Sphingolipids in atherosclerosis: a metabolic underpinning of vascular disease

Although atherosclerotic plaque formation is driven primarily by cholesterol, new data suggest a proatherogenic role for sphingolipids. This role might be especially significant in the context of metabolic syndrome, where overabundance of long-chain saturated fatty acids stimulates sphingolipid synthesis and turnover. Increased levels of different sphingolipids in plasma and the vascular wall are associated strongly with atherosclerosis in patients and in experimental models. Inhibition of serine palmitoyl transferase, the key enzyme of sphingomyelin synthesis, reduced atherosclerosis in apolipoprotein E-deficient mice. Although the exact mechanisms of the antiatherosclerotic effect are still unknown, they likely involve reduction of both lipoprotein-associated and intracellular ceramide and sphingomyelin. In turn, they are involved in lipoprotein aggregation, retention, foam-cell formation, apoptosis and cholesterol synthesis. The ceramide derivative, sphingosine-1-phosphate may, in part, counterbalance ...