Impact of Sphingomyelin Synthase 1 Deficiency on Sphingolipid Metabolism and Atherosclerosis in Mice

Abstract

Objective Sphingomyelin synthase (SMS) catalyzes the conversion of ceramide to sphingomyelin (SM), and sits at the crossroads of sphingolipid biosynthesis. SMS has two isoforms: SMS1 and SMS2. Although they have the same SMS activity, they are different enzymes with distinguishable subcellular localizations and cell expression patterns. It is conceivable that these differences could yield different consequences, in terms of sphingolipid metabolism and its related atherogenesis. Methods and Results we created Sms1 gene knockout (KO) mice and found that Sms1 deficiency significantly decreased plasma, liver, and macrophage SM (59%, 45%, and 54%, respectively), but had only a marginal effect on ceramide levels. Surprisingly, we found that Sms1 deficiency dramatically increased glucosylceramide and GM3 levels in plasma, liver, and macrophages (4 to 12 fold), while Sms2 deficiency had no such effect. We evaluated total SMS activity in tissues and found that Sms1 deficiency causes 77% reduction of SMS activity, indicating SMS1 is the major SMS in macrophages. Moreover, Sms1 deficient-macrophages have significantly higher glucosylceramide synthase activity. We also found that Sms1 deficiency significantly attenuated toll-like 4 receptor-mediated NF-κB and MAP kinase activation after LPS treatment. To evaluate atherogenicity, we transplanted Sms1 KO mouse bone marrow into LDL receptor KO mice (Sms1−/−→Ldlr−/−). After 3 months on a Western diet, these animals showed a significant decrease of atherosclerotic lesions in the root and the entire aorta (35% and 44%, P<0.01, respectively), and macrophage content in lesions (51%, P<0.05), compared with WT→Ldlr−/−) mice. Conclusions Sms1 deficiency decreases SM, but dramatically increases the levels of glycosphingolipids. Atherosclerosis in Sms1−/−→Ldlr−/− mice is significantly decreased.

All members in the sphingomyelin synthase gene family have ceramide phosphoethanolamine synthase activity

“…5B ) KO mice, we did not observe a CPE reduction-mediated accumulation of ceramide. In fact, in the Sms1 KO mice, we observed a reduction in plasma ceramide levels ( 23 ). These results suggest that CPE is not a critical regulator of ceramide levels in vivo.…”

“…Macrophage sphingolipids are involved in reverse cholesterol transport, a process associated with antiatherogenesis ( 22,23 ). Because Smsr is highly expressed in macrophages, we next measured sphingolipids in these cells.…”

Serum sphingolipids: relationships to insulin sensitivity and changes with exercise in humans

“…Similarly, our data suggest a link between serum sphingomyelin and insulin secretion. The mechanism explaining this relationship is not known, but sphingomyelin synthase 1 knockout mice have decreased plasma and islet sphingomyelin levels, glucose intolerance, and deficiencies in insulin secretion (25,40). Therefore, some sphingomyelin species are important players in maintaining glucose homeostasis.…”

Functional characterization of enzymes catalyzing ceramide phosphoethanolamine biosynthesis in mice

“…Ceramides serve as "metabolic hub" and cells are equipped with a multitude of enzymes to modulate their levels. This may explain why genetic ablation of SMS1 and SMS2 in mice causes only a modest increase in tissue ceramide levels [ ( 13,15,27 ), and this study], even though these enzymes normally consume the bulk of newly synthesized ceramides ( 10 ). As tissues of SMSrD348E mutant mice did not contain any signifi cantly elevated levels of sphingoid bases, hexosylceramides, or SM, it is unclear how embryonic cells with disrupted SMSr catalytic activity were able to overcome a deregulation of ER ceramides associated with a disruption in SMSr catalytic activity.…”

“…SMS1 defi ciency in mice causes moderate neonatal lethality, reduced body weight, loss of fat tissue mass, and white adipose tissue function associated with impaired insulin secretion ( 13,14 ). It also decreases SM and elevates glycosphingolipid levels in plasma, liver, and macrophages, and attenuates macrophage activation by NF B and MAPK in response to infl ammatory stimuli ( 15 ). SMS2 defi ciency, on the other hand, ameliorates high fat-induced obesity ( 16,17 ), attenuates lipopolysaccharide-induced lung injury ( 18 ), and reduces atherosclerosis ( 19 ).…”