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Department of Biochemistry and Pharmacy, Åbo Akademi University, Turku, Finland
Correspondence: Address reprint requests to Thomas Nyholm, Dept. of Biochemistry and Pharmacy, Åbo Akademi University, P.O. Box 66, FIN 20521 Turku, Finland. Tel.: 3-582-215-4816; Fax: 3-582-215-4745; E-mail: thomas.nyholm{at}abo.fi.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONEXPERIMENTAL PROCEDURESRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONEXPERIMENTAL PROCEDURESRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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). Because of these different properties it is thought that SMs have stronger intermolecular interactions between neighboring molecules and with cholesterol than PCs (Slotte, 1999; Ohvo-Rekila et al., 2002). It has been suggested that the favorable interactions between SM and cholesterol gives rise to cholesterol and SM-rich domains or rafts. The rafts are believed to be important in cellular processes such as protein and lipid transport and sorting, as well as in signal transduction (Simons and Ikonen, 1997; Brown and London, 2000; Simons and Toomre, 2000). The nature of the interactions between SM and cholesterol remains unclear. However, it seems that the interactions are stabilized by hydrogen bonding (Sankaram and Thompson, 1990; Bittman et al., 1994; Veiga et al., 2001).
Most of the naturally occurring SMs have the phosphocholine headgroup linked to the hydroxyl group on carbon one of a long-chain base (most often an 18-carbon amine diol), and have a long and highly saturated acyl chain linked to the amide group on carbon two of the long-chain base (for a review, see Barenholz, 1984). These SMs have the D-erythro-(2S,3R) configuration of the long-chain base (Sarmientos et al., 1985). In cultured cells (i.e., human skin fibroblast and baby hamster kidney cells) 
90–95% of the SMs contain sphingosine (1,3-dihydroxy-2-amino-4-octadecene) as the long-chain base, whereas the remainder has sphinganine (1,3-dihydroxy-2-amino-4-octadecane) as the base (Ramstedt et al., 1999). The latter SMs are also called dihydrosphingomyelins (DHSM). Although it is currently not known why cells need both SMs and DHSMs, it is remarkable that DHSM accounts for 50% of all phospholipids in human lens membranes (Byrdwell and Borchman, 1997). Human eye lens membranes are known to be highly enriched in both DHSM and cholesterol (Li et al., 1985; Byrdwell and Borchman, 1997). This could indicate that cholesterol interacts especially well with DHSM, and that DHSM possibly could function as an efficient solubilizer of cholesterol in the human lens cells.
The physico-chemical properties of DHSM are not as well documented as those of SM, but it is known that the lack of the trans-double bond between carbons 4 and 5 in DHSM leads to the formation of more ordered membranes with a higher melting temperature (Tm) compared to acyl-chain-matched SM (Barenholz et al., 1976; Kuikka et al., 2001; Nyholm et al., 2003). As a consequence, DHSMs are even more likely than SM to undergo lateral phase separation in bilayer membranes, and may thus contribute to the formation of laterally condensed domains in biomembranes (Brown, 1998; Kuikka et al., 2001).
Sphingolipid and cholesterol-rich cell membranes are known to be resistant to Triton X-100-induced solubilization at low temperatures (Brown and Rose, 1992; Schroeder et al., 1994; London and Brown, 2000). Model membrane studies have shown that pure SM membranes are less resistant to Triton X-100 solubilization compared to DPPC membranes, but that addition of cholesterol increased the resistance markedly (Patra et al., 1999; Nyholm and Slotte, 2001). How cholesterol inclusion affects the resistance to detergent-induced solubilization in DHSM membranes is not known, but it is likely that detergent resistance is linked to the presence of a liquid-ordered phase in cholesterol-rich membranes also containing mostly saturated (sphingo)lipids. In the present work we have studied how the thermotropic phase behavior of 16:0-DHSM and 16:0-SM was affected by the presence of cholesterol and lathosterol, and compared the miscibility of 16:0-DHSM in DPPC and 16:0-SM bilayer membranes. Lathosterol that differs from cholesterol by having a double bond between carbons 7 and 8 (in cholesterol the double bond is positioned between carbons 5 and 6) has been shown to have dramatically different membrane properties than cholesterol (Leppimaki et al., 2000), and was therefore included in the study.
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EXPERIMENTAL PROCEDURES |
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TOPABSTRACTINTRODUCTIONEXPERIMENTAL PROCEDURESRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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), and purified as described for 16:0-SM. Its identity was also verified by mass spectroscopy. Cholesterol and lathosterol were obtained from Sigma Chemicals (St. Louis, MO), whereas 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) was from Avanti Polar Lipids. Stock solutions of lipids were prepared in hexane/2-propanol (3/2, v/v), stored in the dark at -20°C, and warmed to ambient temperature before use. The water used was purified by reverse osmosis followed by passage through a Millipore UF Plus water purification system, to yield a product with a resistivity of 18.2 M
cm.
Differential scanning calorimetry
Differential scanning calorimetry (DSC) measurements were performed in a Calorimetry Sciences Corporation Nano II differential scanning calorimeter (Provo, UT). The samples were prepared from lipid stock solutions, which were evaporated under a constant flow of N2, after which they were placed in vacuum for 1 h. The dry lipids were hydrated in 60°C water and sonicated for 1 min at a 60°C in a Bransonic 2510 bath sonicator (Branson Ultrasonics Corporation, CT). The final concentration of phospholipid in the solutions was 1.4 mM, whereas the final sterol concentration varied between 0 and 0.035 mM. The resulting lipid solutions contained 0, 5, 10, 15, 20, or 25 mol % sterol. The suspensions were degassed under vacuum before being loaded into the DSC. Heating scans were run with a rate of 0.5°C/min. Data analysis was performed using the software provided by the DSC manufacturer (CPcalc 2.1) and Microcal Origin 6.0.
The ideality of the binary phospholipid mixtures was assessed according to Mabrey and Sturtevant (1976). The ideal phase diagram was calculated according to
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and ß are defined as
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HA and HB are the transition enthalpies of the pure lipids, and TA and TB are their absolute transition temperatures. The onset and completion temperatures of the measured data were corrected for the contributions to the total transition widths of the pure phospholipids, as described (Mabrey and Sturtevant, 1976). |
RESULTS |
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TOPABSTRACTINTRODUCTIONEXPERIMENTAL PROCEDURESRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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, 1981; McMullen et al., 1993, 1995; McMullen and McElhaney, 1995; Maulik and Shipley, 1996a). The sharp component results from the melting of cholesterol-poor, and the broad component from the melting of cholesterol-rich, membrane domains. Based on this we will therefore be referring to the higher-melting transition as the sterol-induced transition. Both the enthalpy and the Tm of the transition were affected by an increasing sterol concentration, as shown in Figs. 2 and 3. In 16:0-SM bilayers sterol inclusion decreased the Tm from 41°C in a pure 16:0-SM bilayer to 37.5°C at 20 mol % sterol. The enthalpy of the main transition was decreased almost linearly with the sterol concentration in 16:0-SM bilayers. This finding is in accordance with results published in Maulik and Shipley (1996a). It has been extensively reported that increasing cholesterol concentrations in bilayer membranes leads to diminished phase transition enthalpies (Ladbrooke et al., 1968; McMullen et al., 1993; McMullen and McElhaney, 1995; Mannock et al., 2003). At 25 mol % sterol the main transition disappeared and only the sterol-induced transition remained. Sterol inclusion in 16:0-DHSM bilayers had similar effects on Tm and the enthalpy of the main transition, but the Tm decreased only by 1°C, in contrast to the almost 3.5°C decrease in Tm seen for 16:0-SM bilayers. Furthermore, the main transition was still clearly observable at 25 mol % sterol in 16:0-DHSM, in contrast to the 16:0-SM system. The sterol-induced transition was first detectable at 5 mol % sterol both in 16:0-SM and 16:0-DHSM bilayers. As the sterol concentration in the sphingomyelin bilayers increased, the sterol-induced transition shifted to higher temperatures. Qualitatively similar results have been reported for binary mixtures of egg SM and cholesterol (Mannock et al., 2003). The pretransitions in pure 16:0-SM and 16:0-DHSM bilayers were at 27.5 and 41.5°C, respectively (Kuikka et al., 2001). As the sterol concentration in the bilayers was increased the enthalpy of the pretransitions decreased. At 10 mol % sterol the pretransitions were no longer measurable (data not shown). The pretransitions in 16:0-SM and 16:0-DHSM responded differently to an increased sterol concentration (Fig. 4). In 16:0-SM bilayers the pretransition occurred at higher temperatures as the sterol concentration was increased from 0 to 5 mol %. In 16:0-DHSM bilayers, on the other hand, the pretransition was observed at lower temperatures as the sterol concentration was increased. Inclusion of lathosterol had similar effects on the phase transitions of both the sphingolipid bilayers as had cholesterol. However, in bilayers containing lathosterol the sterol-induced phase transitions were shifted to higher temperatures than in bilayers containing the corresponding concentrations of cholesterol.
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37 kJ/mol (XDHSM = 1) and 28 kJ/mol (XDHSM = 0.5). The main transition temperatures of DPPC and 16:0-DHSM mixtures were lower than that for pure DPPC bilayers until XDHSM >0.5, after which the transition temperature was raised. The enthalpy of the main transition was 27 kJ/mol until XDHSM = 0.5, above which it increased toward 37 kJ/mol in pure DHSM membranes. No low-temperature subtransitions could be observed for pure 16:0-DHSM or 16:0-SM bilayers with the experimental conditions used in this study (data not shown). However, this was seen for pure DPPC (data not shown), as has been reported previously (McMullen and McElhaney, 1995).
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, with the results being shown in Fig. 7. For comparison we also included a phase diagram of binary mixtures of 16:0-SM and DPPC. The phase diagrams for 16:0-SM:DPPC and DPPC:16:0-DHSM mixtures deviated clearly from the simulated ideal curves, while the 16:0-SM:16:0-DHSM phase diagram seemed to mix fairly ideally. Taken together, the results show that 16:0-DHSM mixed better with 16:0-SM than with DPPC.
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). On cooling the bilayers, the pretransition temperatures were at a markedly lower temperature (as compared to the heating thermogram), but the temperature shifts induced by mixing two components had very similar trends as shown in Fig. 8 for the heating thermograms (data for cooling thermograms are not shown).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONEXPERIMENTAL PROCEDURESRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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Sterol interactions with 16:0-DHSM and 16:0-SM
Using DSC we compared how sterol inclusion affected the thermotropic behavior of 16:0-DHSM and 16:0-SM bilayers. The literature already contains a number of publications where the thermal behavior of sphingomyelin and binary mixtures of sphingomyelin and cholesterol have been studied (e.g., Barenholz et al., 1976; Calhoun and Shipley, 1979; Estep et al., 1979, 1981; Maulik and Shipley, 1996a,b; Mannock et al., 2003). The thermotropic behavior of DHSM is not as well documented, and only pure DHSM membranes have been studied up to now (Barenholz et al., 1976; Kuikka et al., 2001).
As expected, the thermograms recorded for the binary cholesterol and 16:0-DHSM or 16:0-SM were bimodal, and the total enthalpy of the transition decreases with an increasing cholesterol concentration. The results with binary cholesterol:16:0-SM mixtures were similar to previously published results (Calhoun and Shipley, 1979; Estep et al., 1979; Maulik and Shipley, 1996b), but with regard to the thermograms recorded on 16:0-DHSM:cholesterol mixtures the results were different. Inclusion of cholesterol affected the Tm of the main transition less in DHSM membrane than in SM membranes. This indicates that the gel phase in 16:0-DHSM membranes was less destabilized by the presence of cholesterol than in 16:0-SM membranes. A similar observation was made in a study of membranes composed of DPPC and sterols with different side chains (McMullen et al., 1995). In that study it was shown that the decrease in Tm upon sterol incorporation was larger when the hydrophobic mismatch between the sterol and DPPC increased. Hence, an interpretation of our results would be that 16:0-DHSM would have a better hydrophobic fit with cholesterol than 16:0-SM, and that the affinity between cholesterol and 16:0-DHSM consequently was greater compared with the 16:0-SM system. This interpretation agrees with the findings in our previous 16:0-DHSM paper (Kuikka et al., 2001). The Tm and cooperativity of the broad component, or the sterol-induced transition, changed in a similar fashion in both SM and DHSM membrane as a function of an increasing cholesterol concentration. However, the enthalpy of the broad transition was markedly lower in 16:0-DHSM membranes than in 16:0-SM membranes.
Thermograms recorded on pure phospholipid membranes showed a pretransition at 41.5°C in DHSM and 27.5°C in SM membranes, which is in fairly good agreement with previous results (Bar et al., 1997; Ramstedt and Slotte, 1999; Kuikka et al., 2001). The slightly lower transition temperatures in both the main and the pretransition observed in this study could be due to a slightly higher degree of impurity in the samples used in the present study. An interesting notion concerning the pretransitions is that inclusion of low cholesterol concentrations shifted the pretransition toward higher temperatures in SM membranes, but toward lower temperatures in DHSM membranes. The cause of this effect remains unclear. In phosphatidylcholine membranes the pretransition has been shown to decrease with increasing cholesterol (McMullen et al., 1993). Previous reports have shown that the pretransition is abolished upon incorporation of 5 mol % cholesterol (McElhaney, 1982; McMullen et al., 1993; McMullen and McElhaney, 1995), which agreed well with what was observed in this work.
An earlier study has shown that lathosterol-phospholipid interactions differ from cholesterol-phospholipid interactions (Leppimaki et al., 2000). In that study it was shown that lathosterol does not stabilize the lamellar-to-hexagonal phase transition of POPE membranes to the same degree as cholesterol. In cells, lathosterol also failed to activate CTP:phosphocholine cytidylyltransferase (in contrast to cholesterol; see Leppimaki et al., 2000), an enzyme which is known to be sensitive to lipid-induced membrane torque tension (Attard et al., 1998). In this study, therefore, it was somewhat surprising that the thermotropic phase behavior of lathosterol-containing DHSM and SM membranes was so similar to that of corresponding cholesterol-containing membranes. From these experiments the only observable difference was that lathosterol affected the Tm of the main transition less than cholesterol, and that the broad, sterol-induced transition occurred at slightly higher temperatures in membranes containing lathosterol than in membranes containing cholesterol. The latter observation would indicate that the sterol-rich domains formed by lathosterol were more stable than domains formed by cholesterol, which also have been observed in other types of experiments (unpublished observation).
16:0-DHSM interactions with 16:0-SM and DPPC
DHSMs have been found both in cultured cells and in commercially available natural sphingomyelin mixtures (e.g., bovine brain SM and egg SM; see Barenholz et al., 1976; Byrdwell and Borchman, 1997; Karlsson et al., 1998; Ramstedt et al., 1999). What role DHSM fulfills in membranes remains unclear. Recent studies have, however, shown that DHSM forms more stable domains with cholesterol than acyl-chain-matched SM, and that Triton X-100 partitioning into egg DHSM is less favorable than into egg SM (Kuikka et al., 2001; Ollila and Slotte, 2002). In a recent study in which the membrane properties of DHSM membranes were examined using fluorescent probes it was observed that 16:0-DSHM formed more ordered membranes than both 16:0-SM and DPPC (Nyholm et al., 2003). Further, the fluorophores used in the aforementioned study reported differences in the interfacial properties of DHSM and SM. In conclusion, the known properties of DSHM suggest that it is an order-making lipid in membranes and could possibly play a role in lateral domain formation in cell membranes. The thermograms of binary mixtures of 16:0-DHSM and DPPC or 16:0-SM showed that 16:0-DHSM formed almost ideal mixtures with SM while the DPPC:DHSM mixtures were less ideal. Analysis of SM:DPPC mixtures showed that these had similar properties as the DPPC:DHSM mixtures. Since sphingomyelins in general have different hydrogen bonding properties than phosphatidylcholines, the nonideal mixing of DPPC in DHSM or SM bilayers could in principle be partly due to changes in the hydrogen bond network at the membrane-water interface. Previously published data on SM:PC mixtures have, however, shown that SM mixes more ideally with DMPC than with DPPC (Calhoun and Shipley, 1979; Lentz et al., 1981; Maulik and Shipley, 1996b; Bar et al., 1997). Hence, the low ideality of DPPC:DHSM mixtures more likely derives from differences in the hydrophobic length of the two lipids. It has been suggested that the PC that most closely resembles 16:0-SM structurally would be a 1-myristoyl-2-palmitoyl-sn-glycero-3-phosphocholine (14:0/16:0-PC) (Maulik and Shipley, 1996b; Holopainen et al., 2000; Li et al., 2001). Fourier transform infrared spectroscopy studies of DPPC:Egg-SM mixtures suggests that mixing of Egg-SM and DPPC do not alter the hydrogen bond network, but that conformational changes in the phospholipids occur (Villalain et al., 1988).
Pretransitions arising from the conversion of the lamellar gel phase to the rippled gel phase have previously been observed in pure 16:0-SM, 16:0-DHSM, and DPPC bilayers (McMullen et al., 1993; McMullen and McElhaney, 1995; Bar et al., 1997; Ramstedt and Slotte, 1999; Kuikka et al., 2001). The origin of the pretransition observed in 16:0-DHSM membranes has not been characterized by other means, but it seems reasonable to assume that it has a similar origin as those observed for DPPC and 16:0-SM membranes.
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CONCLUSIONS |
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TOPABSTRACTINTRODUCTIONEXPERIMENTAL PROCEDURESRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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ACKNOWLEDGEMENTS |
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TOPABSTRACTINTRODUCTIONEXPERIMENTAL PROCEDURESRESULTSDISCUSSIONCONCLUSIONSACKNOWLEDGEMENTSREFERENCES |
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This work was supported by generous grants from the Sigrid Juselius Foundation, the Academy of Finland, the Magnus Ehrnrooth Foundation, and Medicinska Understödsföreningen Liv och Hälsa.
Submitted on November 15, 2002; accepted for publication January 17, 2003.
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T. Mehnert, K. Jacob, R. Bittman, and K. Beyer Structure and Lipid Interaction of N-Palmitoylsphingomyelin in Bilayer Membranes as Revealed by 2H-NMR Spectroscopy Biophys. J., February 1, 2006; 90(3): 939 - 946. [Abstract] [Full Text] [PDF]
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A. Tsamaloukas, H. Szadkowska, P. J. Slotte, and H. Heerklotz Interactions of Cholesterol with Lipid Membranes and Cyclodextrin Characterized by Calorimetry Biophys. J., August 1, 2005; 89(2): 1109 - 1119. [Abstract] [Full Text] [PDF]
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Y. J. E. Bjorkqvist, T. K. M. Nyholm, J. P. Slotte, and B. Ramstedt Domain Formation and Stability in Complex Lipid Bilayers as Reported by Cholestatrienol Biophys. J., June 1, 2005; 88(6): 4054 - 4063. [Abstract] [Full Text] [PDF]
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B. Terova, R. Heczko, and J. P. Slotte On the Importance of the Phosphocholine Methyl Groups for Sphingomyelin/Cholesterol Interactions in Membranes: A Study with Ceramide Phosphoethanolamine Biophys. J., April 1, 2005; 88(4): 2661 - 2669. [Abstract] [Full Text] [PDF]
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B. Malewicz, J. T. Valiyaveettil, K. Jacob, H.-S. Byun, P. Mattjus, W. J. Baumann, R. Bittman, and R. E. Brown The 3-Hydroxy Group and 4,5-trans Double Bond of Sphingomyelin Are Essential for Modulation of Galactosylceramide Transmembrane Asymmetry Biophys. J., April 1, 2005; 88(4): 2670 - 2680. [Abstract] [Full Text] [PDF]
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F.-X. Contreras, G. Basanez, A. Alonso, A. Herrmann, and F. M. Goni Asymmetric Addition of Ceramides but not Dihydroceramides Promotes Transbilayer (Flip-Flop) Lipid Motion in Membranes Biophys. J., January 1, 2005; 88(1): 348 - 359. [Abstract] [Full Text] [PDF]
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