Wild-type levels of ceramide and ceramide-1-phosphate in the retina of ceramide kinase-like-deficient mice

Gräf, Christine; Niwa, Satoru; Müller, Matthias; Kinzel, Bernd; Bornancin, Frédéric

doi:10.1016/j.bbrc.2008.06.002

Cited by 47 publications

(39 citation statements)

References 14 publications

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“…1, panels C and D). The finding for specific loss of D-erytho-C16 C1P is in accord with the recent findings of Bornancin and co-workers (26,27). CERK siRNA also inhibited the increase in the total mass of D-erytho-C16 C1P when stimulated by calcium ionophore (Fig.…”

Section: Resultssupporting

confidence: 82%

“…One inconsistency with our findings of a role for CERK-derived C1P as a major player in cPLA 2 ␣ activation and eicosanoid synthesis in cells and in vivo are recent studies by Bornancin and co-workers (26,27). These researchers found that cells derived from mice with the genetic ablation of CERK had no effect on AA release and eicosanoid synthesis in response to inflammatory agonists.…”

Section: Discussioncontrasting

confidence: 46%

“…1, panel D), which may provide the C1P for activation of cPLA 2 ␣ in the cell models used by the Bornancin group (e.g. peritoneal macrophages) (26). Our presented study utilizes a mutant cPLA 2 ␣, which specifically focuses on the interaction of C1P and cPLA 2 ␣, negating the unknown specificity of CERK for eicosanoid generation in other cell models.…”

Section: Discussionmentioning

confidence: 99%

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Ceramide 1-Phosphate Is Required for the Translocation of Group IVA Cytosolic Phospholipase A2 and Prostaglandin Synthesis

Lamour

Subramanian

Wijesinghe

et al. 2009

Journal of Biological Chemistry

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Little is known about the regulation of eicosanoid synthesis proximal to the activation of cytosolic phospholipase A 2 ␣ (cPLA 2 ␣), the initial rate-limiting step. The current view is that cPLA 2 ␣ associates with intracellular/phosphatidylcholine-rich membranes strictly via hydrophobic interactions in response to an increase of intracellular calcium. In opposition to this accepted mechanism of two decades, ceramide 1-phosphate (C1P) has been shown to increase the membrane association of cPLA 2 ␣ in vitro via a novel site in the cationic ␤-groove of the C2 domain (Stahelin, R. V., Subramanian, P., Vora, M., Cho, W., and Chalfant, C. E. In this study we demonstrate that C1P is a proximal and required bioactive lipid for the translocation of cPLA 2 ␣ to intracellular membranes in response to inflammatory agonists (e.g. calcium ionophore and ATP). Last, the absolute requirement of the C1P/ cPLA 2 ␣ interaction was demonstrated for the production of eicosanoids using murine embryonic fibroblasts (cPLA 2 ␣ ؊/؊ ) coupled to "rescue" studies. Therefore, this study provides a paradigm shift in how cPLA 2 ␣ is activated during inflammation.Eicosanoids are a class of bioactive lipids derived from the 20-carbon fatty acid, arachidonic acid (AA), 2 including prostaglandins, prostacyclins, thromboxanes, and leukotrienes. The production of AA is the initial rate-limiting step in the production of eicosanoids, and the major phospholipase that regulates eicosanoids synthesis in response to agonists is group IVA cytosolic phospholipase A 2 (cPLA 2 ␣) (2, 3). Activation of cPLA 2 in cells requires the association of the enzyme with intracellular membranes in a Ca 2ϩ -dependent manner. This translocation of cPLA 2 ␣ from the cytosol to intracellular membranes is mediated by a Ca 2ϩ -dependent lipid binding domain (CaLB domain) located at the N terminus of the enzyme (4 -7). The CaLB domain is ϳ60 amino acids and binds phosphatidylcholine (PC) in a Ca 2ϩ -dependent manner (3, 8 -10). However, it is not known if physiologic calcium is sufficient to activate and translocate cPLA 2 ␣ to membranes in cells or if activation also requires the generation of other activating lipids, such as the focus of this study, ceramide 1-phosphate (C1P).One possible activating lipid, phosphatidylinositol 4,5-diphosphate, was ruled out by Balboa and co-workers (11) as a lipid co-factor required for the translocation of the enzyme. This group showed that the interaction with this lipid (via its catalytic domain) was required for full activity of cPLA 2 ␣ after the enzyme translocated to the membrane (11). Another recent report by Leslie and co-workers (12) confirmed these findings, and a recent study by our laboratory corroborated these findings utilizing biophysical approaches (1). Specifically, we showed that C1P induced a dramatic increase of cPLA 2 ␣ activity strictly by increasing the residence time of cPLA 2 ␣ to membranes, whereas phosphatidylinositol 4,5-diphosphate enhanced the enzymes catalytic activity and membrane penetration (13,14).Recent...

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Section: Resultssupporting

confidence: 82%

Section: Discussioncontrasting

confidence: 46%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Ceramide 1-Phosphate Is Required for the Translocation of Group IVA Cytosolic Phospholipase A2 and Prostaglandin Synthesis

Lamour

Subramanian

Wijesinghe

et al. 2009

Journal of Biological Chemistry

View full text Add to dashboard Cite

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“…Conversion of Cer by CerK to ceramide-1-phosphate (C1P), which has anti-apoptotic properties, is emerging as an important factor in the regulation of apoptosis (149)(150)(151). CerKL was initially expected to act as a second, specifi c retinal CerK; however, it does not phosphorylate Cer ( 152 ) and its deletion in mice affects neither Cer nor C1P levels in the retina, suggesting it might use a novel lipid substrate, which has proved elusive ( 153 ). In spite of this, overexpression of CerKL isoforms protects cells from membrane permeability to several proteins, including cytochrome c ( 180 ), leading to cell death.…”

Section: Ceramide In the Retinamentioning

confidence: 99%

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

Rotstein

Miranda

Abrahan

et al. 2010

Journal of Lipid Research

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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...

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“…First, in Drosophila models of RP, genetic manipulation of sphingolipid metabolism has protective effects on retinal morphology and function; protection was achieved both by expressing neutral ceramidase in Drosophila eye, to reduce cellular levels of ceramide, and by knocking out one copy of a gene encoding a subunit of serine palmitoyl-CoA transferase (SPT), the enzyme that controls the rate-limiting step of ceramide biosynthesis (14). In humans, a direct genetic link between retinal degeneration and sphingolipidmediated apoptosis has been established with the discovery that a loss-of-function mutation in CERKL, a gene expressing ceramide kinase-like protein, caused autosomal recessive RP (15,16), although debate exists on the pathway leading to cell death in individuals with this mutation (17). In rat retinal neuronal primary cultures, oxidative stress increased ceramide levels and caused apoptosis, whereas these effects were blocked by addition of docosahexaenoic acid to stimulate antiapoptotic responses (18).…”

mentioning

confidence: 99%

Inhibition of ceramide biosynthesis preserves photoreceptor structure and function in a mouse model of retinitis pigmentosa

Strettoi

Gargini

Novelli

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Retinitis pigmentosa (RP) is a genetic disease causing progressive apoptotic death of photoreceptors and, ultimately, incurable blindness. Using the retinal degeneration 10 (rd10) mouse model of RP, we investigated the role of ceramide, a proapoptotic sphingolipid, in retinal degeneration. We also tested the possibility that photoreceptor loss can be slowed or blocked by interfering with the ceramide signaling pathway of apoptosis in vivo. Retinal ceramide levels increased in rd10 mice during the period of maximum photoreceptor death. Single intraocular injections of myriocin, a powerful inhibitor of serine palmitoyl-CoA transferase, the ratelimiting enzyme of ceramide biosynthesis, lowered retinal ceramide levels to normal values and rescued photoreceptors from apoptotic death. Noninvasive treatment was achieved using eye drops consisting of a suspension of solid lipid nanoparticles loaded with myriocin. Short-term noninvasive treatment lowered retinal ceramide in a manner similar to intraocular injections, indicating that nanoparticles functioned as a vector permitting transcorneal drug administration. Prolonged treatment (10-20 d) with solid lipid nanoparticles increased photoreceptor survival, preserved photoreceptor morphology, and extended the ability of the retina to respond to light as assessed by electroretinography. In conclusion, pharmacological targeting of ceramide biosynthesis slowed the progression of RP in a mouse model, and therefore may represent a therapeutic approach to treating this disease in humans. Transcorneal administration of drugs carried in solid lipid nanoparticles, as experimented in this study, may facilitate continuous, noninvasive treatment of patients with RP and other retinal pathologies.sphingolipid | apoptosis | electroretinography | morphology

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Wild-type levels of ceramide and ceramide-1-phosphate in the retina of ceramide kinase-like-deficient mice

Cited by 47 publications

References 14 publications

Ceramide 1-Phosphate Is Required for the Translocation of Group IVA Cytosolic Phospholipase A2 and Prostaglandin Synthesis

Ceramide 1-Phosphate Is Required for the Translocation of Group IVA Cytosolic Phospholipase A2 and Prostaglandin Synthesis

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

Inhibition of ceramide biosynthesis preserves photoreceptor structure and function in a mouse model of retinitis pigmentosa

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