1,720,979 research outputs found
Disturbed lipid metabolism underlies immune cel dysfunction in multiple sclerosis
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Lipophagy: a new player in CNS disorders
No full textLipophagy is the process of selective degradation of lipid droplets (LDs) by autophagy. Several studies have highlighted the importance of lipophagy in regulating cellular lipid levels in various tissues and disease conditions. In recent years, disruption of autophagy and accumulation of LDs have been reported as pathological hallmarks in several neurodegenerative and neuroinflammatory diseases, raising the question whether lipophagy is a process that is important in the progression of these disorders. This supports the growing interest in lipid metabolism as a major player in neurodegeneration, and the emerging understanding of several neurological pathologies as not only proteinopathies but also lipidopathies. In this review we discuss the importance of lipophagy in the most common central nervous system diseases. We examine the latest evidence for the reported interplay between abnormalities in lipid accumulation and autophagy, and propose lipophagy as a potentially important mechanism in neurodegeneration
The ubiquitous role of ubiquitination in lipid metabolism
No full textLipids are essential molecules that play key roles in cell physiology by serving as structural components, for storage of energy, and in signal transduction. Hence, efficient regulation and maintenance of lipid homeostasis are crucial for normal cellular and tissue function. In the past decade, increasing research has shown the importance of ubiquitination in regulating the stability of key players in different aspects of lipid metabolism. This review describes recent insights into the regulation of lipid metabolism by ubiquitin signaling, discusses how ubiquitination can be targeted in diseases characterized by lipid dysregulation, and identifies areas that require further research.The work has been supported by the Flemish Fund for Scientific Research (FWO Vlaanderen; 1141920N). N.Z. is support by a Vici grant from The Netherlands Organization for Scientific Research (NWO; 016.176.643). Figures were created with the
use of Biorender.com
Lipid metabolism, remodelling and intercellular transfer in the CNS
No full textLipid metabolism encompasses the catabolism and anabolism of lipids, and is fundamental for the maintenance of cellular homeostasis, particularly within the lipid-rich CNS. Increasing evidence further underscores the importance of lipid remodelling and transfer within and between glial cells and neurons as key orchestrators of CNS lipid homeostasis. In this Review, we summarize and discuss the complex landscape of processes involved in lipid metabolism, remodelling and intercellular transfer in the CNS. Highlighted are key pathways, including those mediating lipid (and lipid droplet) biogenesis and breakdown, lipid oxidation and phospholipid metabolism, as well as cell-cell lipid transfer mediated via lipoproteins, extracellular vesicles and tunnelling nanotubes. We further explore how the dysregulation of these pathways contributes to the onset and progression of neurodegenerative diseases, and examine the homeostatic and pathogenic impacts of environment, diet and lifestyle on CNS lipid metabolism.The authors thank all members of the Bogie, Hendriks and Miron laboratories for the discussions. The research of S.V. is funded by the FWO Vlaanderen (1246724N) and Charcot Research Foundation (CHARCO24VS). V.E.M is funded by the John David Eaton Chair in Multiple Sclerosis Research (Barlo MS Centre, St. Michael’s Hospital Foundation), the Sloan-Hall MS Basic Research Fund, MS Canada and a Senior Non-Clinical Research Fellowship from the Medical Research Council. J.J.A.H is funded by the Research Foundation of Flanders (FWO Vlaanderen; G0A7922, G0A7922, S01623N) and the Charcot Research Foundation (CHARCO23HJ, CHARCO24HJ). J.F.J.B is funded by the Research Foundation of Flanders (FWO Vlaanderen; G075823, G0A3B24), Charcot Research Foundation (CHARCO23BJ, CHARCO24BJ), Geneeskundige Stichting Koningin Elisabeth (G.S.K.E; GSKE-BOGJ), MS Liga Vlaanderen (MSLIGABOGJ) and the special research fund Hasselt University (22DOC38BOF, 23INC06BOF)
Targeting lipophagy in macrophages improves repair in multiple sclerosis
No full textFoamy macrophages containing abundant intracellular myelin remnants are an important pathological hallmark of multiple sclerosis. Reducing the intracellular lipid burden in foamy macrophages is considered a promising therapeutic strategy to induce a phagocyte phenotype that promotes central nervous system repair. Recent research from our group showed that sustained intracellular accumulation of myelin-derived lipids skews these phagocytes toward a disease-promoting and more inflammatory phenotype. Our data now demonstrate that disturbed lipophagy, a selective form of autophagy that helps with the degradation of lipid droplets, contributes to the induction of this phenotype. Stimulating autophagy using the natural disaccharide trehalose reduced the lipid load and inflammatory phenotype of myelin-laden macrophages. Importantly, trehalose was able to boost remyelination in the ex vivo brain slice model and the in vivo cuprizone-induced demyelination model. In summary, our results provide a molecular rationale for impaired metabolism of myelin-derived lipids in macrophages, and identify lipophagy induction as a promising treatment strategy to promote remyelination.The work has been supported by the Flemish Fund for ScientificResearch (FWO Vlaanderen; 1141920N, 12U7718N and 1502120N), theBelgian Charcot Foundation (Fondation Charcot 2020-0004), and thespecial research fund UHasselt (BOF
Global deletion of the LXR-regulated gene EEPD1 reveals macrophage-specific changes in lipid metabolism and cholesterol efflux
No full textBackground and aims: We recently reported that Endonuclease/Exonuclease/Phosphatase family Domain containing 1 (EEPD1) is a transcriptional target of the sterol-responsive nuclear Liver X Receptors (LXR) in macrophages. The aim of this study is to clarify the in vivo role of EEPD1 in whole-body and macrophage lipid handling, and in the development of atherosclerosis. Methods: We developed mice with global deletion of Eepd1 and challenged them with a high-fat- and a Westerntype diet. Bone marrow-derived macrophages (BMDM) were used for profiling transcriptomic and lipidomic changes, and evaluating cholesterol efflux in the absence of Eepd1. We transplanted bone marrow from wildtype and Eepd1KO mice into LdlrKO recipients to assess the role of myeloid-specific EEPD1 in atherogenesis. Results: Eepd1KO mice were indistinguishable from wildtype controls when fed a low-fat diet. However, when challenged with a high-fat diet or a cholesterol-containing western diet, Eepd1KO displayed enhanced weight gain, with no evident changes in plasma and hepatic lipid levels observed. Consistent with our earlier report, BMDM isolated from Eepd1KO mice had attenuated LXR-stimulated cholesterol efflux to high density lipoprotein and Apolipoprotein A1 when compared to wildtype cells. The transcriptomic and lipidomic landscape of these cells revealed a small reduction in expression of cholesterol biosynthetic genes in LXR-stimulated Eepd1KO cells, and prominent changes in diacylglycerol and hexosylceramides level and species. Changes were also observed in triglyceride and cholesterol-ester species. Myeloid-specific loss of Eepd1 did not alter atherosclerotic plaque size and collagen content in bone marrow-transplanted LdlrKO recipients. Conclusions: Loss of Eepd1 results in an altered lipidomic landscape and reduced LXR-stimulated cholesterol efflux in BMDM, but myeloid-specific loss of Eepd1 does not influence atherogenesis in mice.Financial support
N.Z. is an Established Investigator of the Dutch Heart Foundation (2013T111) and is supported by a Vici grant from the Netherlands Organization for Scientific Research (NWO; 016.176.643) and an NWO ENW grant (M.22.034; GENESIS).
Acknowledgments
We thank Ezra van der Wel for help with the atherosclerosis lesion analysis. We also thank Nienke van Loon for her assistance and all members of the Zelcer group, Irith Koster, and Jayron Habibe for their valuable feedback and recommendations. We acknowledge the Core Facility Metabolomics of the AMC (www.cfmetabolomics.nl) for executing the lipidomics analysis
Stearoyl-CoA desaturase-1: a potential therapeutic target for neurological disorders
No full textDisturbances in the fatty acid lipidome are increasingly recognized as key drivers in the progression of various brain disorders. In this review article, we delve into the impact of Δ9 fatty acid desaturases, with a particular focus on stearoyl-CoA desaturase-1 (SCD1), within the setting of neuroinflammation, neurodegeneration, and brain repair. Over the past years, it was established that inhibition or deficiency of SCD1 not only suppresses neuroinflammation but also protects against neurodegeneration in conditions such as multiple sclerosis, Alzheimer's disease, and Parkinson's disease. This protective effect is achieved through different mechanisms including enhanced remyelination, reversal of synaptic and cognitive impairments, and mitigation of α-synuclein toxicity. Intriguingly, metabolic rerouting of fatty acids via SCD1 improves the pathology associated with X-linked adrenoleukodystrophy, suggesting context-dependent benign and harmful effects of SCD1 inhibition in the brain. Here, we summarize and discuss the cellular and molecular mechanisms underlying both the beneficial and detrimental effects of SCD1 in these neurological disorders. We explore commonalities and distinctions, shedding light on potential therapeutic challenges. Additionally, we touch upon future research directions that promise to deepen our understanding of SCD1 biology in brain disorders and potentially enhance the clinical utility of SCD1 inhibitors.This work was funded by the Flemish Fund for Scientific Research (FWO Vlaanderen), the Belgian Charcot Foundation, GSK Funding, the special research fund UHasselt (BOF), and the Transnational University Limburg (TUL)
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
ApoA-I mimetic peptide 5A boosts remyelination by promoting myelin debris clearance
No full textArticle The ApoA-I mimetic peptide 5A enhances remyelination by promoting clearance and degradation of myelin debris Graphical abstract Highlights d ApoA-I mimetic peptide 5A enhances remyelination in a phagocyte-dependent manner d In addition to promoting lipid efflux, peptide 5A enhances clearance of myelin debris d Peptide 5A drives clearance of myelin debris via the fatty acid translocase CD3
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