Regulation of ceramide-induced neuronal death: Cell metabolism meets neurodegeneration

Journal of Lipid Research Volume 55, 20142521 the metabolic pathway ( 3 ). Ceramide undergoes anabolic reactions to generate sphingomyelin and various glycosphingolipids, or catabolic reactions, which lead to the generation of sphingosine and sphingosine-1-phosphate (S1P). Alterations in ceramide metabolism have been implicated in many pathophysiologies, including aging ( 4-6 ), neurodegeneration ( 7,8 ), metabolic diseases ( 9-15 ), cancer (16)(17)(18)(19)(20), and stress responses ( 5 ). However, the mechanisms that regulate cellular ceramide levels under physiologic and pathophysiologic conditions are still not well-understood.Changes in the levels of ceramide and other sphingolipid metabolites have been shown to affect macroautophagy (referred to hereafter as autophagy) in a variety of cell types ( 21-27 ). Autophagy is a catabolic process that starts with the generation of a double-membrane cup-like phagophore from the ER or other sources ( 28, 29 ); the phagophore then captures cellular material and matures into an autophagosome that will subsequently fuse with a lysosome to form an autolysosome, enabling degradation of the engulfed material. This process is crucial for removal of pathogens and damaged proteins and organelles, as well as for the reutilization of nutrients to generate energy and maintain homeostasis. Clearance of toxic or defective cellular components protects from degenerative, metabolic, and infl ammatory diseases ( 30 ). Some forms of autophagy are specifi c, uniquely targeting mitochondria (mitophagy) ( 31 ), segments of the ER (ER-phagy or reticulophagy) ( 32 ), or triglyceride stores (lipophagy) ( 33 ) for degradation. Impaired autophagy is encountered, along with increased ceramide levels, in a number of pathophysiologic conditions, including aging ( 34, 35 ), neurodegeneration ( 36, 37 ), obesity ( 10 ), and type 2 diabetes ( 9 ).Abstract Sphingolipid levels are tightly regulated to maintain cellular homeostasis. During pathologic conditions such as in aging, infl ammation, and metabolic and neurodegenerative diseases, levels of some sphingolipids, including the bioactive metabolite ceramide, are elevated. Sphingolipid metabolism has been linked to autophagy, a critical catabolic process in both normal cell function and disease; however, the in vivo relevance of the interaction is not wellunderstood. Here, we show that blocking autophagy in the liver by deletion of the Atg7 gene, which is essential for autophagosome formation, causes an increase in sphingolipid metabolites including ceramide. We also show that overexpression of serine palmitoyltransferase to elevate de novo sphingolipid biosynthesis induces autophagy in the liver. The results reveal autophagy as a process that limits excessive ceramide levels and that is induced by excessive elevation of de novo sphingolipid synthesis in the liver. Dysfunctional autophagy may be an underlying mechanism causing elevations in ceramide that may contribute to pathogenesis in diseases. Sphingolipids are a structurally and functionally di...

Section: Gfp-lc3mentioning

confidence: 99%

Autophagy regulates sphingolipid levels in the liver

Alexaki

Gupta

Majumder

et al. 2014

“…One of Cer's best recognized functions is being a mediator of cell death. Multiple endogenous and exogenous stimulants including tumor necrosis factor (TNF)-␣ , FAS ligands, anticancer drugs, oxidative stress, ionizing and ultraviolet (UV) radiation, and serum or trophic factor deprivation ( 6,7,(19)(20)(21) increase Cer intracellular levels, and this increase precedes the onset of apoptosis in many cell types ( 32,33 ).…”

Section: The Sphingolipids: a Vast Familymentioning

confidence: 99%

Regulating survival and development in the retina: key roles for simple sphingolipids

Rotstein

Miranda

Abrahan

et al. 2010

tions as structural membrane components and energetic fuels. However, the fi ndings of the previous half century have extended these roles, shedding light on their indisputable relevance as signaling molecules controlling key aspects of cellular life and development. The identifi cation of diacylglycerol and inositol 1,4,5 triphosphate ( 1 ) as second messengers seemed at the time a peculiarity of these lipids. The subsequent fi ndings of the roles of arachidonic acid metabolites ( 2 ), platelet activating factor ( 3 ), and other minor inositol lipids ( 4 ) in cell signaling began to establish that being intracellular messengers was not an oddity but a habitual task for lipids in cells. The family of lipid signaling molecules largely expanded in the last two decades, when several sphingolipids were successively shown to regulate a multiplicity of cell functions. Sphingosine (Sph) was the fi rst sphingolipid to be established as a bioactive lipid, involved in the regulation of protein kinase (PK)C activity ( 5 ). Ceramide (Cer) and sphingosine-1-phosphate (S1P) were next shown to signal a myriad of cell functions and the number of sphingolipid molecules with bioactive properties has gone on enlarging in recent years ( 6, 7 ).Though a vast literature exists on the functions of sphingolipids in several tissues, less is known concerning its roles in the eye, and in the retina in particular. Accumulation of sphingolipids originated in defects in the lysosomal Abstract Many sphingolipids have key functions in the regulation of crucial cellular processes. Ceramide (Cer) and sphingosine (Sph) induce growth arrest and cell death in multiple situations of cellular stress. On the contrary, sphingosine-1-phosphate (S1P), the product of Sph phosphorylation, promotes proliferation, differentiation, and survival in different cell systems. This review summarizes the roles of these simple sphingolipids in different tissues and then analyzes their possible functions in the retina. Alterations in proliferation, neovascularization, differentiation, and cell death are critical in major retina diseases and collective evidence points to a role for sphingolipids in these processes. Cer induces infl ammation and apoptosis in endothelial and retinal pigmented epithelium cells, leading to several retinopathies. S1P can prevent this death but also promotes cell proliferation that might lead to neovascularization and fibrosis. Recent data support Cer and Sph as crucial mediators in the induction of photoreceptor apoptosis in diverse models of oxidative damage and neurodegeneration, and suggest that regulating their metabolism can prevent this death. New evidence proposes a central role for S1P controlling photoreceptor survival and differentiation. Finally, this review discusses the ability of trophic factors to regulate sphingolipid metabolism and transactivate S1P signaling pathways to control survival and development in retina photoreceptors. When asked about the roles of cellular lipids, the fi rst thought usually coming to our minds re...

“…In past decades, accumulating evidence suggested that ceramide, the core lipid of sphingolipid metabolism, is a key factor in apoptotic cell death ( 4,(22)(23)(24)(25). Various external stressors, such as hypoxia, chemotherapeutic agents, heat, ultravioAbstract Light-induced retinal degeneration (LIRD) in albino rats causes apoptotic photoreceptor cell death.…”

mentioning

confidence: 99%

Inhibition of de novo ceramide biosynthesis by FTY720 protects rat retina from light-induced degeneration

Chen

Tran

Eckerd

et al. 2013

This article is available online at http://www.jlr.org pigmentosa and age-related macular degeneration ( 1-3 ). Very few effective therapies exist for this heterogeneous group of diseases because of the complex pathophysiology associated with genetic and environmental factors. Researchers are looking for cellular second messengers involved in the process of cell death which can be targeted for therapies. The sphingolipid metabolite ceramide is a deadly second messenger in the cell and can induce apoptosis through various mechanisms ( 4 ). Recently, increases in ceramide levels have been shown to be associated with photoreceptor and retinal pigment epithelium (RPE) cell death ( 5-8 ). Here we investigated whether ceramide is involved in photoreceptor cell death in light-induced retinal degeneration (LIRD).LIRD is a useful model for studying the mechanism of photoreceptor cell death because intense light exposure induces oxidative stress-mediated apoptosis of photoreceptor cells and causes retinal degeneration ( 3, 9 ). Since its development in 1966 by Noell et al. ( 10 ), this model, in combination with genetic knock-out models (1)(2)(3)(11)(12)(13)(14), has been extensively used to discover many fundamental mechanisms of photoreceptor function and to test various neuroprotective compounds ( 15-21 ).However, the precise mechanism of light-induced retinal degeneration is currently unclear ( 3, 13 ). In past decades, accumulating evidence suggested that ceramide, the core lipid of sphingolipid metabolism, is a key factor in apoptotic cell death ( 4,(22)(23)(24)(25). Various external stressors, such as hypoxia, chemotherapeutic agents, heat, ultravioAbstract Light-induced retinal degeneration (LIRD) in albino rats causes apoptotic photoreceptor cell death. Ceramide is a second messenger for apoptosis. We tested whether increases in ceramide mediate photoreceptor apoptosis in LIRD and if inhibition of ceramide synthesis protects the retina. Sprague-Dawley rats were exposed to 2,700 lux white light for 6 h, and the retinal levels of ceramide and its intermediary metabolites were measured by GC-MS or electrospray ionization tandem mass spectrometry. Enzymes of the de novo biosynthetic and sphingomyelinase pathways of ceramide generation were assayed, and gene expression was measured. The dosage and temporal effect of the ceramide synthase inhibitor FTY720 on the LIRD retina were measured by histological and functional analyses. Retinal ceramide levels increased coincident with the increase of dihydroceramide at various time points after light stress. Light stress in retina induces ceramide generation predominantly through the de novo pathway, which was prevented by systemic administration of FTY720 (10 mg/kg) leading to the protection of retinal structure and function. The neuroprotection of FTY720 was independent of its immunosuppressive action. We conclude that ceramide increase by de novo biosynthesis mediates photoreceptor apoptosis in the LIRD model and that inhibition of ceramide production protects the retina ag...