ELOVL4: Very long-chain fatty acids serve an eclectic role in mammalian health and function

Hopiavuori, Blake R.; Anderson, Robert E.; Agbaga, Martin-Paul

doi:10.1016/j.preteyeres.2018.10.004

Cited by 64 publications

(70 citation statements)

References 117 publications

(255 reference statements)

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“…The correlation between ELOVL2 overexpression and molecular signatures of extracellular vesicles suggests that formation and release of extracellular vesicles is one of the cell processes by which ELOVL2 controls GBM tumor development. This possibility is coherent with the reported involvement of another member of the family, ELOVL4, in the formation of synaptic vesicles in the brain and retina [29].…”

Section: Discussionsupporting

confidence: 90%

“…This result further strengthens the relationship between the expression of the lipid subgroup, ELOVL2 expression and the tumorigenic state of the cells. Another member of the ELOVL family, ELOVL4, was involved in extracellular vesicle formation and release [29]. This prompted us to determine whether ELOVL2 expression is associated with molecular signatures of extracellular vesicles at the single cell level.…”

Section: Specific Amino Acid and Lipid Metabolic Pathways Distinguishmentioning

confidence: 99%

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Capture at the single cell level of metabolic modules distinguishing aggressive and indolent glioblastoma cells

Saurty

Bellenger

El-Habr

et al. 2019

Preprint

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Glioblastoma cell ability to adapt their functioning to microenvironment changes is a source of the extensive intra-tumor heterogeneity characteristic of this devastating malignant brain tumor. A systemic view of the metabolic pathways underlying glioblastoma cell functioning states is lacking.We analyzed public single cell RNA-sequencing data from glioblastoma surgical resections, which offer the closest available view of tumor cell heterogeneity as encountered at the time of patients' diagnosis. Unsupervised analyses revealed that information dispersed throughout the cell transcript repertoires encoded the identity of each tumor and masked information related to cell functioning states. Data reduction based on an experimentally-defined signature of transcription factors overcame this hurdle. It allowed cell grouping according to their tumorigenic potential, regardless of their tumor of origin. The approach relevance was validated using an independent dataset of glioblastoma tissue transcriptomes, patient-derived cell lines and orthotopic xenografts.Overexpression of genes coding for amino acid and lipid metabolism enzymes involved in antioxidative, energetic and cell membrane processes characterized cells with high tumorigenic potential. Modeling of their expression network highlighted the very long chain polyunsaturated fatty acid synthesis pathway at the core of the network. Expression of its most downstream enzymatic component, ELOVL2, was associated with worsened patient survival, and required for cell tumorigenic properties in vivo. Our results demonstrate the power of signature-driven analyses of single cell transcriptomes to obtain an integrated view of metabolic pathways at play within the heterogeneous cell landscape of patient tumors.

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Section: Discussionsupporting

confidence: 90%

Section: Specific Amino Acid and Lipid Metabolic Pathways Distinguishmentioning

confidence: 99%

Capture at the single cell level of metabolic modules distinguishing aggressive and indolent glioblastoma cells

Saurty

Bellenger

El-Habr

et al. 2019

Preprint

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“…For example, the shift in the DHA/AA ratio may be proinflammatory (SanGiovanni and Chew, 2005). Of particular interest is the observed reduction in VLCFAs, as evolving evidence suggests a complex involvement of VLCFAs in supporting retinal structure and function, particularly in the context of hereditary retinal degenerations, including Stargardt-3 macular degeneration (Hopiavuori et al, 2019). Finally, a recent study reported that Mfsd2a suppresses transcellular transport in endothelial cells of the retinal vasculature (Chow and Gu, 2017).…”

Section: Discussionmentioning

confidence: 99%

Disrupted Blood-Retina Lysophosphatidylcholine Transport Impairs Photoreceptor Health But Not Visual Signal Transduction

et al. 2019

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Retinal photoreceptor cells contain the highest concentration of docosahexaenoic acid (DHA) in our bodies, and it has been long assumed that this is critical for supporting normal vision. Indeed, early studies using DHA dietary restriction documented reduced light sensitivity by DHA-deprived retinas. Recently, it has been demonstrated that a major route of DHA entry in the retina is the delivery across the blood-retina barrier by the sodium-dependent lipid transporter, Mfsd2a. This discovery opened a unique opportunity to analyze photoreceptor health and function in DHA-deprived retinas using the Mfsd2a knockout mouse as animal model. Our lipidome analyses of Mfsd2a ؊/؊ retinas and outer segment membranes corroborated the previously reported decrease in the fraction of DHA-containing phospholipids and a compensatory increase in phospholipids containing arachidonic acid. We also revealed an increase in the retinal content of monounsaturated fatty acids and a reduction in very long chain fatty acids. These changes could be explained by a combination of reduced DHA supply to the retina and a concomitant upregulation of several fatty acid desaturases controlled by sterol regulatory element-binding transcription factors, which are upregulated in Mfsd2a ؊/؊ retinas. Mfsd2a ؊/؊ retinas undergo slow progressive degeneration, with ϳ30% of photoreceptor cells lost by the age of 6 months. Despite this pathology, the ultrastructure Mfsd2a ؊/؊ photoreceptors and their ability to produce light responses were essentially normal. These data demonstrate that, whereas maintaining the lysophosphatidylcholine route of DHA supply to the retina is essential for long-term photoreceptor survival, it is not important for supporting normal phototransduction.

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“…These data suggest the potential involvement of ELOVL4 and IL-33 in the pathophysiology of ORCM. ELOVL4 is an elongase that participates in the biosynthesis of very-long-chain (VLC, ≥ C28) saturated fatty acid (VLC-SFA) and polyunsaturated fatty acid (VLC-PUFA) in different tissues (Hopiavuori et al, 2019), and plays a key role in the retinal function (Harkewicz et al, 2012). The increased deposition of long-chain fatty acids in adipocytes is one of the main characteristics of obesity (Walewski et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Critical Roles of ELVOL4 and IL-33 in the Progression of Obesity-Related Cardiomyopathy via Integrated Bioinformatics Analysis

Tao

Wang

et al. 2020

Front. Physiol.

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The molecular mechanisms underlying obesity-related cardiomyopathy (ORCM) progression involve multiple signaling pathways, and the pharmacological treatment for ORCM is still limited. Thus, it is necessary to explore new targets and develop novel therapies. Microarray analysis for gene expression profiles using different bioinformatics tools has been an effective strategy for identifying novel targets for various diseases. In this study, we aimed to explore the potential genes related to ORCM using the integrated bioinformatics analysis. The GSE18897 (whole blood expression profiling of obese diet-sensitive, obese diet-resistant, and lean human subjects) and GSE47022 (regular weight C57BL/6 and diet-induced obese C57BL/6 mice) were used for bioinformatics analysis. Weighted gene co-expression network analysis (WGCNA) of GSE18897 was employed to investigate gene modules that were strongly correlated with clinical phenotypes. Gene Ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed on the co-expression genes. The expression levels of the hub genes were validated in the clinical samples. Yellow co-expression module of WGCNA in GSE18897 was found to be significantly related to the caloric restriction treatment. In addition, GO functional enrichment analysis and KEGG pathway analysis were performed on the coexpression genes in yellow co-expression module, which showed an association with oxygen transport and the porphyrins pathway. Overlap analysis of yellow co-expression module genes from GSE18897 andGSE47022 revealed six upregulated genes, and further experimental validation results showed that elongation of very-long-chain fatty acids protein 4 (ELOVL4), matrix metalloproteinase-8 (MMP-8), and interleukin-33 (IL-33) were upregulated in the peripheral blood from patients with ORCM compared to that in the controls. The bioinformatics analysis revealed that ELOVL4 expression levels are positively correlated with that of IL-33. Collectively, using WGCNA in combination with integrated bioinformatics analysis, the hub genes of ELVOL4 and IL-33 might serve as potential biomarkers for diagnosis and/or therapeutic targets for ORCM. The detailed roles of ELVOL4 and IL-33 in the pathophysiology of ORCM still require further investigation.

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ELOVL4: Very long-chain fatty acids serve an eclectic role in mammalian health and function

Cited by 64 publications

References 117 publications

Capture at the single cell level of metabolic modules distinguishing aggressive and indolent glioblastoma cells

Capture at the single cell level of metabolic modules distinguishing aggressive and indolent glioblastoma cells

Disrupted Blood-Retina Lysophosphatidylcholine Transport Impairs Photoreceptor Health But Not Visual Signal Transduction

Critical Roles of ELVOL4 and IL-33 in the Progression of Obesity-Related Cardiomyopathy via Integrated Bioinformatics Analysis

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