Associations between plasma ceramides and cognitive and neuropsychiatric manifestations in Parkinson's disease dementia
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AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO
The success of anticancer therapies that target ceramide requires a better understanding of ceramide metabolism. We hypothesized that ceramide-induced apoptosis in human breast cancer cells depends on the concentration of ceramide and the relative proportions of two metabolites: glucosylceramide (GC) and sphingomyelin (SPM). To investigate this hypothesis, we exposed MDA-MB-231 human breast cancer cells to increasing concentrations of [14C]C6-ceramide, a short-chain, cell-permeable ceramide analog. Lipid analysis was conducted by thin-layer chromatography and liquid scintillation counting. At a low concentration (0.63 \#956;M; 0.25 \#956;g/ml), ceramide did not affect cell viability; cells converted > 80% of C6-ceramide to C6-SPM and only 4% to C6-GC. As ceramide concentration increased, so did its rate of conversion to GC; at 6.3 \#956;M, > 70% of ceramide was converted GC and only 16% to SPM. At a ceramide concentration of 25 \#956;M, > 75% of ceramide was converted to GC and 14% to SPM, and cell viability dropped to 62% at 24 h. This response was similar in three other human breast cancer cell lines (MDA-MB-435, MCF-7, and T47D). Incubation of MDA-MB-231 cells with 1-phenyl-2-hexadecanoylamino-3-morpholino-1-propanol (PPMP), a specific GCS inhibitor, blocked conversion of C6-ceramide to GC. As a result, SPM synthesis increased to 75% and GC synthesis fell to 5%. Interestingly, cell viability dropped to zero after a 24-h exposure to C6-ceramide plus PPMP. This finding suggests that generating excess SPM does not block apoptosis. Our results reveal cellular trends in C6-ceramide metabolism, but they might not reflect scavenger pathways utilized to channel endogenous ceramides generated by anticancer agents. We are currently investigating the cyclosporin A analog PSC 833; this P-glycoprotein antagonist generates de novo (dihydro)ceramides (4-fold increase over control; 5.0 \#956;M; 24 h) and is cytotoxic (IC50= 6 \#956;M) in MDA-MB-231 cells. Our goal is to determine the metabolic fate of endogenously generated apoptosis-inducing lipids and thereby identify therapeutic targets on the metabolic pathway [Support: NIH/NIGMS grant no. GM077391].
Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5541.
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Abstract Background Ceramide is a crucial lipid in the stratum corneum ( SC ) which maintains the barrier function and hydration of the skin. In atopic dermatitis ( AD ) patients who have defective skin barrier function, ceramide levels are altered. We previously reported that although the amount of total ceramide was lower in involved skin compared with uninvolved skin of AD patients and with healthy control skin, the amounts of smaller ceramide species of Cer[ NS ] (<40 total carbons, which are total carbons of both sphingoid base and amide‐linked fatty acid), especially Cer[ NS ] with 34 total carbons (C34‐Cer[ NS ]), were higher. However, the enzyme(s) that produces the higher levels of smaller ceramide species in involved skin of AD patients was unclear. Objective To identify the enzyme(s) that produces higher levels of smaller ceramide species of Cer[ NS ] in the involved skin of AD patients. Methods Eight female Caucasian subjects who were diagnosed with AD on their arms (age range: 21–45 years) were enroled in this study. We compared ceramide levels in the SC and the expression levels of enzymes involved in ceramide metabolism using real‐time PCR and immunohistochemistry between involved and uninvolved skin of AD patients. Results Level of mRNA encoding ceramide synthase 4 ( CERS 4), which is one of the enzymes that synthesize ceramide from a sphingoid base and an amide‐linked fatty acid, was significantly higher in involved skin than in uninvolved skin ( P < 0.01). Additionally, the protein expression level of CERS 4 in the epidermis was also higher in involved skin compared with uninvolved skin. The expression level of CERS 4 correlated with the amount of C34‐Cer[ NS ] ( P < 0.01) and the skin hydration value ( P < 0.05). Conclusions The elevated expression level of CERS 4 contributes to the increase of C34‐Cer[ NS ] and the impaired SC barrier function in involved skin of AD patients.
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Acid sphingomyelinase
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A feature of emphysema is the destruction of the walls of the airspaces in the bronchioles. Ceramide is a membrane sphingolipid that induces apoptosis. In lung samples from human emphysema, ceramide levels were much higher than in lungs from patients without emphysema. Emphysema can be induced in rats or mice with the vascular endothelial growth factor receptor antagonist SU5416, and this is associated with increased levels of ceramide. Fumonisin B1 is a specific inhibitor of dihydroceramide synthase. Fumonisin B1 inhibited the production of ceramide in response to SU5416, and reduced the SU5418-induced increase in alveolar diameter and number of severely damaged distal airspaces. A synthetic short-chain ceramide, C12 ceramide instilled into the trachea of mice increased lung ceramide levels, and induced alveolar cell apoptosis and septal destruction. These results suggest that ceramide is a target in emphysema, and ways of reducing the effects of ceramide in the lung need to be investigated.
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Ceramide accumulation in the cell can occur from either hydrolysis of sphingomyelin or by de novo synthesis. In this study, we found that blocking de novo ceramide synthesis significantly inhibits ceramide accumulation and subsequent cell death in response to tumor necrosis factor α. When cells were pre‐treated with glutathione, a proposed cellular regulator of neutral sphingomyelinase, inhibition of ceramide accumulation at early time points was achieved with attenuation of cell death. Inhibition of both pathways achieved near‐complete inhibition of ceramide accumulation and cell death indicating that both pathways of ceramide generation are stimulated. This illustrates the complexity of ceramide generation in cytokine action.
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A new ceramide consisting of 6-hydroxysphingosine linked to a non-hydroxyacid was found in human epidermal lipid. This ceramide was sought because its fatty acid and sphingoid moieties are present in other combinations in human epidermal ceramides. To isolate the new ceramide, the mixture of ceramides in human epidermal lipid was first separated into fractions by thin-layer chromatography (TLC), and then each fraction was further purified by TLC after acetylation of all hydroxyl groups. TLC after acetylation revealed that one of the fractions isolated in the first TLC step contained two components, namely, the ceramide consisting of sphingosine linked to an α-hydroxyacid and an unknown ceramide. The new ceramide constituted about 9% of the total ceramides, and was shown by NMR spectroscopy to be N-acyl-6-hydroxysphingosine.— Stewart, M. E., and D. T. Downing. A new 6-hydroxy-4-sphingenine-containing ceramide in human skin. J. Lipid Res. 1999. 40: 1434–1439.
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