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Long-chain ceramides are cell non-autonomous signals linking lipotoxicity to endoplasmic reticulum stress in skeletal muscle.

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العنوان: Long-chain ceramides are cell non-autonomous signals linking lipotoxicity to endoplasmic reticulum stress in skeletal muscle.
المؤلفون: McNally BD; Department of Biochemistry, University of Cambridge, Cambridge, CB2 1GA, UK., Ashley DF; Department of Biochemistry, University of Cambridge, Cambridge, CB2 1GA, UK., Hänschke L; Life & Medical Sciences Institute (LIMES) Development, Genetics & Molecular Physiology Unit, University of Bonn, Carl-Troll-Straße, 31, 53115, Bonn, Germany., Daou HN; School of Medicine, University of Leeds, Leeds, LS2 9JT, UK., Watt NT; School of Medicine, University of Leeds, Leeds, LS2 9JT, UK., Murfitt SA; Department of Biochemistry, University of Cambridge, Cambridge, CB2 1GA, UK., MacCannell ADV; School of Medicine, University of Leeds, Leeds, LS2 9JT, UK., Whitehead A; School of Medicine, University of Leeds, Leeds, LS2 9JT, UK., Bowen TS; Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT, UK., Sanders FWB; Department of Biochemistry, University of Cambridge, Cambridge, CB2 1GA, UK., Vacca M; Department of Biochemistry, University of Cambridge, Cambridge, CB2 1GA, UK.; Clinica Medica 'Frugoni', Interdisciplinar Department of Medicine, University of Bari 'Aldo Moro', Bari, Italy., Witte KK; School of Medicine, University of Leeds, Leeds, LS2 9JT, UK., Davies GR; Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Cambridge, UK., Bauer R; Life & Medical Sciences Institute (LIMES) Development, Genetics & Molecular Physiology Unit, University of Bonn, Carl-Troll-Straße, 31, 53115, Bonn, Germany., Griffin JL; Department of Biochemistry, University of Cambridge, Cambridge, CB2 1GA, UK.; Department of Metabolism, Digestion and Reproduction, Imperial College London, London, UK., Roberts LD; School of Medicine, University of Leeds, Leeds, LS2 9JT, UK. L.D.Roberts@leeds.ac.uk.
المصدر: Nature communications [Nat Commun] 2022 Apr 01; Vol. 13 (1), pp. 1748. Date of Electronic Publication: 2022 Apr 01.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE
أسماء مطبوعة: Original Publication: [London] : Nature Pub. Group
مواضيع طبية MeSH: Ceramides*/metabolism , Endoplasmic Reticulum Stress*/physiology, Animals ; Endoplasmic Reticulum/metabolism ; Mice ; Muscle, Skeletal/metabolism ; Unfolded Protein Response
مستخلص: The endoplasmic reticulum (ER) regulates cellular protein and lipid biosynthesis. ER dysfunction leads to protein misfolding and the unfolded protein response (UPR), which limits protein synthesis to prevent cytotoxicity. Chronic ER stress in skeletal muscle is a unifying mechanism linking lipotoxicity to metabolic disease. Unidentified signals from cells undergoing ER stress propagate paracrine and systemic UPR activation. Here, we induce ER stress and lipotoxicity in myotubes. We observe ER stress-inducing lipid cell non-autonomous signal(s). Lipidomics identifies that palmitate-induced cell stress induces long-chain ceramide 40:1 and 42:1 secretion. Ceramide synthesis through the ceramide synthase 2 de novo pathway is regulated by UPR kinase Perk. Inactivation of CerS2 in mice reduces systemic and muscle ceramide signals and muscle UPR activation. The ceramides are packaged into extracellular vesicles, secreted and induce UPR activation in naïve myotubes through dihydroceramide accumulation. This study furthers our understanding of ER stress by identifying UPR-inducing cell non-autonomous signals.
(© 2022. The Author(s).)
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معلومات مُعتمدة: MR/R014086/1 United Kingdom MRC_ Medical Research Council; MC_PC_13030 United Kingdom MRC_ Medical Research Council; BB/R013500/1 United Kingdom BB_ Biotechnology and Biological Sciences Research Council; BB/T004231/1 United Kingdom BB_ Biotechnology and Biological Sciences Research Council; MC_UU_00014/5 United Kingdom MRC_ Medical Research Council; MR/P011705/1 United Kingdom MRC_ Medical Research Council; MC_UP_A090_1006 United Kingdom MRC_ Medical Research Council; MR/P01836X/1 United Kingdom MRC_ Medical Research Council; 16/0005382 United Kingdom DUK_ Diabetes UK
المشرفين على المادة: 0 (Ceramides)
تواريخ الأحداث: Date Created: 20220402 Date Completed: 20220405 Latest Revision: 20230705
رمز التحديث: 20230705
مُعرف محوري في PubMed: PMC8975934
DOI: 10.1038/s41467-022-29363-9
PMID: 35365625
قاعدة البيانات: MEDLINE
الوصف
تدمد:2041-1723
DOI:10.1038/s41467-022-29363-9