Further evaluation of plasma sphingomyelin levels as a risk factor for coronary artery disease

Schlitt, Axel; Blankenberg, Stefan; Yan, Di; Gizycki, Hans von; Buerke, Michael; Werdan, Karl; Bickel, Christoph; Lackner, Karl J.; Meyer, J.; Rupprecht, Hans J.; Jiang, Xian‐Cheng

doi:10.1186/1743-7075-3-5

Cited by 114 publications

(67 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…We found that higher plasma SM levels and SM/PC ratios are independent risk factors for coronary heart disease (19,20). We believe that LDL retained in atherosclerotic lesions is acted on by an arterial wall sphingomyelinase, which promotes aggregation by converting SM to ceramide (10 -12).…”

Section: Discussionmentioning

confidence: 91%

“…It has been shown that plasma SM levels in these mice are 4-fold higher than in WT animals (16), and this may contribute to increased atherosclerosis (17,18). It has also been shown that in humans, higher plasma SM levels and SM/PC ratios are independent risk factors for coronary heart disease (19,20). All these data suggest that plasma SM plays a critical role in the development of atherosclerosis.…”

mentioning

confidence: 93%

See 1 more Smart Citation

Liver-specific Deficiency of Serine Palmitoyltransferase Subunit 2 Decreases Plasma Sphingomyelin and Increases Apolipoprotein E Levels

Liu

Chakraborty

et al. 2009

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Sphingomyelin (SM) is one of the major lipid components of plasma lipoproteins. Serine palmitoyltransferase (SPT) is the key enzyme in SM biosynthesis. Mice totally lacking in SPT are embryonic lethal. The liver is the major site for plasma lipoprotein biosynthesis, secretion, and degradation, and in this study we utilized a liver-specific knock-out approach for evaluating liver SPT activity and also its role in plasma SM and lipoprotein metabolism. We found that a deficiency of liver-specific Sptlc2 (a subunit of SPT) decreased liver SPT protein mass and activity by 95 and 92%, respectively, but had no effect on other tissues. Liver Sptlc2 deficiency decreased plasma SM levels (in both high density lipoprotein and non-high density lipoprotein fractions) by 36 and 35% (p < 0.01), respectively, and increased phosphatidylcholine levels by 19% (p < 0.05), thus increasing the phosphatidylcholine/SM ratio by 77% (p < 0.001), compared with controls. This deficiency also decreased SM levels in the liver by 38% (p < 0.01) and in the hepatocyte plasma membranes (based on a lysenin-mediated cell lysis assay). Liver-specific Sptlc2 deficiency significantly increased hepatocyte apoE secretion and thus increased plasma apoE levels 3.5-fold (p < 0.0001). Furthermore, plasma from Sptlc2 knock-out mice had a significantly stronger potential for promoting cholesterol efflux from macrophages than from wild-type mice (p < 0.01) because of a greater amount of apoE in the circulation. As a result of these findings, we believe that the ability to control liver SPT activity could result in regulation of lipoprotein metabolism and might have an impact on the development of atherosclerosis. Sphingomyelin (SM),2 an amphipathic phospholipid located in the surface monolayer of all classes of plasma lipoproteins (LDL/very low density lipoprotein, 70 -75%; HDL, 25-30%) (1), has significant effects on lipoprotein metabolism.A number of studies indicate that plasma SM levels influence the metabolism of apoB-containing lipoproteins. It has been reported that SM, but not cholesterol, significantly inhibits triglyceride lipolysis by lipoprotein lipase (2, 3). It has also been found that SM in lipoproteins delays remnant clearance by decreasing the binding of apoE to cell membrane receptors (4).Plasma SM levels also influence high density lipoprotein (HDL) metabolism. There have been reports that SM affects the structure of discoidal and spherical HDL (5). SM can inhibit lecithin-cholesterol acyltransferase by decreasing its binding to HDL (6). A negative correlation between the SM content of HDL and lecithin-cholesterol acyltransferase activity was observed in studies with proteoliposomes or reconstituted HDL (7). SM-rich recombinant HDL can inhibit scavenger receptor class B type I-mediated cholesterol ester-selective uptake in HepG2 cells (8).It is known that subendothelial retention and aggregation of atherogenic lipoproteins play an important role in atherogenesis (9). LDL extracted from human atherosclerotic lesions is highly enriched in SM ...

show abstract

Section: Discussionmentioning

confidence: 91%

mentioning

confidence: 93%

Liver-specific Deficiency of Serine Palmitoyltransferase Subunit 2 Decreases Plasma Sphingomyelin and Increases Apolipoprotein E Levels

Liu

Chakraborty

et al. 2009

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…Likewise, it was reported recently that animals overexpressing PLTP exhibit hepatic very low density lipoprotein (VLDL) overproduction (7) and increased athero-susceptibility (8). Associations of plasma PLTP activity with elevated apoB levels (9) and increased cardiovascular risk (10) have been found in humans as well. These findings have led to an interest in PLTP as a potential therapeutic target.…”

mentioning

confidence: 96%

Phospholipid Transfer Protein Deficiency Impairs Apolipoprotein-B Secretion from Hepatocytes by Stimulating a Proteolytic Pathway through a Relative Deficiency of Vitamin E and an Increase in Intracellular Oxidants

Jiang

Liu

et al. 2005

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Genetic deficiency of the plasma phospholipid transfer protein (PLTP) in mice unexpectedly causes a substantial impairment in liver secretion of apolipoprotein-B (apoB), the major protein of atherogenic lipoproteins. To explore the mechanism, we examined the three known pathways for hepatic apoB secretory control, namely endoplasmic reticulum (ER)/proteasome-associated degradation (ERAD), post-ER pre-secretory proteolysis (PERPP), and receptor-mediated degradation, also known as re-uptake. First, we found that ERAD and cell surface re-uptake were not active in PLTP-null hepatocytes. Moreover, ERto-Golgi blockade by brefeldin A, which enhances ERAD, equalized total apoB recovery from PLTP-null and wildtype cells, indicating that the relevant process occurs post-ER. Second, because PERPP can be stimulated by intracellular reactive oxygen species (ROS), we examined hepatic redox status. Although we found previously that PLTP-null mice exhibit elevated plasma concentrations of vitamin E, a lipid anti-oxidant, we now discovered that their livers contain significantly less vitamin E and significantly more lipid peroxides than do livers of wild-type mice. Third, to establish a causal connection, the addition of vitamin E or treatment with an inhibitor of intracellular iron-dependent peroxidation, desferrioxamine, abolished the elevation in cellular ROS as well as the defect in apoB secretion from PLTP-null hepatocytes. Overall, we conclude that PLTP deficiency decreases liver vitamin E content, increases hepatic oxidant tone, and substantially enhances ROS-dependent destruction of newly synthesized apoB via a post-ER process. These findings are likely to be broadly relevant to hepatic apoB secretory control in vivo.The plasma phospholipid transfer protein (PLTP) 1 is a key participant in the transport of hydrophobic molecules within the circulation. Partially purified PLTP was originally shown in vitro to mediate the transfer and exchange of phospholipids between plasma lipoproteins (1-3). Purified PLTP in vitro also transfers ␣-tocopherol (vitamin E), a naturally occurring hydrophobic anti-oxidant (4). To examine PLTP in vivo, we engineered genetically deficient mice and found that the loss of PLTP lowered plasma high density lipoprotein levels and altered plasma ␣-tocopherol transport, consistent with the previous work in vitro (5). Unexpectedly, however, we also found that PLTP deficiency caused a large impairment in the hepatic secretion of apolipoprotein-B (apoB), the major protein of atherogenic lipoproteins (6). The net effect of these changes was a decreased susceptibility to atherosclerosis (6). Likewise, it was reported recently that animals overexpressing PLTP exhibit hepatic very low density lipoprotein (VLDL) overproduction (7) and increased athero-susceptibility (8). Associations of plasma PLTP activity with elevated apoB levels (9) and increased cardiovascular risk (10) have been found in humans as well. These findings have led to an interest in PLTP as a potential therapeutic target. Nevertheless, the...

show abstract

“…Changes in SM were most closely related to PE, and Cer to lysoPC (Figure S6). A trend in reduced plasma SM levels has been previously reported for patients undergoing statin treatment 38 . These results show a clear difference in the effect of monotherapy vs. combination therapy upon circulating levels of the ratio SM|Cer/(SM|Cer+PC).…”

Section: Discussionmentioning

confidence: 54%

“…Another potential mechanism for pleiotropic effects was observed in an analysis of the relative levels of SM and PC, the SM/(SM+PC) ratio, of which both increases 37, 38 and decreases 39 have been reported to be associated with increased cardiovascular risk. The SM/PC ratio has been suggested as diagnostic marker for increased lipoprotein modifications in hyperlipidemic patients 40 .…”

Section: Discussionmentioning

confidence: 99%

High-Dose Simvastatin Exhibits Enhanced Lipid-Lowering Effects Relative to Simvastatin/Ezetimibe Combination Therapy

Snowden

Settergren

D’Alexandri

et al. 2014

Circ Cardiovasc Genet

View full text Add to dashboard Cite

Statins are the frontline in cholesterol reduction therapies; however use in combination with agents that possess complimentary mechanisms of action may achieve further reductions in LDL-C. Thirty-nine patients were treated with either 80mg simvastatin (n=20) or 10mg simvastatin plus 10mg ezetimibe (n=19) for 6 weeks. Dosing was designed to produce comparable LDL-C reductions, while enabling assessment of potential simvastatin-associated pleiotropic effects. Baseline and post-treatment plasma were analyzed for lipid mediators (e.g., eicosanoids, endocannabinoids) and structural lipids by liquid chromatography tandem mass spectrometry. Following statistical analysis and orthogonal projections to latent structures (OPLS) multivariate modeling, no changes were observed in lipid mediator levels, while global structural lipids were reduced in response to both mono- (R2Y=0.74, Q2=0.66, CV-ANOVA p=7.0×10-8) and combination therapy (R2Y=0.67, Q2=0.54, CV-ANOVA p=2.6×10−5). OPLS modeling identified a subset of 12 lipids that classified the two treatment groups after 6 weeks (R2Y=0.65, Q2=0.61, CV-ANOVA p=5.4×10−8). Decreases in the lipid species PC(15:0/18:2) and HexCer(d18:1/24:0) were the strongest discriminators of LDL-C reductions for both treatment groups (q<0.00005), while PE(36:3e) contributed most to distinguishing treatment groups (q=0.017). Shifts in lipid composition were similar for high-dose simvastatin and simvastatin/ezetimibe combination therapy, but the magnitude of the reduction was linked to simvastatin dosage. Simvastatin therapy did not affect circulating levels of lipid mediators, suggesting that pleiotropic effects are not associated with eicosanoid production. Only high-dose simvastatin reduced the relative proportion of sphingomyelin and ceramide to phosphatidylcholine (q=0.008), suggesting a pleiotropic effect previously associated with a reduced risk of cardiovascular disease.

show abstract

Further evaluation of plasma sphingomyelin levels as a risk factor for coronary artery disease

Cited by 114 publications

References 36 publications

Liver-specific Deficiency of Serine Palmitoyltransferase Subunit 2 Decreases Plasma Sphingomyelin and Increases Apolipoprotein E Levels

Liver-specific Deficiency of Serine Palmitoyltransferase Subunit 2 Decreases Plasma Sphingomyelin and Increases Apolipoprotein E Levels

Phospholipid Transfer Protein Deficiency Impairs Apolipoprotein-B Secretion from Hepatocytes by Stimulating a Proteolytic Pathway through a Relative Deficiency of Vitamin E and an Increase in Intracellular Oxidants

High-Dose Simvastatin Exhibits Enhanced Lipid-Lowering Effects Relative to Simvastatin/Ezetimibe Combination Therapy

Contact Info

Product

Resources

About