Effect of Myriocin on Plasma Sphingolipid Metabolism and Atherosclerosis in apoE-deficient Mice

Sphingolipids play a very important role in cell membrane formation, signal transduction, and plasma lipoprotein metabolism, all of which may well have an impact on the development of atherosclerosis. To investigate the relationship between sphingolipid metabolism and atherosclerosis, we utilized my...

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Bibliographic Details
Published in:The Journal of biological chemistry 2005-03, Vol.280 (11), p.10284-10289
Main Authors: Hojjati, Mohammad Reza, Li, Zhiqiang, Zhou, Hongwen, Tang, Songshan, Huan, Chongmin, Ooi, Everlyn, Lu, Shendi, Jiang, Xian-Cheng
Format: Article
Language:English
Subjects:
Acyltransferases - antagonists & inhibitors
Acyltransferases - chemistry
Animal Feed
Animals
Aorta - metabolism
Apolipoproteins E - metabolism
Arteriosclerosis - blood
Arteriosclerosis - metabolism
Arteriosclerosis - pathology
Ceramides - blood
Cholesterol - metabolism
Fatty Acids, Monounsaturated - chemistry
Fatty Acids, Monounsaturated - pharmacology
Immunosuppressive Agents - pharmacology
Lipid Metabolism
Lipids - blood
Lipoproteins - metabolism
Lysophospholipids - metabolism
Mass Spectrometry
Mice
Mice, Knockout
Phosphatidylcholines - blood
Serine C-Palmitoyltransferase
Signal Transduction
Sphingolipids - blood
Sphingolipids - metabolism
Sphingosine - analogs & derivatives
Sphingosine - metabolism
Time Factors
Triglycerides - metabolism
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Summary:Sphingolipids play a very important role in cell membrane formation, signal transduction, and plasma lipoprotein metabolism, all of which may well have an impact on the development of atherosclerosis. To investigate the relationship between sphingolipid metabolism and atherosclerosis, we utilized myriocin to inhibit mouse serine palmitoyl-CoA transferase (SPT), the key enzyme for sphingolipid biosynthesis. We injected 8-week-old apoE-deficient mice with myriocin (0.3 mg/kg/every other day, intraperitoneal) for 60 days. On a chow diet, myriocin treatment caused a significant decrease (50%) in liver SPT activity (p < 0.001), significant decreases in plasma sphingomyelin, ceramide, and sphingosine-1-phosphate levels (54, 32, and 73%, respectively) (p < 0.0001), and a significant increase in plasma phosphatidylcholine levels (91%) (p < 0.0001). Plasma total cholesterol and triglyceride levels demonstrated no significant changes, but there was a significant decrease in atherosclerotic lesion area (42% in root and 36% in en face assays) (p < 0.01). On a high fat diet, myriocin treatment caused marked decreases in plasma sphingomyelin, ceramide, and sphingosine-1-phosphate levels (59, 66, and 81%, respectively) (p < 0.0001), and a marked increase in plasma phosphatidylcholine levels (100%) (p < 0.0001). Total cholesterol and triglyceride demonstrated no significant changes, but there was a significant decrease in atherosclerotic lesion area (39% in root and 37% in en face assays) (p < 0.01). These results indicate that, apart from cholesterol levels, sphingolipids have an effect on atherosclerotic development and that SPT has proatherogenic properties. Thus, inhibition of SPT activity could be an alternative treatment for atherosclerosis.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M412348200