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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL068585-10
Application #
8309175
Study Section
Special Emphasis Panel (ZRG1-CVS-F (03))
Program Officer
Ershow, Abby
Project Start
2001-12-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2014-07-31
Support Year
10
Fiscal Year
2012
Total Cost
$388,575
Indirect Cost
$141,075
Name
University of Illinois at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Yang, Peng; Belikova, Natalia A; Billheimer, Jeff et al. (2014) Inhibition of endothelial lipase activity by sphingomyelin in the lipoproteins. Lipids 49:987-96
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
Subbaiah, Papasani V; Sircar, Debajit; Aizezi, Buzulagu et al. (2010) Differential effects of conjugated linoleic acid isomers on the biophysical and biochemical properties of model membranes. Biochim Biophys Acta 1798:506-14
Chen, Yong; Ott, Christopher J; Townsend, Kay et al. (2009) Cholesterol Supplementation During Production Increases the Infectivity of Retroviral and Lentiviral Vectors Pseudotyped with the Vesicular Stomatitis Virus Glycoprotein (VSV-G). Biochem Eng J 44:199-207
Subbaiah, Papasani V; Sowa, Jennifer M; Singh, Dev K (2008) Sphingolipids and cellular cholesterol homeostasis. Effect of ceramide on cholesterol trafficking and HMG CoA reductase activity. Arch Biochem Biophys 474:32-8
Chen, Su; Subbaiah, Papasani V (2007) Phospholipid and fatty acid specificity of endothelial lipase: potential role of the enzyme in the delivery of docosahexaenoic acid (DHA) to tissues. Biochim Biophys Acta 1771:1319-28
Singh, Dev K; Gesquiere, Laurence R; Subbaiah, Papasani V (2007) Role of sphingomyelin and ceramide in the regulation of the activity and fatty acid specificity of group V secretory phospholipase A2. Arch Biochem Biophys 459:280-7
Singh, Dev K; Subbaiah, Papasani V (2007) Modulation of the activity and arachidonic acid selectivity of group X secretory phospholipase A2 by sphingolipids. J Lipid Res 48:683-92
Sircar, Debajit; Subbaiah, Papasani V (2007) Isoprostane measurement in plasma and urine by liquid chromatography-mass spectrometry with one-step sample preparation. Clin Chem 53:251-8
Subbaiah, Papasani V; Horvath, Peter; Achar, Srinivasa B (2006) Regulation of the activity and fatty acid specificity of lecithin-cholesterol acyltransferase by sphingomyelin and its metabolites, ceramide and ceramide phosphate. Biochemistry 45:5029-38

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