LAUSR

Sphingolipids play a physiologically major role in the human body. They not only serve as essential constituents of the membrane but also make microdomains called lipid rafts with cholesterol on the cell surface for transporting substances in and out of the cells. Sphingomyelin constitutes myelin sheath and red blood cell membrane. In contrast, if sphingomyelin is abnormally stored in the reticuloendothelial system and neurons of the body, lethal damage can occur after birth. This situation occurs in Niemann–Pick disease type A and B genetically lacking sphingomyelinase, which degrades sphingomyelin. In plasma, about 20% of lipoprotein phospholipids is sphingomyelin, most of which exists in VLDL and LDL1). Sphingomyelin on the surface of LDL particles interferes in the reaction between LDL and LDL receptors 2, 3) and promotes LDL aggregation 2). Aggregated LDL is captured by scavenger receptors of macrophages. These phenomena mean that sphingomyelin in LDL has pro-atherogenicity. As reported previously, the ingestion of plant stanol decreased the amount of sphingomyelin in LDL and lowered the aggregation susceptibility of LDL particles4). Sphingomyelin consists of ceramide (N-acyl sphingosine) and phosphoryl choline. Ceramide consists of sphingosine and a fatty acid (Fig.1). Ceramide and sphingosine also belong to sphingolipid. Ceramide is related to atherosclerosis. Meeusen et al. demonstrated that the number of plasma ceramides was associated with major adverse cardiovascular events in their cohort of 495 participants5). Concerning the molecular species of ceramides, they showed that N-palmitoyl sphingosine [Cer(16:0)], N-stearoyl-sphingosine [Cer(18:0)], and N-nervonoyl-sphingosine [Cer(24:1)] are significantly predictive of a major cardiovascular outcome at 4 years of follow-up. Recently, ceramide has also been reported to be involved in the pathogenesis of type 2 diabetes mellitus. Neeland et al. reported that plasma ceramides, especially bound to saturated fatty acids, are related to visceral adiposity, insulin resistance, and the development of type 2 diabetes6). Fretts et al. also reported that plasma ceramide, especially Cer(16:0), Cer(18:0), N-arachidoyl-sphingosine [Cer(20:0)], and N-behenoyl-sphingosine [Cer(22:0)], are associated with a higher risk of diabetes7). In this issue of Journal of Atherosclerosis and Thrombosis, Kurano et al. reported that they measured ceramides and sphingosine, including dihydrosphingosine, a molecule that is closely related to sphingosine (Fig.1), in each serum lipoprotein and lipoprotein-deleted fraction of healthy controls and patients with diabetes and compared the distribution of these sphingolipids between the two populations8). Some of their patients with type 2 diabetic mellitus had complications related to cardiovascular diseases and diabetic nephropathy. They separated lipoproteins from the serum of all participants using sequential ultracentrifugation and measured sphingolipids in each fraction using the LC-MS/MS system. Although several researchers have mentioned the relationship between serum ceramides and atherosclerosis or metabolic deterioration in humans, the distribution of sphingolipids among lipoproteins is rarely observed. Therefore, the research of Kurano et al. is well noted. The important points they found are as follows: 1) the levels of ceramide, sphingosine, and dihydosphingosine in HDL were lower, whereas those in lipoproteindepleted fractions were higher in patients with diabetes; 2) the contents of sphingosine, Cer(16:0) and N-lignoceroyl-sphingosine [Cer(24:0)] in the LDL fraction were higher in the group with diabetes, and levels of ceramides in LDL were negatively associated with the presence of cardiovascular diseases