Lipid metabolic changes caused by short-chain ceramides and the connectionwith apoptosis

Authors
Citation
D. Allan, Lipid metabolic changes caused by short-chain ceramides and the connectionwith apoptosis, BIOCHEM J, 345, 2000, pp. 603-610
Citations number
28
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Biochemistry & Biophysics
Journal title
BIOCHEMICAL JOURNAL
ISSN journal
0264-6021 → ACNP
Volume
345
Year of publication
2000
Part
3
Pages
603 - 610
Database
ISI
SICI code
0264-6021(20000201)345:<603:LMCCBS>2.0.ZU;2-W
Abstract
The effects of the short-chain ceramides D-erythro-N-acetylsphingosine (C-2 -ceramide), 6-[N-(7-nitrobenz-2-oxa-1,3-diazole-4-yl)amino]hexanoyl-D-eryth ro-sphingosine (NBD-ceramide) and N-[4,4-difluoro-5,7-dimethyl-4-bora-3a,4a -diaza-s-indacene-3-pentanoyl]-D-erythro-sphingosine (DMB-ceramide) on the incorporation of [C-14]acetate into baby-hamster kidney (BHK) fibroblasts h ave been examined. C-2-ceramide at concentrations up to 20 mu M caused an i nhibition of synthesis of phosphatidylcholine (PtdCho), sphingolipids and c holesterol within 2 h. Similar effects in BHK cells were seen using other r adioactive tracers ([H-3]water, [H-3]palmitate and [H-3]choline) and using HL60 cells labelled with [C-14]acetate. The inhibition of PtdCho synthesis corresponded to an accumulation of label in diacylglycerol and triacylglyce rol, probably as a consequence of cytidylyltransferase blockade. With [H-3] choline label, the decrease in sphingomyelin synthesis could be partly acco unted for by accumulation of a slow-moving lipid, likely to be C-2-sphingom yelin. NBD-ceramide also reduced sphingomyelin and cholesterol biosynthesis , but had much less effect on PtdCho and acylglycerols. In contrast, the on ly apparent effect of DMB-ceramide was to inhibit synthesis of sphingomyeli n, with a reciprocal increase in DMB-sphingomyelin synthesis. However, all of these short-chain ceramides caused massive apoptosis after 18 h, whereas addition of N-acetyldihydrosphingosine or elevation of natural ceramide by treatment of cells with sphingomyelinase had little effect on lipid synthe sis or apoptosis. The present findings suggest that the apoptotic effect of short-chain ceramides is sometimes associated with inhibition of cytidylyl transferase, but is more closely correlated with a competitive inhibition o f normal sphingomyelin biosynthesis.