Increased sphingomyelin content of plasma lipoproteins in apolipoprotein E knockout mice reflects combined production and catabolic defects and enhances reactivity with mammalian sphingomyelinase.

Jeong, Tae Sook; Schissel, Scott L.; Tabas, Ira; Pownall, Henry J.; Tall, Alan R.; Jiang, Xian Cheng

doi:10.1172/jci870

Cited by 128 publications

(119 citation statements)

References 45 publications

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“…11 The concentration of SM relative to total phospholipids (principally phosphatidylcholine [PC] and SM), ie, SM/(SMϩPC), is an important determinant of the susceptibility of lipoprotein SM to SMase. 8,12 These findings suggest that plasma SM levels and the relative SM concentration might be risk factors for atherosclerosis. However, plasma SM levels have never been systematically assessed as a risk factor for atherosclerosis in humans.…”

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confidence: 86%

“…In addition, the OR for CAD for the relative concentration of SM, ie, the SM/(SMϩPC) ratio, was significantly higher for the third and fourth quartiles compared with the first quartile (Pϭ0.0218 and Pϭ0.0028, respectively), indicating that the relative concentration of SM was also associated with CAD, independent of age, diabetes, smoking, hypertension, LDL-C, HDL-C, logarithmically transformed triglycerides, remnant cholesterol, fibrinogen, and CRP (Table 3). 11,12,21 has suggested that plasma SM levels could also be related to atherosclerosis. However, this has never been systematically assessed, partly because of the difficulties of measuring SM in large numbers of samples.…”

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confidence: 99%

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Plasma Sphingomyelin Level as a Risk Factor for Coronary Artery Disease

Jiang

Paultre

Pearson

et al. 2000

ATVB

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Abstract-Only a fraction of the clinical complications of atherosclerosis are explained by known risk factors. Animal studies have shown that plasma sphingomyelin (SM) levels are closely related to the development of atherosclerosis. SM carried into the arterial wall on atherogenic lipoproteins may be locally hydrolyzed by sphingomyelinase, promoting lipoprotein aggregation and macrophage foam cell formation. A novel, high-throughput, enzymatic method to measure plasma SM levels has been developed. Plasma SM levels were related to the presence of coronary artery disease (CAD) in a biethnic angiographic case-control study (279 cases and 277 controls). Plasma SM levels were higher in CAD patients than in control subjects (60Ϯ29 versus 49Ϯ21 mg/dL, respectively; PϽ0.0001). Moreover, the ratio of SM to SMϩphosphatidylcholine (PC) was also significantly higher in cases than in controls (0.33Ϯ0.13 versus 0.29Ϯ0.10, respectively; PϽ0.0001). Similar relationships were observed in African Americans and whites. Plasma SM levels showed a significant correlation with remnant cholesterol levels (rϭ0. 51, PϽ0.0001). By use of multivariate logistic regression analysis, plasma SM levels and the SM/(SMϩPC) ratio were found to have independent predictive value for CAD after adjusting for other risk factors, including remnants. The odds ratio (OR) for CAD was significantly higher for the third and fourth quartiles of plasma SM levels (OR T he association of lipid abnormalities and coronary atherosclerosis is well established. Case-control and prospective epidemiological studies have shown a direct correlation between coronary artery disease (CAD) and serum levels of total cholesterol and LDL cholesterol (LDL-C) and an inverse relationship between CAD and HDL cholesterol (HDL-C) levels. 1 However, compared with plasma cholesterol measurements, very little attention has been given to the relationship between phospholipids and CAD. 2,3 Atherogenesis is initiated by the interaction of cholesterol-rich lipoproteins, such as LDL, with the arterial wall. 4,5 The uptake of lipoprotein cholesterol by macrophages, leading to foam cell formation, is a central event in the initiation and progression of atherosclerosis. 6 However, native LDL is incapable of generating foam cells from macrophages. Thus, it is thought that LDL is modified in the arterial wall by processes such as oxidation, leading to macrophage chemotaxis and the uptake of modified LDL by macrophage foam cells. 7 Retention of lipoproteins on the subendothelial matrix, followed by aggregation, has also emerged as a central pathogenic process in macrophage foam cell formation and atherogenesis. 8 Lipoprotein aggregation in the vessel wall may result from enzymatic modification of LDL, induced by locally produced sphingomyelinase (SMase). 9 It has long been known that sphingomyelin (SM) accumulates in human and animal atheroma and that the major source is plasma lipoproteins. 10 Plasma SM levels are increased in human familial hyperlipidemias, especially in familial hypercholester...

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confidence: 86%

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confidence: 99%

Plasma Sphingomyelin Level as a Risk Factor for Coronary Artery Disease

Jiang

Paultre

Pearson

et al. 2000

ATVB

348

250

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“…Sphingolipid enrichment in vitro increased aggregation of mouse lipoproteins. Macrophage-derived SMase was also shown to stimulate the aggregation of very low density lipoproteins (VLDL) and LDL [12]. Thus, lipoprotein aggregation induced by SMase is dependent on ceramide increase.…”

Section: Lipoproteins and Ceramidementioning

confidence: 99%

“…Sphingomyelin, which is transported into the arterial wall by atherogenic lipoproteins, is in turn affected by arterial wall SMase, increasing in ceramide content and promoting lipoprotein aggregation [2]. LDL extracted from human atherosclerotic lesions is highly enriched in sphingomyelin compared with plasma LDL [12,13].…”

Section: Lipoproteins and Ceramidementioning

confidence: 99%

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Ceramide: A common pathway for atherosclerosis?

et al. 2008

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Plasma sphingomyelin concentration is correlated with the development of atherosclerosis. It has been found to exist in significantly higher concentrations in aortic plaque. This appears to have clinical relevance as well as it has been shown to be an independent predictor of coronary artery disease. Ceramide, the backbone of sphingolipids, is the key component which affects atherosclerotic changes through its important second-messenger role. This paper sheds light on some of the current literature supporting the significance of ceramide with respect to its interactions with lipids, inflammatory cytokines, homocysteine and matrix metalloproteinases. Furthermore, the potential therapeutic implications of modulating ceramide concentrations are also discussed.

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Apolipoprotein E and Reverse Cholesterol Transport: The Role of Recycling in Plasma and Intracellular Lipid Trafficking

Swift

Hasty

Linton

et al. 2007

High‐Density Lipoproteins

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Apolipoprotein E (apoE) is unique among the apoproteins because of its many different functions in biology, ranging from modulation of plasma lipoprotein metabolism, through control of cellular cholesterol homeostasis, to regulation of neuronal function. Although apoE is synthesized by several tissues and cell types, its circulating levels are influenced primarily by the liver. Within the plasma compartment apoE readily redistributes among chylomicrons, remnant particles, and high-density lipoproteins (HDL), where it has functional roles both in directing triglyceride-rich particles to sites of catabolism and clearance and in determining size expansion of the HDL. Its role as a ligand for the receptor-mediated endocytosis of lipoproteins is well established [1-3]. It is recognized by the low-density lipoprotein (LDL) receptor (LDLR) [2,3], the LDLR-related protein 1 (LRP1) [1,4,5], and heparan sulfate proteoglycans (HSPG), either alone [6,7] or in concert with the LRP1 [8]. Additionally, within the periphery apoE interacts with lipoprotein lipase (LPL) and hepatic lipase (HL) to modulate triglyceride hydrolysis [9,10]. Within the cell apoE is known to serve many biologically relevant roles. Studies have suggested that apoE directs the intracellular routing of internalized remnant lipoproteins [11,12] and modulates intracellular lipid metabolism, in particular the hydrolysis and utilization of triglyceride [13]. In hepatocytes, it plays a critical role in the assembly and secretion of VLDL, augmenting the incorporation of triglycerides into newly forming particles [14][15][16]. Finally, apoE is a critical component of the reverse cholesterol transport (RCT) pathway. It promotes cholesterol efflux from macrophages [17-19] and plays major roles in HDL formation, maturation, and hepatic uptake, as well as in the selective uptake of HDL cholesteryl ester by the liver [20][21][22][23]. ApoE is also expressed by macrophage-derived foam cells, while a number of studies support an important antiatherogenic role for macrophage apoE in vivo [24][25][26][27].The unique nature of apoE is also demonstrated by the fact that, after internalization, this apoprotein follows specialized cellular pathways allowing it to exert maximum impact on cellular lipid homeostasis. In particular, studies both in our High-Density Lipoproteins: From Basic Biology to Clinical Aspects. Edited by Christopher J. Fielding

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Increased sphingomyelin content of plasma lipoproteins in apolipoprotein E knockout mice reflects combined production and catabolic defects and enhances reactivity with mammalian sphingomyelinase.

Cited by 128 publications

References 45 publications

Plasma Sphingomyelin Level as a Risk Factor for Coronary Artery Disease

Plasma Sphingomyelin Level as a Risk Factor for Coronary Artery Disease

Ceramide: A common pathway for atherosclerosis?

Apolipoprotein E and Reverse Cholesterol Transport: The Role of Recycling in Plasma and Intracellular Lipid Trafficking

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