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PubMed2006

Modulation of the activity and arachidonic acid selectivity of group X secretory phospholipase A2 by sphingolipids.

To investigate the role of sphingomyelin (SM) in the regulation of inflammatory reactions, we studied its effect on the activity and fatty acid specificity of group X secretory phospholipase A(2) (sPLA(2)X). Compared with other phospholipases, recombinant sPLA(2)X released more arachidonate from HDL. Pretreatment of HDL with sphingomyelinase (SMase) C activated the sPLA(2)X activity, but the release of arachidonate was stimulated less than that of linoleate. In liposomes containing synthetic phosphatidylcholines (PCs), sPLA(2)X showed no clear selectivity among the various sn-2 unsaturated fatty acids. However, when SM was incorporated into liposomes at 30 mol%, the enzyme exhibited strong preference for arachidonate, although its overall activity was inhibited. Degradation of liposomal SM by SMase C resulted in sPLA(2)X activation and loss of its arachidonate preference. Incorporation of ceramide into HDL or PC liposomes activated the enzyme activity, the release of arachidonate being stimulated more than that of linoleate. SM-deficient cells released more arachidonate than normal cells in response to exogenous sPLA(2)X. SMase pretreatment of normal cells stimulated the release of arachidonate by the exogenous sPLA(2)X. These results show that SM not only inhibits sPLA(2)X activity but also contributes to its selectivity for arachidonate, whereas ceramide stimulates the hydrolysis of arachidonate-containing PCs.

Animals↗
PubMed1993

Epithelial sphingolipid sorting is insensitive to reorganization of the Golgi by nocodazole, but is abolished by monensin in MDCK cells and by brefeldin A in Caco-2 cells.

In epithelial MDCK and Caco-2 cells, short-chain analogs of glucosylceramide and sphingomyelin are delivered from the Golgi to the cell surface with different apical/basolateral polarities, which results in an apical enrichment of the glycolipid glucosylceramide over the phospholipid sphingomyelin. Here, we have interfered with the integrity of the Golgi complex in various ways and tested the effects on lipid transport and sorting. Nocodazole, which depolymerizes microtubules, dispersed the Golgi over the cytoplasm of MDCK cells and reduced transport of newly synthesized C6-NBD-(N-6[7-nitro-2,1,3-benzoxadiazol-4-yl]aminocaproyl)-glucosy lceramide and C6-NBD-sphingomyelin to the apical surface by 40%. The lipids were not mistargeted to the basolateral surface and upon removal of nocodazole, apical transport recovered. Nocodazole did not affect the apical enrichment of glucosylceramide over sphingomyelin. The ionophore monensin led to swelling of the Golgi of MDCK cells and inhibited lipid transport to the cell surface by 30-50%. Whereas sphingomyelin transport to both surface domains was equally affected, monensin mainly inhibited apical transport of glucosylceramide. At 10-20 microM of monensin, the two lipids displayed the same polarity of delivery: sorting between the two lipids was abolished. Brefeldin A at 1 microgram/ml, which resulted in disruption of the Golgi in HepG2 cells and completely inhibited protein secretion, had no inhibitory effect on transport of the C6-NBD-lipids to the surface. The same was observed in Caco-2 cells. However, brefeldin A selectively shifted transport of sphingomyelin towards the apical direction which abolished the apical enrichment of glucosylceramide over sphingomyelin. Caco-2 cells were used because in MDCK cells brefeldin A did not change Golgi structure nor lipid transport and sorting. In summary, modification of the Golgi by monensin and brefeldin A, but not nocodazole, interfered with the sorting event by which glucosylceramide is enriched over sphingomyelin in the transport pathway from the Golgi to the apical surface.

Animals↗
PubMed1999

The human multidrug resistance protein MRP1 translocates sphingolipid analogs across the plasma membrane.

Recently, we have provided evidence that the ABC-transporter MDR1 P-glycoprotein translocates analogs of various lipid classes across the apical plasma membrane of polarized LLC-PK1 cells transfected with MDR1 cDNA. Here, we show that expression of the basolateral ABC-transporter MRP1 (the multidrug resistance protein) induced lipid transport to the exoplasmic leaflet of the basolateral plasma membrane of LLC-PK1 cells at 15 degreesC. C6-NBD-glucosylceramide synthesized on the cytosolic side of the Golgi complex, but not C6-NBD-sphingomyelin synthesized in the Golgi lumen, became accessible to depletion by BSA in the basal culture medium. This suggests the absence of vesicular traffic and direct translocation of C6-NBD-glucosylceramide by MRP1 across the basolateral membrane. In line with this, transport of the lipid to the exoplasmic leaflet depended on the intracellular glutathione concentration and was inhibited by the MRP1-inhibitors sulfinpyrazone and indomethacin, but not by the MDR1 P-glycoprotein inhibitor PSC 833. In contrast to the broad substrate specificity of the MDR1 P-glycoprotein, MRP1 selectively transported C6-NBD-glucosylceramide and C6-NBD-sphingomyelin, the latter only when it was released from the Golgi lumen by brefeldin A. This shows the specific nature of the lipid translocation. We conclude that the transport activity of MDR1 P-glycoprotein and MRP1 must be taken into account in studies on the transport of lipids to the cell surface.

Animals↗
PubMed1996

Effects of mepanipyrim on intracellular trafficking: a comparative study on its effects on exocytic and endocytic trafficking of proteins, sphingolipids, and cholesterol.

Mepanipyrim, N-(4-methyl-6-prop-1-ynylpyrimidin-2-yl)aniline, diminished the cell surface expression of envelope glycoproteins of Newcastle disease and vesicular stomatitis viruses at concentrations where their synthesis was not profoundly affected. Intoxication by diphtheria toxin and ricin and recycling of transferrin were not affected even when cells were treated with mepanipyrim for 2 h before the addition of these probes, indicating that mepanipyrim does not act on the endocytic and recycling pathways of these proteins. Metabolic conversion of C6-NBD-ceramide to sphingomyelin and its back-exchange to the medium was also not affected, but synthesis and back-exchange of C6-NBD glucosylceramide were greatly influenced, and an accumulation of LDL-derived, unesterified cholesterol was induced by the drug. These results are discussed relating to the site(s) of action of mepanipyrim.

Animals↗
PubMed2006

Paired helical filaments contain small amounts of cholesterol, phosphatidylcholine and sphingolipids.

By using qualitative and quantitative high-performance thin layer chromatography (hpTLC) we found lipids associated with purified Alzheimer's (AD) paired helical filaments (PHF) in an amount of 1.4+/-0.2% of the total anhydrous mass. Compared to normal brain tissue these lipids have an unusual lipid class composition. The most prominent lipid classes were phosphatidylcholine (PC), cholesterol (CH), galactocerebrosides (GC) and sphingomyelin (SM). In addition, the use of micro high-performance liquid chromatography (HPLC) in combination with matrix-assisted laser desorption and ionisation time-of-flight mass spectrometry (MALDI-TOF-MS) allowed the determination of the molecular species of the polar membrane lipid classes present in PHF. The lipid pattern of intracellular PHF shows many characteristics of the conserved lipid pattern previously described for extracellular amyloid fibrils, suggesting similarities in their pathway of formation.

Aged↗
PubMed1999

Lipid phosphate phosphohydrolase-1 degrades exogenous glycerolipid and sphingolipid phosphate esters.

Lipid phosphate phosphohydrolase (LPP)-1 cDNA was cloned from a rat liver cDNA library. It codes for a 32-kDa protein that shares 87 and 82% amino acid sequence identities with putative products of murine and human LPP-1 cDNAs, respectively. Membrane fractions of rat2 fibroblasts that stably expressed mouse or rat LPP-1 exhibited 3.1-3. 6-fold higher specific activities for phosphatidate dephosphorylation compared with vector controls. Increases in the dephosphorylation of lysophosphatidate, ceramide 1-phosphate, sphingosine 1-phosphate and diacylglycerol pyrophosphate were similar to those for phosphatidate. Rat2 fibroblasts expressing mouse LPP-1 cDNA showed 1.6-2.3-fold increases in the hydrolysis of exogenous lysophosphatidate, phosphatidate and ceramide 1-phosphate compared with vector control cells. Recombinant LPP-1 was located partially in plasma membranes with its C-terminus on the cytosolic surface. Lysophosphatidate dephosphorylation was inhibited by extracellular Ca2+ and this inhibition was diminished by extracellular Mg2+. Changing intracellular Ca2+ concentrations did not alter exogenous lysophosphatidate dephosphorylation significantly. Permeabilized fibroblasts showed relatively little latency for the dephosphorylation of exogenous lysophosphatidate. LPP-1 expression decreased the activation of mitogen-activated protein kinase and DNA synthesis by exogenous lysophosphatidate. The product of LPP-1 cDNA is concluded to act partly to degrade exogenous lysophosphatidate and thereby regulate its effects on cell signalling.

Animals↗