Interactions between sphingomyelin and cholesterol in low density lipoproteins and model membranes

Guarino, Andrew J.; Lee, Sum P.; Wrenn, Steven P.

doi:10.1016/j.jcis.2005.06.043

Cited by 15 publications

(8 citation statements)

References 31 publications

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“…The exposure of ceramiderich domains at the surface of particles due to the local activity of SMase enhances aggregation [28], binding to heparan sulfate proteoglycans [29], and binding of apoE [30]. This increases cellular uptake of particles via the LDL receptor-related protein [29].…”

Section: Phosphatidylcholinementioning

confidence: 99%

HDL Lipids and Insulin Resistance

et al. 2010

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There is renewed interest in high-density lipoproteins (HDLs) due to recent findings linking atherosclerosis to the formation of dysfunctional HDL. This article focuses on the universe of HDL lipids and their potential protective or proinflammatory roles in vascular disease and insulin resistance. HDL carries a wide array of lipids including sterols, triglycerides, fat-soluble vitamins, and a large number of phospholipids, including phosphatidylcholine, sphingomyelin, and ceramide with many biological functions. Ceramide has been implicated in the pathogenesis of insulin resistance and has many proinflammatory properties. In contrast, sphingosine-1-phosphate, which is transported mainly in HDL, has anti-inflammatory properties that may be atheroprotective and may account for some of the beneficial effects of HDL. However, the complexity of the HDL lipidome is only beginning to reveal itself. The emergence of new analytical technologies should rapidly increase our understanding of the function of HDL lipids and their role in disease states.

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Section: Phosphatidylcholinementioning

confidence: 99%

HDL Lipids and Insulin Resistance

et al. 2010

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“…Together, these observations have been interpreted as evidence for lateral segregation of DHE in model and cell membranes at high sterol mole fractions. ,, We argue that such lateral segregation will precede eventual sterol precipitation, as it takes place above the maximal solubility of a membrane for a given sterol . Supporting that notion, Wrenn and co-workers found lateral segregation of DHE in a FRET assay to dansylated phospholipids to precede the formation of fluorescent sterol crystals in model membranes and lipoproteins. , These combined results suggest that intrinsically fluorescent sterols, such as DHE, are highly suitable to study not only sterol aggregation in solution but also sterol precipitation from membranes. This will help one to elucidate the molecular mechanisms behind pathological cholesterol crystal formation using spectroscopic and imaging approaches with DHE and other intrinsically fluorescent sterols.…”

Section: Discussionmentioning

confidence: 56%

“…77 Supporting that notion, Wrenn and co-workers found lateral segregation of DHE in a FRET assay to dansylated phospholipids to precede the formation of fluorescent sterol crystals in model membranes and lipoproteins. 78,79 These combined results suggest that intrinsically fluorescent sterols, such as DHE, are highly suitable to study not only sterol aggregation in solution but also sterol precipitation from membranes. This will help one to elucidate the molecular mechanisms behind pathological cholesterol crystal formation using spectroscopic and imaging approaches with DHE and other intrinsically fluorescent sterols.…”

Section: ■ Conclusionmentioning

confidence: 95%

Photophysical and Structural Characterization of Intrinsically Fluorescent Sterol Aggregates

et al. 2021

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Self-association of cholesterol into aggregates and crystals is a hallmark of developing atherosclerosis. Intrinsically fluorescent sterols, such as dehydroergosterol (DHE), can be used to study sterol aggregation by fluorescence spectroscopy and microscopy, but a thorough understanding of DHE’s photophysical and structural properties in the aggregated state is missing. Here, we show that DHE forms submicron fluorescent aggregates when evaporated from an ethanol solution. Using atomic force microscopy, we find that DHE, like cholesterol, forms compact oblate-shape aggregates of <100 nm in diameter. DHE’s fluorescence is lowered in the aggregate compared to the monomeric form, and characteristic spectral changes accompany the aggregation process. Electronic structure calculations of DHE dimers in water indicate that Frenkel-type exciton coupling contributes to the lowered DHE fluorescence in the aggregates. Using molecular dynamics (MD) simulations, we show that DHE forms compact aggregates on the nanosecond scale and with strong intermolecular attraction, in which a broad range of orientations, and therefore electronic couplings, will take place. Tight packing of DHE in aggregates also lowers the apparent absorption cross section, further reducing the molecular brightness of the aggregates. Our results pave the way for systematic solubility studies of intrinsically fluorescent analogues of biologically relevant sterols.

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“…[7] Intestinal CEase facilitates the absorption of cholesteryl esters and cholesterol, whereas ah igh plasma activity of this enzyme was found to be correlated with increased total plasma cholesterol and low-density lipoprotein (LDL) cholesterol levels. [9][10][11] These resultsa nd furtherf indings from in vitro and in vivo studies led to the hypothesis that CEase inhibitors might lower plasma LDL levels and may thus act as antiatherosclerotic agents. [9][10][11] These resultsa nd furtherf indings from in vitro and in vivo studies led to the hypothesis that CEase inhibitors might lower plasma LDL levels and may thus act as antiatherosclerotic agents.…”

Section: Introductionmentioning

confidence: 90%

“…[7,8] Furthermore, plasma CEase may contributet oC HD by converting "larger andl ess atherogenic LDL to smaller and more atherogenic LDL subspecies" [8] and by being involved in the generation of cholesterol crystals in LDL aggregates, which are thought of as ah allmark of atherosclerotic plaques and represent ap ossible source of inflammation. [9][10][11] These resultsa nd furtherf indings from in vitro and in vivo studies led to the hypothesis that CEase inhibitors might lower plasma LDL levels and may thus act as antiatherosclerotic agents. [12][13][14][15][16] Most of the initially developed CEase inhibitor classes contain electrophilic sites that are attacked by the active site serine residue (e.g.,b oronic acids, [17] carbamates, [17][18][19][20][21] phosphoisocoumarines, [22] andt hieno [1,3]oxazin-4ones 29 and 30; [23] Figure 1), whereas recently reported rhodanine [24] and thiazolidinedione [24] inhibitors as well as 2-(1 Hindol-3-yl)-4-phenylquinolines [25] do not appear to modify the catalytic triad (Ser-His-Asp).…”

Section: Introductionmentioning

confidence: 90%

ω‐Phthalimidoalkyl Aryl Ureas as Potent and Selective Inhibitors of Cholesterol Esterase

et al. 2018

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Cholesterol esterase (CEase), a serine hydrolase thought to be involved in atherogenesis and thus coronary heart disease, is considered as a target for inhibitor development. We investigated recombinant human and murine CEases with a new fluorometric assay in a structure-activity relationship study of a small library of ω-phthalimidoalkyl aryl ureas. The urea motif with an attached 3,5-bis(trifluoromethyl)phenyl group and the aromatic character of the ω-phthalimide residue were most important for inhibitory activity. In addition, an alkyl chain composed of three or four methylene groups, connecting the urea and phthalimide moieties, was found to be an optimal spacer for inhibitors. The so-optimized compounds 2 [1-(3,5-bis(trifluoromethyl)phenyl)-3-(3-(1,3-dioxoisoindolin-2-yl)propyl)urea] and 21 [1-(3,5-bis(trifluoromethyl)phenyl)-3-(4-(1,3-dioxoisoindolin-2-yl)butyl)urea] exhibited dissociation constants (K ) of 1-19 μm on the two CEases and showed either a competitive (2 on the human enzyme and 21 on the murine enzyme) or a noncompetitive mode of inhibition. Two related serine hydrolases-monoacylglycerol lipase and fatty acid amide hydrolase-were inhibited by ω-phthalimidoalkyl aryl ureas to a lesser extent.

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Interactions between sphingomyelin and cholesterol in low density lipoproteins and model membranes

Cited by 15 publications

References 31 publications

HDL Lipids and Insulin Resistance

HDL Lipids and Insulin Resistance

Photophysical and Structural Characterization of Intrinsically Fluorescent Sterol Aggregates

ω‐Phthalimidoalkyl Aryl Ureas as Potent and Selective Inhibitors of Cholesterol Esterase

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