Long-chain ceramides are cell non-autonomous signals linking lipotoxicity to endoplasmic reticulum stress in skeletal muscle, 2022, McNally et al.

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Long-chain ceramides are cell non-autonomous signals linking lipotoxicity to endoplasmic reticulum stress in skeletal muscle
McNally, Ben D.; Ashley, Dean F.; Hänschke, Lea; Daou, Hélène N.; Watt, Nicole T.; Murfitt, Steven A.; MacCannell, Amanda D. V.; Whitehead, Anna; Bowen, T. Scott; Sanders, Francis W. B.; Vacca, Michele; Witte, Klaus K.; Davies, Graeme R.; Bauer, Reinhard; Griffin, Julian L.; Roberts, Lee D.

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.

Link | PDF (Nature Communications)

 

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The endoplasmic reticulum (ER) is a cellular organelle with a key role in both protein synthesis and folding, and lipid biosynthesis. Disruption to ER function results in organelle stress and the accumulation of misfolded proteins.

lipid species are thought to induce metabolic dysfunction in insulin-sensitive tissues such as liver, adipose tissue and skeletal muscle through effects termed lipotoxicity. Skeletal muscle is a key regulator of systemic metabolic homoeostasis.

ER stress triggers the unfolded protein response (UPR), a protective signalling cascade. The UPR is composed of three arms, mediated by the kinases protein kinase R-like endoplasmic reticulum kinase (Perk; encoded by EIF2AK3) and inositol-requiring enzyme 1 (Ire1; encoded by ERN1), and the transmembrane transcription factor, activating transcription factor 6 (Atf6). Signalling through these proteins increases cellular protein chaperones and disulphide isomerases, activates protein degradation pathways, and inhibits protein translation. These protective responses reduce protein load on the ER and improve protein folding.

recent studies suggest that UPR signalling can be propagated in both a paracrine manner and systemically by cell non-autonomous signals

 

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Extracellular vesicles (EVs) have emerged as important vehicles for signalling mediators. There is developing recognition that bioactive lipid signals may be partitioned into EVs

Ceramides are highly hydrophobic molecules and therefore unlikely to be secreted via canonical membrane transporters. Our data suggests that EVs represent a vehicle for long-chain ceramide extracellular transport in ER stress.

We show that palmitate-mediated activation of the Perk-arm of the UPR stimulates an increase in the de novo synthesis, via CerS2, of long-chain ceramides (ceramide 40:1 and 42:1). These ceramides are packaged into extracellular vesicles, secreted, and propagate activation of the UPR [...] our work does not preclude the presence of other metabolite factors, protein signals, or bioactive lipids that may contribute to cell non-autonomous UPR activation. Indeed, our data suggest the presence of an, as yet unidentified, aqueous soluble metabolite factor(s) secreted from palmitate-treated myocytes which also activate UPR gene expression. These findings have consequences for our understanding of both the mechanisms of lipotoxicity and the regulation of ER stress and UPR activation.

Ceramides have previously been implicated in both the development of metabolic disease and the regulation of ER stress.

A short-chain ceramide analogue, infused into the hypothalamus of rats increases hypothalamic ER stress, and reduces the thermogenic capacity of brown adipose tissue, thus, highlighting that ceramide-induced ER stress in one tissue can have a metabolic impact on distal tissues. Evidence is emerging that skeletal muscle ceramide metabolism has a key role in the regulation of systemic physiology.

Our work in skeletal muscle may have relevance to the mechanisms of lipotoxcity-induced ER stress in other tissues such as adipose tissue, liver, pancreas and the hypothalamus, where future work may identify that cell non-autonomous ceramide signalling contributes to dysfunction in metabolic disease in these tissues.

Mitochondria also contain a discreet UPR initiated when mitochondrial integrity and function are impaired. This mitochondrial UPR may also be regulated by paracrine signals with recent work identifying Wnt proteins in paracrine activation of the mitochondrial UPR*. However, a role for bioactive lipids in this process remains unexplored.

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*The Mitochondrial Unfolded Protein Response Is Mediated Cell-Non-autonomously by Retromer-Dependent Wnt Signaling (2018, Cell)