presumably by increasing intracellular ATP production. Thus, nervonic acid can be a potential therapeutic for individuals with ALD, which can alter cellular biochemistry and improve its function.
| S-EPMC9294126 | biostudies-literature