Long-chain ceramides are cell non-autonomous signals linking lipotoxicity to endoplasmic reticulum stress in skeletal muscle.
Long-chain ceramides are cell non-autonomous signals linking lipotoxicity to endoplasmic reticulum stress in skeletal muscle.
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DOI：
10.1038/s41467-022-29363-9
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发表时间：
2022-04-01
影响因子：
16.6
通讯作者：
Roberts LD
中科院分区：
文献类型：
--
作者：
McNally BD;Ashley DF;Hänschke L;Daou HN;Watt NT;Murfitt SA;MacCannell ADV;Whitehead A;Bowen TS;Sanders FWB;Vacca M;Witte KK;Davies GR;Bauer R;Griffin JL;Roberts LD
内质网（ER）调节细胞蛋白质和脂质的生物合成。ER功能障碍导致蛋白质错误折叠和未折叠蛋白质反应（UPR），其限制蛋白质合成以防止细胞毒性。骨骼肌中的慢性内质网应激是将脂毒性与代谢疾病联系起来的统一机制。来自经历ER应激的细胞的未知信号传播旁分泌和系统性UPR激活。在这里，我们诱导内质网应激和脂毒性的肌管。我们观察到ER应激诱导的脂质细胞非自主信号。脂质组学鉴定棕榈酸诱导的细胞应激诱导长链神经酰胺40：1和42：1分泌。通过神经酰胺合成酶2从头途径的神经酰胺合成受UPR激酶Perk调节。CerS2在小鼠中的失活降低了全身和肌肉神经酰胺信号以及肌肉UPR活化。神经酰胺被包装到细胞外囊泡中，分泌并通过二氢神经酰胺积累诱导幼稚肌管中的UPR活化。本研究通过识别UPR诱导的细胞非自主信号，进一步加深了我们对ER应激的理解。内质网应激诱导细胞非自主性未折叠蛋白反应（UPR）激活。在这里，作者表明，长链神经酰胺是从肌细胞分泌的细胞外囊泡，并诱导细胞非自主的UPR激活肌细胞响应脂毒性。
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. Endoplasmic Reticulum stress induces cell non-autonomous Unfolded Protein Response (UPR) activation. Here the authors show that long-chain ceramides are secreted from muscle cells in extracellular vesicles and induce cell non-autonomous UPR activation in muscle cells in response to lipotoxcity.
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影响因子：
4.6
作者：
Burrello J;Biemmi V;Dei Cas M;Amongero M;Bolis S;Lazzarini E;Bollini S;Vassalli G;Paroni R;Barile L
通讯作者：
Barile L
影响因子：
4.6
作者：
Levy, Michal;Futerman, Anthony H.
通讯作者：
Futerman, Anthony H.
影响因子：
4.3
作者：
Basit, Abdul;Piomelli, Daniele;Armirotti, Andrea
通讯作者：
Armirotti, Andrea
DOI：
10.1152/ajpendo.00038.2010
发表时间：
2010-11-01
影响因子：
5.1
作者：
Deldicque, Louise;Cani, Patrice D.;Baar, Keith
通讯作者：
Baar, Keith
影响因子：
13.3
作者：
Hernández-Tiedra S;Fabriàs G;Dávila D;Salanueva ÍJ;Casas J;Montes LR;Antón Z;García-Taboada E;Salazar-Roa M;Lorente M;Nylandsted J;Armstrong J;López-Valero I;McKee CS;Serrano-Puebla A;García-López R;González-Martínez J;Abad JL;Hanada K;Boya P;Goñi F;Guzmán M;Lovat P;Jäättelä M;Alonso A;Velasco G
通讯作者：
Velasco G