Background: Exosome is a membrane vesicle released from several types of cells, including neurons. Results: Neuronal exosomes accelerate A␤ fibril formation, and the exosome-associated A␤ is taken into microglia to degrade it. Conclusion: Exosomes promote A␤ clearance. Significance: These findings provide a new function of exosome in the brain and also suggest its involvement in the development of Alzheimer disease.

Very long-chain fatty acids (VLCFAs) exert a variety of cellular functions and are associated with numerous diseases. However, the precise pathway behind their elongation has remained elusive. Moreover, few regulatory mechanisms for VLCFAs synthesis have been identified. Elongases catalyze the first of four steps in the VLCFA elongation cycle; mammals have seven elongases (ELO-VL1-7). In the present study, we determined the precise substrate specificities of all the ELOVLs by in vitro analyses. Particularly notable was the high activity exhibited by ELOVL1 toward saturated and monounsaturated C20-and C22-CoAs, and that it was essential for the production of C24 sphingolipids, which are unique in their capacity to interdigitate within the membrane as a result of their long chain length. We further established that ELOVL1 activity is regulated with the ceramide synthase CERS2, an enzyme essential for C24 sphingolipid synthesis. This regulation may ensure that the production of C24-CoA by elongation is coordinated with its utilization. Finally, knockdown of ELOVL1 caused a reduction in the activity of the Src kinase LYN, confirming that C24-sphingolipids are particularly important in membrane microdomain function.acyl-CoA | lipid metabolism | monounsaturated fatty acid | polyunsaturated fatty acid | saturated fatty acid

Background: Exosome, a type of extracellular vesicles, can associate with A␤ in vitro. Results: Intracerebrally injected exosomes trapped A␤ on surface glycosphingolipids and transported it into microglia in AD mouse brains, resulting in reductions in A␤ pathology. Conclusion: Exogenous exosomes act as potent scavengers for A␤ in mouse brains. Significance: The findings provide a novel therapeutic approach for AD.

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Lipid microdomains or caveolae, small invaginations of plasma membrane, have emerged as important elements for lipid uptake and glucose homeostasis. Sphingomyelin (SM) is one of the major phospholipids of the lipid microdomains. In this study, we investigated the physiological function of sphingomyelin synthase 2 (SMS2) using SMS2 knock-out mice, and we found that SMS2 deficiency prevents high fat diet-induced obesity and insulin resistance. Interestingly, in the liver of SMS2 knock-out mice, large and mature lipid droplets were scarcely observed. Treatment with siRNA for SMS2 also decreased the large lipid droplets in HepG2 cells. Additionally, the siRNA of SMS2 decreased the accumulation of triglyceride in liver of leptin-deficient (ob/ob) mice, strongly suggesting that SMS2 is involved in lipid droplet formation. Furthermore, we found that SMS2 exists in lipid microdomains and partially associates with the fatty acid transporter CD36/FAT and with caveolin 1, a scaffolding protein of caveolae. Because CD36/FAT and caveolin 1 exist in lipid microdomains and are coordinately involved in lipid droplet formation, SMS2 is implicated in the modulation of the SM in lipid microdomains, resulting in the regulation of CD36/FAT and caveolae. Here, we established new cell lines, in which we can completely distinguish SMS2 activity from SMS1 activity, and we demonstrated that SMS2 could convert ceramide produced in the outer leaflet of the plasma membrane into SM. Our findings demonstrate the novel and dynamic regulation of lipid microdomains via conformational changes in lipids on the plasma membrane by SMS2, which is responsible for obesity and type 2 diabetes.

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Ceramide kinase (CERK) catalyzes the conversion of ceramide to ceramide 1-phosphate (C1P) and is known to be activated by calcium. Although several groups have examined the functions of CERK and its product C1P, the functions of C1P and CERK are not understood. We studied the RBL-2H3 cell line, a widely used model for mast cells, and found that CERK and C1P are required for activation of the degranulation process in mast cells. We found that C1P formation was enhanced during activation induced by IgE/antigen or by Ca 2؉ ionophore A23187. The formation of C1P required the intracellular elevation of Ca 2؉ . We generated RBL-2H3 cells that stably express CERK, and when these cells were treated with A23187, a concomitant C1P formation was observed and degranulation increased 4-fold, compared with mock transfectants. The cell-permeable Nacetylsphingosine (C 2 -ceramide), a poor substrate of CERK, inhibited both the formation of C1P and degranulation, indicating that C1P formation was necessary for degranulation. Exogenous introduction of CERK into permeabilized RBL-2H3 cells caused degranulation. We identified a cytosolic localization of CERK that provides exposure to cytosolic Ca 2؉ . Taken together, these results indicate that C1P formation is a necessary step in the degranulation pathway in RBL-2H3 cells.

Objective:Recent studies indicate that sphingolipids, sphingomyelin (SM) and ceramide (Cer) are associated with the development of metabolic syndrome. However, detailed profiles of serum sphingolipids in the pathogenesis of this syndrome are lacking. Here we have investigated the relationship between the molecular species of sphingolipids in serum and the clinical features of metabolic syndrome, such as obesity, insulin resistance, fatty liver disease and atherogenic dyslipidemia.Subjects:We collected serum from obese (body mass index, BMI⩾35, n=12) and control (BMI=20−22, n=11) volunteers (18−27 years old), measured the levels of molecular species of SM and Cer in the serum by liquid chromatography-mass spectrometry and analyzed the parameters for insulin resistance, liver function and lipid metabolism by biochemical blood test.Results:The SM C18:0 and C24:0 levels were higher, and the C20:0 and C22:0 levels tended to be higher in the obese group than in the control group. SM C18:0, C20:0, C22:0 and C24:0 significantly correlated with the parameters for obesity, insulin resistance, liver function and lipid metabolism, respectively. In addition, some Cer species tended to correlate with these parameters. However, SM species containing unsaturated acyl chains and most of the Cer species were not associated with these parameters.Conclusions:The present results demonstrate that the high levels of serum SM species with distinct saturated acyl chains (C18:0, C20:0, C22:0 and C24:0) closely correlate with the parameters of obesity, insulin resistance, liver function and lipid metabolism, suggesting that these SM species are associated with the development of metabolic syndrome and serve as novel biomarkers of metabolic syndrome and its associated diseases.