Ceramide Generation by the Reaper Protein Is Not Blocked by the Caspase Inhibitor, p35

Bose, Ron; Chen, Po; Loconti, Andrea; Grüllich, Carsten; Abrams, John; Kolesnick, Richard

doi:10.1074/jbc.273.44.28852

Cited by 45 publications

(35 citation statements)

References 59 publications

(66 reference statements)

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“…The samples were evaporated under a nitrogen stream, redissolved in 1,2 mL of 1M KOH in 90% methanol and heated at 90°C for 60 min to convert ceramide into sphingosine. This digestion procedure does not convert complex sphingolipids, such as sphingomyelin, galactosylceramide or glucosylceramide, into free sphingoid bases [30]. Samples were then partitioned by the addition of chloroform and water.…”

Section: Methodsmentioning

confidence: 99%

Hyperthyroidism Evokes Myocardial Ceramide Accumulation

Mikłosz

Łukaszuk

Chabowski

et al. 2015

Cell Physiol Biochem

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Background: Thyroid hormones (THs) are key regulators of cardiac physiology as well as modulators of different cellular signals including the sphingomyelin/ceramide pathway. The objective of this study was to examine the effect of hyperthyroidism on the metabolism of sphingolipids in the muscle heart. Methods: Male Wistar rats were treated for 10 days with triiodothyronine (T₃) at a dose of 50µg/100g of body weight. Animals were then anaesthetized and samples of the left ventricle were excised. Results: We have demonstrated that prolonged, in vivo, T₃ treatment increased the content of sphinganine (SFA), sphingosine (SFO), ceramide (CER) and sphingomyelin (SM), but decreased the level of sphingosine-1-phosphate (S1P) in cardiac muscle. Accordingly, the changes in sphingolipids content were accompanied by a lesser activity of neutral sphingomyelinase and without significant changes in ceramidases activity. Hyperthyroidism also induced activation of AMP-activated protein kinase (AMPK) with subsequently increased expression of mitochondrial proteins: cytochrome c oxidase IV (COX IV), β-hydroxyacyl-CoA dehydrogenase (β-HAD), carnityne palmitoyltransferase I (CPT I) and nuclear peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α). Conclusions: We conclude that prolonged T₃ treatment increases sphingolipids metabolism which is reflected by higher concentration of SFA and CER in heart muscle. Furthermore, hyperthyroidism-induced increase in heart sphingomyelin (SM) concentration might be one of the mechanisms underlying maintenance of CER at relatively low level by its conversion to SM together with decreased S1P content.

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Section: Methodsmentioning

confidence: 99%

Hyperthyroidism Evokes Myocardial Ceramide Accumulation

Mikłosz

Łukaszuk

Chabowski

et al. 2015

Cell Physiol Biochem

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“…Lipids were extracted, and ceramide was quantified by the diacylglycerol kinase reaction as described previously (18).…”

Section: Methodsmentioning

confidence: 99%

Natural Ceramide Reverses Fas Resistance of Acid Sphingomyelinase −− Hepatocytes

Pâris¹,

Grassmé

Cremesti³

et al. 2001

Journal of Biological Chemistry

116

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The role of the second messenger ceramide in Fasmediated death requires clarification. To address this issue, we generated hepatocytes from paired acid sphingomyelinase (ASMase; asmase) ؉/؉ and asmase ؊/؊ mice. asmase ؊/؊ hepatocytes, derived from 8-week-old mice, manifested normal sphingomyelin content and normal morphological, biochemical, and biologic features. Nonetheless, ASMase-deficient hepatocytes did not display rapid ceramide elevation or apoptosis in response to Jo2 anti-Fas antibody. asmase ؊/؊ hepatocytes were not inherently resistant to apoptosis because staurosporine, which did not induce early ceramide elevation, stimulated a normal apoptotic response. The addition of low nanomolar quantities of natural C 16 -ceramide, which by itself did not induce apoptosis, completely restored the apoptotic response to anti-Fas in asmase ؊/؊ hepatocytes. Other sphingolipids did not replace natural ceramide and restore Fas sensitivity. Overcoming resistance to Fas in asmase ؊/؊ hepatocytes by natural ceramide is evidence that it is the lack of ceramide and not ASMase which determines the apoptotic phenotype. The ability of natural ceramide to rescue the phenotype without reversing the genotype provides evidence that ceramide is obligate for Fas induction of apoptosis in hepatocytes.

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“…During embryogenesis, apoptosis is a normal process for programmed removal of unneeded cells and sculpting of tissues (Abrams et al, 1993). In flies, increased embryonic expression of the death-inducing signal Reaper triggers ceramide generation and activation of caspases, effectors of cell death (Pronk et al, 1996;Bose et al, 1998). A block of Sph-1-phosphate hydroylsis in sply mutants results in increased embryonic apoptosis (Herr et al, 2003).…”

Section: Null Slab Mutants Show No Detectable Increase In Cell Deathmentioning

confidence: 99%

Ceramidase Regulates Synaptic Vesicle Exocytosis and Trafficking

Rohrbough¹,

Rushton²,

Palanker³

et al. 2004

J. Neurosci.

100

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A screen for Drosophila synaptic dysfunction mutants identified slug-a-bed (slab). The slab gene encodes ceramidase, a central enzyme in sphingolipid metabolism and regulation. Sphingolipids are major constituents of lipid rafts, membrane domains with roles in vesicle trafficking, and signaling pathways. Null slab mutants arrest as fully developed embryos with severely reduced movement. The SLAB protein is widely expressed in different tissues but enriched in neurons at all stages of development. Targeted neuronal expression of slab rescues mutant lethality, demonstrating the essential neuronal function of the protein. C 5 -ceramide applied to living preparations is rapidly accumulated at neuromuscular junction (NMJ) synapses dependent on the SLAB expression level, indicating that synaptic sphingolipid trafficking and distribution is regulated by SLAB function. Evoked synaptic currents at slab mutant NMJs are reduced by 50 -70%, whereas postsynaptic glutamate-gated currents are normal, demonstrating a specific presynaptic impairment. Hypertonic saline-evoked synaptic vesicle fusion is similarly impaired by 50 -70%, demonstrating a loss of readily releasable vesicles. In addition, FM1-43 dye uptake is reduced in slab mutant presynaptic terminals, indicating a smaller cycling vesicle pool. Ultrastructural analyses of mutants reveal a normal vesicle distribution clustered and docked at active zones, but fewer vesicles in reserve regions, and a twofold to threefold increased incidence of vesicles linked together and tethered at the plasma membrane. These results indicate that SLAB ceramidase function controls presynaptic terminal sphingolipid composition to regulate vesicle fusion and trafficking, and thus the strength and reliability of synaptic transmission.

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Ceramide Generation by the Reaper Protein Is Not Blocked by the Caspase Inhibitor, p35

Cited by 45 publications

References 59 publications

Hyperthyroidism Evokes Myocardial Ceramide Accumulation

Hyperthyroidism Evokes Myocardial Ceramide Accumulation

Natural Ceramide Reverses Fas Resistance of Acid Sphingomyelinase −− Hepatocytes

Ceramidase Regulates Synaptic Vesicle Exocytosis and Trafficking

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