Short chain ceramides

T. C. Stover, A. Sharma, G. P. Robertson, and M. Kester. Systemic delivery of liposomal short-chain ceramide limits solid tumor growth in murine models of breast adenocarcinoma. Clin. Cancer Res. 11 3465-3474 (2005). 

H]-ethanolamine into PE was inhibited by C6-ceramide in a dose and time-dependent manner (b) delayed disappearance of label from CDP-choline and CDP-ethanolamine in pulse-chase experiments indicated impaired conversion of these CDP-metaboUtes to PC and PE by CPT and EPT, respectively (c) the activities of CPT and EPT are decreased upon C6-ceramide treatment (see Eigure 2 adapted from Bladergroen et al. 1999b). In contrast to BHK cells the activity of CT was not affected significantly in rat-2 fibroblasts by short-chain ceramides. 

Allan, D., 2000, Lipid metabolic changes caused by short-chain ceramides and the connection with apoptosis. Biochem. J. 345 603-610... 

Recently, it has been shown that cell-permeable ceramides dramatically inhibited the synthesis of the two major membrane phospholipids, PC and PE (Bladergroen et al, 1999b Allan, 2000). The inhibition of phospholipid synthesis was rapid, within 2 h, and resulted in massive apoptosis after 16-24 h. The mechanism by which short-chain ceramides exert their effect on phospholipid synthesis is possibly cell type dependent. In baby-hamster kidney (BHK) fibroblasts PC synthesis was reduced at the level of CT, the putative rate-determining enzyme in the CDP-choline pathway (Allan, 2000). This conclusion was based solely on radio-label studies in combination with an earlier published observation (Wieder et al., 1995) showing that C2-SM (the SM generated from C2-ceramide by SM synthase, which was actively synthesized in the BHK-cells) inhibited CT activity in vitro. On the other hand, data obtained from studies with rat-2 fibroblasts clearly showed that short-chain ceramides regulate the synthesis of PC and PE mainly at the final step of the CDP-pathways. This conclusion was based on the following observations (a) incorporation of [3H]-choline into PC and... 

Short-chain analogs of D-e/7f/zro-ceramide trigger apoptosis, thereby mimicking the activity of endogenous ceramide. However, biophysical studies indicate that short-chain ceramides perturb the physical properties of model membrane bilayers differently than their long-chain counterparts. For example, they did not form the ceramide-rich domains that are observed characteristically with C16 0- and C18 0-ceramide (70). A study of the ability of ceramide analogs to displace sterols from rafts indicated that C12 0- and C16 0-ceramides are faithful mimics of natural ceramides in model bilayers (71). 

It is known that the short-chain ceramides often do not mimic the endogenous long-chain ceramides produced as a result of SHM-ase activity. However, the lipophilic nature of the both short- and long-chained ceramides makes these molecules likely candidates for altering biological processes as components of the lipid bUayer (Gidwani et al., 2003). We can therefore predict that ceramides accumulated in the lung because of exposure of CEES can alter the activity of the membrane-bound enzymes like CPT and can also act as a membrane perturbant. 

Gidwani, A., Brown, H.A., Holowka, D., and Baird, B. (2003). Disruption of Upid order by short-chain ceramides correlates with inhibition of phospholipase D and downstream signaling by FcepsilonRI. 

Ridgvray ND, Meriiam DL. Metabolism of short-chain ceramide and dihydroceramide analogues in Chinese hamster ovary (CHO) cells. Biochim Biophys Acta 1256(1995) 57-70. 

Sot J, Aranda FJ, Collado MI, Goni FM, Alonso A. Different effects of long- and short-chain ceramides on the gel-fluid and lamellar-hexagonal transitions of phospholipids a calorimetric, NMR, and x-ray diffraction study. Biophys J 88(2005) 3368-3380. 

Stover, T. and Kester, M. Liposomal delivery enhances short-chain ceramide-induced apoptosis of breast cancer cells. J Pharmacol Exp Ther, 307, 2003, 468-475. 

Perivascular and intra-arterial administration of neutral sphingomyelinase or exogenous short-chain ceramide resulted in a potent concentration-dependent constriction of cortical venules, followed by increased venular waU permeability, post-capillary venule rupture and micro-hemorrhaging (Altura et al, 2002). Treatment with antioxidants, calcium channel blockers and inhibitors of nuclear factor-KB activation could attenuate the effects of neutral sphingomyelinase and ceramide. These results suggest that ceramide can play a role in vasoconstriction and may be involved in the mechanisms resulting in brain injury and stroke. 

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