Sphingomyelin (SM) is the most abundant phospholipid in plasma next to phosphatidylcholine (PC), and is an essential component of cell membrane rafts. Although recent epidemiologic studies suggest that high SM levels in plasma increase the risk of atherosclerosis, the underlying mechanisms are unknown, because the normal functions of SM have not been elucidated. We propose that, because of its unique structure, and localization in the outer surface of cells, SM protects the integrity of cell membranes by inhibiting the phospholipase and lipid peroxidation reactions. Furthermore, we propose that because of its affinity to cholesterol, SM regulates cell cholesterol homeostasis and reverse cholesterol transport. Dysregulation of these functions could lead to inflammation and promote atherosclerosis.
In Aim 1, we propose to test the hypothesis that SM regulates reverse cholesterol transport, focusing on its role in the efflux of cholesterol from macrophages, and in the esterification of cholesterol by LCAT. The novel hypothesis that SM acts as a chaperone for cholesterol during ABCG1 transporter-mediated efflux will be explored. The role of SM in the regulation of LCAT in physiological systems will be studied.
In Aim 2, we will investigate the hypothesis that SM acts as an anti-inflammatory lipid by inhibiting the formation of pro-inflammatory lipids such as lyso PC, arachidonate, oxidized phospholipids and oxysterols. The hypothesis that SM competitively inhibits all enzymes that utilize PC as substrate will be tested with respect to secretory phospholipases and endothelial lipase. The inhibitory role of SM in the generation of pro-inflammatory oxidized PCs and oxysterols will be tested in lipoproteins and cell membranes. The effect of SM deficiency on the macrophage and neutrophil function, including cytokine production and superoxide generation, will be studied in myeloid-specific SM-deficient mice.
In Aim 3, the role of SM and ceramide in cellular cholesterol homeostasis will be studied by determining their effects on cholesterol trafficking between cellular compartments and between cells and their environment. These studies will provide novel insights into the physiological role of this important phospholipid, and could possibly identify novel therapeutic targets against inflammation and atherosclerosis.

Public Health Relevance

The studies proposed here will investigate the physiological role of sphingomyelin (SM) a special lipid molecule prevalent in plasma and in outer cell membrane. They will specifically focus on the role of SM as an ant-inflammatory molecule that protects cells against environmental insults. These studies could lead not only to new understanding of mechanisms of inflammation and heart disease, but also to better therapeutic strategies. First, are there any macrophage pathways for cholesterol metabolism that are up- or down regulated by ablation of ABCG1? There could be changes in cellular cholesterol content, cholesterol esterases, ACAT, ABCA1, or possibly SR-B1 that could affect efflux. Second, there are other mechanisms that effect efflux, particularly spontaneous transfer, which Rothblat et al have shown to be important in some contexts (ATVB 2006 26:541-7) and efflux mediated by apo E (ATVB 2006 26:157-62). Lastly, it would be useful to compare efflux with net change in cholesterol by a non radio tracer method that would measure both medium and cellular cholesterol content. Radio tracers reveal how fast FC leaves the cell but not how much unlabeled cholesterol re enters the cell from donors in the medium.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-CVS-F (03))
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Ershow, Abby
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University of Illinois at Chicago
Internal Medicine/Medicine
Schools of Medicine
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Yang, Peng; Subbaiah, Papasani V (2015) Regulation of hepatic lipase activity by sphingomyelin in plasma lipoproteins. Biochim Biophys Acta 1851:1327-36
Yang, Peng; Belikova, Natalia A; Billheimer, Jeff et al. (2014) Inhibition of endothelial lipase activity by sphingomyelin in the lipoproteins. Lipids 49:987-96
Huang, Zhi H; Reardon, Catherine A; Subbaiah, Papasani V et al. (2013) ApoE derived from adipose tissue does not suppress atherosclerosis or correct hyperlipidemia in apoE knockout mice. J Lipid Res 54:202-13
Subbaiah, Papasani Venkata; Jiang, Xian-Cheng; Belikova, Natalia A et al. (2012) Regulation of plasma cholesterol esterification by sphingomyelin: effect of physiological variations of plasma sphingomyelin on lecithin-cholesterol acyltransferase activity. Biochim Biophys Acta 1821:908-13
Shentu, Tzu Pin; Singh, Dev K; Oh, Myung-Jin et al. (2012) The role of oxysterols in control of endothelial stiffness. J Lipid Res 53:1348-58
Chen, Su; Belikova, Natalia A; Subbaiah, Papasani V (2012) Structural elucidation of molecular species of pacific oyster ether amino phospholipids by normal-phase liquid chromatography/negative-ion electrospray ionization and quadrupole/multiple-stage linear ion-trap mass spectrometry. Anal Chim Acta 735:76-89
Subbaiah, Papasani V; Gould, Ian G; Lal, Samanta et al. (2011) Incorporation profiles of conjugated linoleic acid isomers in cell membranes and their positional distribution in phospholipids. Biochim Biophys Acta 1811:17-24
Zhao, Guijun; Subbaiah, P V; Chiu, See-Wing et al. (2011) Conjugated double bonds in lipid bilayers: a molecular dynamics simulation study. Chem Phys Lipids 164:251-7
Luque, Raul M; Lin, Qing; Córdoba-Chacón, José et al. (2011) Metabolic impact of adult-onset, isolated, growth hormone deficiency (AOiGHD) due to destruction of pituitary somatotropes. PLoS One 6:e15767
Zhao, Guijun; Subbaiah, P V; Mintzer, Evan et al. (2011) Molecular dynamic simulation study of cholesterol and conjugated double bonds in lipid bilayers. Chem Phys Lipids 164:811-8

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