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 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.
Hojjati
Mohammad Reza
MR
Department of Anatomy and Cell Biology, State University of New York Downstate Medical Center, 450 Clarkson Ave., Brooklyn, New York 11203, USA.
Li
Zhiqiang
Z
Zhou
Hongwen
H
Tang
Songshan
S
Huan
Chongmin
C
Ooi
Everlyn
E
Lu
Shendi
S
Jiang
Xian-Cheng
XC
D000217:Acyltransferases / Q000037:antagonists & inhibitors / Q000737:chemistry; D000821:Animal Feed; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001057:Apolipoproteins E / Q000378:metabolism*; D001161:Arteriosclerosis / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D002518:Ceramides / Q000097:blood; D002784:Cholesterol / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000737:chemistry / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D050356:Lipid Metabolism; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000378:metabolism; D008246:Lysophospholipids / Q000378:metabolism; D013058:Mass Spectrometry; D051379:Mice; D018345:Mice, Knockout; D010713:Phosphatidylcholines / Q000097:blood; D051102:Serine C-Palmitoyltransferase; D015398:Signal Transduction; D013107:Sphingolipids / Q000097:blood / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D013997:Time Factors; D014280:Triglycerides / Q000378:metabolism
D001057:Apolipoproteins E; D002518:Ceramides; D005229:Fatty Acids, Monounsaturated; D007166:Immunosuppressive Agents; D008055:Lipids; D008074:Lipoproteins; D008246:Lysophospholipids; D010713:Phosphatidylcholines; D013107:Sphingolipids; D014280:Triglycerides; C060506:sphingosine 1-phosphate; D002784:Cholesterol; D000217:Acyltransferases; D051102:Serine C-Palmitoyltransferase; D013110:Sphingosine; C001996:thermozymocidin