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

Abstract

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.Sphingolipids have many biological functions, including cell membrane formation, signal transduction, and lipid metabolism, and all of these may be related to the development of atherosclerosis. Serine palmitoyl-CoA transferase (SPT) 1 is the rate-limiting enzyme in the biosynthesis of sphingolipids (1). It has long been known that SPT plays an important role in the metabolism of sphingolipids, but its role in other lipid metabolisms and atherosclerosis has not been unequivocally determined. When SPT activity is increased in rat liver (2) and lung (3), sphingolipid formation is likewise increased. The activity of SPT is heightened in the aortas of rabbits fed a high cholesterol diet (4). Two candidate cDNAs for yeast SPT, termed LCB1 and LCB2, have been cloned (5, 6), and the translated sequences indicate that their gene products have a 21% amino acid sequence identity (6). The lack of SPT activity in a yeast strain defective in LCB1 or LCB2, together with the protein similarity data, suggest that the two genes encode subunits of SPT (6). Mouse and human LCB1 and LCB2 cDNA homologues have also been cloned (7,8). In mouse, the two mRNAs have the same tissue distribution (lung, kidney Ͼ brain Ͼ cartilage, skin Ͼ heart Ͼ liver Ͼ muscle), and the ratio of the amounts of the two transcri...

Ablation of ceramide synthase 2 exacerbates dextran sodium sulphate‐induced colitis in mice due to increased intestinal permeability

“…Treatment of myriocin, a serine palmitoyltransferase inhibitor, decreased levels of SLs including long‐chain bases and C16‐ceramide as reported previously 42 (Fig. 10A and B).…”

The SPTLC3 Subunit of Serine Palmitoyltransferase Generates Short Chain Sphingoid Bases

“…In this respect it is interesting that elevated plasma sphingolipid levels are associated with an increased risk of developing atherosclerosis and coronary heart disease (29,30). Myriocin lowered plasma sphingolipids in ApoE knock-out mice and significantly reduced the formation of atherosclerotic lesions in these mice and showed a significant delay of disease progression (31)(32)(33). Because treatment with myriocin would be expected to lower the levels of both C 16 -and C 18 -based sphingolipids it would be interesting to determine whether one of the two subclasses is primarily involved in the pathogenesis of atherosclerosis.…”

Ceramide: A common pathway for atherosclerosis?

“…However, they did not show the decrease in total cholesterol, triglycerides, VLDL and LDL. This was attributed to the mode of administration, which was oral in Park et al's study and intraperitoneal for Hojjati et al Myriocin did nevertheless cause a decrease in atherosclerotic lesions in mice on both chow and high fat, high cholesterol diets [84]. On a western diet, Hojjati et al were able to show a mean decrease of 37% in atherosclerotic lesion [84].…”

“…This was attributed to the mode of administration, which was oral in Park et al's study and intraperitoneal for Hojjati et al Myriocin did nevertheless cause a decrease in atherosclerotic lesions in mice on both chow and high fat, high cholesterol diets [84]. On a western diet, Hojjati et al were able to show a mean decrease of 37% in atherosclerotic lesion [84]. Myriocin is also able to reduce levels of inflammatory proteins, suggesting a very significant role in reducing the extent of atherosclerotic lesions [83].…”