Sphingomyelin and Cholesterol: From Membrane Biophysics and Rafts to Potential Medical Applications

Barenholz, Yechezkel

doi:10.1007/978-1-4757-5806-1_5

Cited by 120 publications

(109 citation statements)

References 155 publications

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“…The reverse is true for cholesterol efflux, namely, high levels of SM in rHDL significantly increase it. These findings are in accordance with the known high affinity binding of SM with cholesterol, thus preventing its desorption from SM-rich rHDL in the uptake process, and promoting desorption from macrophage membrane in the efflux process (13). At the end of the procedure for rHDL making, described in the Methods section, each species was analyzed for its total cholesterol and protein content.…”

Section: Discussionsupporting

confidence: 81%

“…The interaction between cholesterol and SM is the basis for the formation and maintenance of cholesterol/sphingolipid-enriched nano-and micro-domains (referred to as membrane "rafts") in the plane of plasma and other organelle (i.e., Golgi) membranes (13). SM is thought to bind cholesterol with high affinity and inhibit its efflux from the plasma membrane by preventing cholesterol desorption (14).…”

Section: Introductionmentioning

confidence: 99%

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Reverse cholesterol transport is regulated by varying fatty acyl chain saturation and sphingomyelin content in reconstituted high-density lipoproteins

2007

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Because phospholipid composition of HDL plays a vital role in its reverse cholesterol transport (RCT) function, we studied RCT in vitro (uptake and efflux) with reconstituted HDLs (rHDLs) containing phosphatidylcholine with fatty acids of increasing saturation levels (stearic, oleic, linoleic, linolenic), and without or with sphingomyelin. Uptake significantly increased from basal value when phosphatidylcholine component included up to 50% (%mol) of oleic or linolenic acid, but did not change with linoleic acid. Increasing oleic and linoleic acids to 100% (%mol) significantly decreased uptake, but increasing linolenic acid to the same value did not affect it. Sphingomyelin in rHDL significantly decreased uptake, but only with phosphatidylcholine containing unsaturated fatty acids, and not with saturated fatty acid. Efflux was not affected in a dose-dependent manner when oleic or linoleic acid content was increased, but was significantly increased with levels of linolenic acid up to 25% (%mol) in phosphatidylcholine, and was dramatically lowered with higher levels. Sphingomyelin in rHDL (phosphatidylcholine:sphingomyelin, 20:80, mol:mol) significantly increased efflux only with oleic or linoleic acid-containing rHDLs, compared to efflux without sphingomyelin. In conclusion, enrichment of phosphatidylcholine component up to 25% (%mol) as linolenic acid has a beneficial effect on RCT, while a higher percentage of it or other unsaturated fatty acids seems to be detrimental. Also, high sphingomyelin content decreases uptake with rHDL containing unsaturated fatty acids, whereas it increases efflux for rHDL containing oleic or linoleic acid. These results show for the first time the importance of sphingomyelin in RCT in a well-defined in vitro system.

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Section: Discussionsupporting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Reverse cholesterol transport is regulated by varying fatty acyl chain saturation and sphingomyelin content in reconstituted high-density lipoproteins

2007

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“…Furthermore, the inhibitory effect of SM is also predominantly on the first step, because the phospholipase A reaction of the enzyme is as sensitive as cholesterol esterification reaction (Fig. 5) (18), even though SM is known to specifically interact with cholesterol molecule (41,42). Thus it appears unlikely that the ceramide effect is due to the displacement of cholesterol from the ordered domains of the membrane.…”

Section: Discussionmentioning

confidence: 99%

Regulation of the Activity and Fatty Acid Specificity of Lecithin-Cholesterol Acyltransferase by Sphingomyelin and Its Metabolites, Ceramide and Ceramide Phosphate

2006

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Sphingomyelin (SM), the second most abundant phospholipid in plasma lipoproteins, was previously shown to be a physiological inhibitor of the lecithin-cholesterol acyltransferase (LCAT) reaction. In this study, we investigated the effects of its metabolites, ceramide and ceramide phosphate, on the activity and fatty acid specificity of LCAT in vitro. Treatment of SM-containing substrate with SMase C, which hydrolyzes SM to ceramide, abolished the inhibitory effect of SM, whereas treatment with SMase D, which hydrolyzes it to ceramide phosphate, increased the inhibition. Although incorporation of ceramide into the substrate in the absence of SM activated the LCAT reaction only modestly, its co-incorporation with SM neutralized the inhibitory effect of SM. Ceramide phosphate, on the other hand, inhibited the LCAT reaction more strongly than SM. The effects of the sphingolipids were similar on the phospholipase A and cholesterol esterification reactions of the enzyme, indicating that they regulate the binding of phosphatidylcholine (PC) to the active site, rather than the esterification step. Ceramide incorporation into the substrate stimulated the synthesis of unsaturated cholesteryl esters at the expense of saturated esters. However these effects on fatty acid specificity disappeared when the PC substrates were incorporated into an inert diether PC matrix, suggesting that ceramide increases the availability of polyunsaturated PCs to the enzyme by altering the macromolecular structure of the substrate particle. Since the plasma ceramide levels are increased during inflammation, these results indicate that the activity and fatty acid specificity of LCAT may be altered during the inflammatory response. Abbreviations usedApo : apolipoprotein; CE: cholesteryl ester; FC: free (unesterified) cholesterol; HDL: high density lipoproteins; LCAT: lecithin-cholesterol acyltransferase; LDL: low density lipoproteins; PC: phosphatidylcholine; PLA: phospholipase A; SM: sphingomyelin; SMase: sphingomyelinase Sphingomyelin (SM) is one of the most abundant phospholipids in cell membranes and lipoproteins, constituting up to 30% of certain lipoprotein fractions (1,2). Although its role as a structural component of membranes, and as a precursor of signaling molecules has been well recognized, its function in plasma lipoproteins has received less attention. Recent studies show that plasma SM may be an independent risk factor for atherosclerosis (3), and that a reduction in SM levels by myriocin treatment reduces atherosclerosis in apo E deficient mice (4,5). While the exact mechanism of the proatherogenic effect of SM is unknown, one proposed mechanism involves the generation of ceramide in LDL by the action of arterial SMase, which causes † Supported by a grant from National Institutes of Health, HL 68585. increased retention, aggregation and oxidation of LDL, with subsequent uptake by the scavenger receptors of the macrophage (3). The formation of large amounts of ceramide in the plasma compartment is unlikely because of the...

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“…Nevertheless, they are not essential to membrane integrity, being rare among prokaryotes and scant in several of the eukaryotic organelles. Rather, they confer important properties on the plasma membrane and the endomembrane organelles with which the plasma membrane is in intermittent continuity [1,2]. Through their interactions with phospholipids and sphingolipids, sterols lower bilayer permeability by reducing the free volume created by the thermal motion of the fatty-acyl chains.…”

Section: Introductionmentioning

confidence: 99%

Cholesterol homeostasis and the escape tendency (activity) of plasma membrane cholesterol

Lange

Steck

2008

Progress in Lipid Research

145

192

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We review evidence that sterols can form stoichiometric complexes with certain bilayer phospholipids, and sphingomyelin in particular. These complexes appear to be the basis for the formation of condensed and ordered liquid phases, (micro)domains and/or rafts in both artificial and biological membranes. The sterol content of a membrane can exceed the complexing capacity of its phospholipids. The excess, uncomplexed membrane sterol molecules have a relatively high escape tendency, also referred to as fugacity or chemical activity (and, here, simply activity). Cholesterol is also activated when certain membrane intercalating amphipaths displace it from the phospholipid complexes. Active cholesterol projects from the bilayer and is therefore highly susceptible to attack by cholesterol oxidase. Similarly, active cholesterol rapidly exits the plasma membrane to extracellular acceptors such as cyclodextrin and high-density lipoproteins. For the same reason, the pool of cholesterol in the ER (endoplasmic reticulum) increases sharply when cell surface cholesterol is incremented above the physiological set-point; i.e., equivalence with the complexing phospholipids. As a result, the escape tendency of the excess cholesterol not only returns the plasma membrane bilayer to its set point but also serves as a feedback signal to intracellular homeostatic elements to down-regulate cholesterol accretion.

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Sphingomyelin and Cholesterol: From Membrane Biophysics and Rafts to Potential Medical Applications

Cited by 120 publications

References 155 publications

Reverse cholesterol transport is regulated by varying fatty acyl chain saturation and sphingomyelin content in reconstituted high-density lipoproteins

Reverse cholesterol transport is regulated by varying fatty acyl chain saturation and sphingomyelin content in reconstituted high-density lipoproteins

Regulation of the Activity and Fatty Acid Specificity of Lecithin-Cholesterol Acyltransferase by Sphingomyelin and Its Metabolites, Ceramide and Ceramide Phosphate

Cholesterol homeostasis and the escape tendency (activity) of plasma membrane cholesterol

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