Modulation of lipoprotein metabolism by inhibition of sphingomyelin synthesis in ApoE knockout mice

Park, Tae‐Sik; Panek, Robert L.; Rekhter, Mark D.; Mueller, Sandra Bak; Rosebury, Wendy S.; Robertson, Andrew W.; Hanselman, Jeffrey C.; Kindt, Erick; Homan, Reynold; Karathanasis, Sotirios K.

doi:10.1016/j.atherosclerosis.2005.12.029

Cited by 88 publications

(69 citation statements)

References 35 publications

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“…Park et al have shown that giving myriocin significantly decreased the levels of sphingomyelin in a dose dependent manner. Furthermore, they were able to show that myriocin also lowered total cholesterol, triglycerides, VLDL and LDL [82,83]. This is not very surprising, though, as myriocin has been found to cause suppression of HMG CoA reductase.…”

Section: Ceramide and Potential Therapeuticsmentioning

confidence: 82%

“…On a western diet, Hojjati et al were able to show a mean decrease of 37% in atherosclerotic lesion [84]. Myriocin is also able to reduce levels of inflammatory proteins, suggesting a very significant role in reducing the extent of atherosclerotic lesions [83]. Furthermore, treatment with myriocin resulted in less lesion necrosis.…”

Section: Ceramide and Potential Therapeuticsmentioning

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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Section: Ceramide and Potential Therapeuticsmentioning

confidence: 82%

Section: Ceramide and Potential Therapeuticsmentioning

confidence: 99%

Ceramide: A common pathway for atherosclerosis?

et al. 2008

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“…In this respect it is interesting that elevated plasma sphingolipid levels are associated with an increased risk of developing atherosclerosis and coronary heart disease (29,30). Myriocin lowered plasma sphingolipids in ApoE knock-out mice and significantly reduced the formation of atherosclerotic lesions in these mice and showed a significant delay of disease progression (31)(32)(33). Because treatment with myriocin would be expected to lower the levels of both C 16 -and C 18 -based sphingolipids it would be interesting to determine whether one of the two subclasses is primarily involved in the pathogenesis of atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

The SPTLC3 Subunit of Serine Palmitoyltransferase Generates Short Chain Sphingoid Bases

Hornemann

Penno

Rütti

et al. 2009

Journal of Biological Chemistry

159

118

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The enzyme serine palmitoyltransferase (SPT) catalyzes the rate-limiting step in the de novo synthesis of sphingolipids. Previously the mammalian SPT was described as a heterodimer composed of two subunits, SPTLC1 and SPTLC2. Recently we identified a novel third SPT subunit (SPTLC3). SPTLC3 shows about 68% identity to SPTLC2 and also includes a pyridoxal phosphate consensus motif. Here we report that the overexpression of SPTLC3 in HEK293 cells leads to the formation of two new sphingoid base metabolites, namely C 16 -sphinganine and C 16 -sphingosine. SPTLC3-expressing cells have higher in vitro SPT activities with lauryl-and myristoyl-CoA than SPTLC2-expressing cells, and SPTLC3 mRNA expression levels correlate closely with the C 16 -sphinganine synthesis rates in various human and murine cell lines. Approximately 15% of the total sphingolipids in human plasma contain a C 16 backbone and are found in the high density and low density but not the very low density lipoprotein fraction. In conclusion, we show that the SPTLC3 subunit generates C 16 -sphingoid bases and that sphingolipids with a C 16 backbone constitute a significant proportion of human plasma sphingolipids.Sphingolipids comprise a class of bioactive lipids that contribute to plasma membrane and plasma lipoprotein formation and exert a broad range of cellular signaling functions such as cell proliferation, endocytosis, and the response of cells to inflammatory and apoptotic stress signals (1-4).Sphingolipids are derived from the aliphatic amino alcohol sphingosine, which is formed from the precursors L-serine and palmitoyl-CoA. The condensation of serine with palmitoylCoA is catalyzed by the enzyme serine palmitoyltransferase (SPT) 3 (EC 2.3.1.50) and leads to the intermediate 3-ketodihydrosphingosine. 3-Ketodihydrosphingosine is then rapidly converted to dihydrosphingosine (sphinganine) and dihydroceramide. The desaturation of dihydroceramide generates ceramide, and the breakdown of ceramide by ceramidase finally forms sphingosine. The sphingosine backbone of ceramide is usually O-linked to a polar head group such as phosphocholine or carbohydrates and amide-linked to an acyl group. The combination of the sphingosine backbone with different head groups, in particular with various oligosaccharides, leads to a complex variety of different sphingolipid metabolites (5, 6). Moreover, it was shown recently that SPT is also able to use L-alanine as an alternative substrate, thereby generating the atypical sphingoid base 1-deoxysphinganine (7).SPT belongs to the family of pyridoxal phosphate-dependent ␣-oxoamine synthases. Other members of this family include 5-aminolevulinic acid synthase, 2-amino-3 ketobutyrate ligase, and 8-amino-7-oxononanoate synthase (8). SPT is ubiquitously expressed, and enzyme activity has been detected in all tissues tested so far including brain, lung, liver, kidney, and muscle (9). SPT is essential for embryonic development, and homozygous SPT knock-out mice are not viable (10). SPT has been believed to be a heterodimer compose...

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“…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).…”

Section: Abbreviations Usedmentioning

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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Modulation of lipoprotein metabolism by inhibition of sphingomyelin synthesis in ApoE knockout mice

Cited by 88 publications

References 35 publications

Ceramide: A common pathway for atherosclerosis?

Ceramide: A common pathway for atherosclerosis?

The SPTLC3 Subunit of Serine Palmitoyltransferase Generates Short Chain Sphingoid Bases

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

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