Involvement of de NovoCeramide Biosynthesis in Tumor Necrosis Factor-α/Cycloheximide-induced Cerebral Endothelial Cell Death

Xu, Jianlong; Yeh, Chen‐Hsiung; Chen, Shawei; He, Luming; Sensi, Stefano L.; Canzoniero, Lorella M.T.; Choi, Dennis W.; Hsu, Chung Y.

doi:10.1074/jbc.273.26.16521

Cited by 175 publications

(150 citation statements)

References 42 publications

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“…Previously, it was suggested that heat stress signaling could also be mediated via de novo synthesis of sphingoid bases (9,10). Also in mammalian cells, de novo synthesis of ceramide has been suggested to be important in apoptosis (32)(33)(34)(35). Despite our data, we cannot rule out the possibility that the generation of PHS by hydrolysis of other sphingolipids such as PHC, inositol phosphoceramide, and others may also play a role in growth inhibition.…”

Section: Discussioncontrasting

confidence: 50%

Phytosphingosine as a Specific Inhibitor of Growth and Nutrient Import in Saccharomyces cerevisiae

Chung¹,

Mao²,

Heitman³

et al. 2001

Journal of Biological Chemistry

110

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In this study, we used a combination of pharmacological and genetic approaches to determine which endogenous sphingolipid is the likely mediator of growth inhibition. When cells were treated with exogenous phytosphingosine (PHS, 20 M) or structurally similar or metabolically related molecules, including 3-ketodihydrosphingosine, dihydrosphingosine, C 2 -phytoceramide (PHC), and stearylamine, only PHS inhibited growth. Also, PHS was shown to inhibit uptake of uracil, tryptophan, leucine, and histidine. Again this effect was specific to PHS. Because of the dynamic nature of sphingolipid metabolism, however, it was difficult to conclude that growth inhibition was caused by PHS itself. By using mutant yeast strains defective in various steps in sphingolipid metabolism, we further determined the specificity of PHS. The elo2⌬ strain, which is defective in the conversion of PHS to PHC, was shown to have slower biosynthesis of ceramides and to be hypersensitive to PHS (5 M), suggesting that PHS does not need to be converted to PHC. The lcb4⌬ lcb5⌬ strain is defective in the conversion of PHS to PHS 1-phosphate, and it was as sensitive to PHS as the wild-type strain. The syr2⌬ mutant strain was defective in the conversion of DHS to PHS. Interestingly, this strain was resistant to high concentrations of DHS (40 M) that inhibited the growth of an isogenic wild-type strain, demonstrating that DHS needs to be converted to PHS to inhibit growth. Together, these data demonstrate that the active sphingolipid species that inhibits yeast growth is PHS or a closely related and yet unidentified metabolite.Certain sphingolipid metabolites including ceramide, sphingosine, and sphingosine 1-phosphate have pleiotropic effects on cellular growth and proliferation. The yeast Saccharomyces cerevisiae has emerged as an excellent model system for studying sphingolipid-mediated signal transduction. First, compared with over 300 different kinds of sphingolipids found in mammalian cells, there is only a limited number of sphingolipid species in the yeast, which simplifies lipid analysis (2, 3). Moreover, the basic structure, biosynthesis, and metabolism of sphingolipids are well conserved between mammalian and yeast systems. Second, many yeast genes in the sphingolipid biosynthetic and metabolic pathways have been cloned, providing opportunities for studying the effects of endogenous sphingolipids using genetics tools. Finally, although this is not exclusive to sphingolipid studies, yeast genetics provide excellent tools to identify and characterize components in signal transduction pathways (4 -6).Evidence for conservation of the sphingolipid signaling pathway in yeast comes from several studies. These include demonstrating that D-erythro-ceramide inhibited yeast cell growth in liquid culture and activated a protein phosphatase 2A that could be inhibited by okadaic acid (7). Later, Nickels and Broach (8) showed that ceramide inhibited yeast cell growth by arresting cell cycle at G 1 phase and that ceramide-activated protein phosphatase is com...

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Section: Discussioncontrasting

confidence: 50%

Phytosphingosine as a Specific Inhibitor of Growth and Nutrient Import in Saccharomyces cerevisiae

Chung¹,

Mao²,

Heitman³

et al. 2001

Journal of Biological Chemistry

110

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“…TNF-␣ has been shown to elevate cellular ceramide by both stimulating de novo ceramide synthesis (82,83) and increasing ceramide generation from sphingomyelin hydrolysis (84). In this study, we found an age-associated elevation in both TNF-␣ and ceramide and, thus, one might argue that the higher ceramide levels are due to elevated TNF-␣ production with aging.…”

Section: Discussionsupporting

confidence: 45%

Aging Up-Regulates Expression of Inflammatory Mediators in Mouse Adipose Tissue

Ren

Pae

et al. 2007

The Journal of Immunology

255

209

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The incidence of type 2 diabetes (T2D) increases with age. Low‐grade inflammation in AT is implicated in development of insulin resistance and T2D. We conducted a study to determine if inflammatory responses are upregulated with age in AT. Results show that visceral AT from old mice had significantly higher expression of mRNA levels of IL‐1β, IL‐6, TNF‐α, and COX‐2 than those of young mice (263, 208, 165, and 73%, higher respectively). In determining the relative contribution of different components of AT to these age‐related changes, we found that adipocytes (AD) from old mice produced significantly more (2 to 3 folds) IL‐6 and PGE2 than those from young mice while no significant age difference was observed in their production by stromal vascular cells. There was no significant effect of age on number of Mϕ/g AT and Mϕ of either age group produced significantly more IL‐6 when incubated in conditioned medium from old AD compared to that of young. Blocking NF‐κB activation reduced IL‐6 production while addition of ceramide or sphingomyelinase increased IL‐6 production in young AD to a level comparable to that of old AD. Inhibiting de novo ceramide synthesis reduced IL‐6 production by AD. NF‐κB regulates expression of inflammatory products including COX‐2 and IL‐6. Ceramide was shown to increase COX‐2 expression in aged Mϕ through NF‐κB activation. Thus, these data suggest a potential role for ceramide and NF‐κB in the age‐related increase of AT inflammation. Further research is needed to fully determine the underlying mechanisms of the observed effects and their contribution to T2D in the aged. Supported by USDA #58‐1950‐9‐001 and NIA #R01 AG009140‐10A1.

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“…Therefore, TNF-α, one of many cytokines, holds a very central role in arteriosclerosis. A direct relationship has been identified between TNF-α and ceramide, in which TNF-α has been shown to be responsible for increases in intracellular (vascular endothelial cells) ceramide content [24,25]. Zhang et al found that TNF-α could trigger SMase and augment superoxide anion generation in endothelial cells.…”

Section: Tumor Necrosis Factor-α and Ceramidementioning

confidence: 99%

“…Zhang et al found that TNF-α could trigger SMase and augment superoxide anion generation in endothelial cells. Furthermore, they found that, indeed, TNF-α caused a rapid increase of superoxide free radical within 2 minutes, but the effect was not sustained and dissipated after 60 minutes [24,25]. TNF-α can stimulate ceramide formation via the activation of both neutral and acid SMases, accompanied by ROS such as superoxide anion production [26].…”

Section: Tumor Necrosis Factor-α and Ceramidementioning

confidence: 99%

Ceramide: A common pathway for atherosclerosis?

et al. 2008

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Plasma sphingomyelin concentration is correlated with the development of atherosclerosis. It has been found to exist in significantly higher concentrations in aortic plaque. This appears to have clinical relevance as well as it has been shown to be an independent predictor of coronary artery disease. Ceramide, the backbone of sphingolipids, is the key component which affects atherosclerotic changes through its important second-messenger role. This paper sheds light on some of the current literature supporting the significance of ceramide with respect to its interactions with lipids, inflammatory cytokines, homocysteine and matrix metalloproteinases. Furthermore, the potential therapeutic implications of modulating ceramide concentrations are also discussed.

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Involvement of de NovoCeramide Biosynthesis in Tumor Necrosis Factor-α/Cycloheximide-induced Cerebral Endothelial Cell Death

Cited by 175 publications

References 42 publications

Phytosphingosine as a Specific Inhibitor of Growth and Nutrient Import in Saccharomyces cerevisiae

Phytosphingosine as a Specific Inhibitor of Growth and Nutrient Import in Saccharomyces cerevisiae

Aging Up-Regulates Expression of Inflammatory Mediators in Mouse Adipose Tissue

Ceramide: A common pathway for atherosclerosis?

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