Sphingomyelin Synthase 2 Is One of the Determinants for Plasma and Liver Sphingomyelin Levels in Mice

Department of Anatomy and Cell Biology, State University of New York Downstate Medical Center, 450 Clarkson Ave, Box 5, Brooklyn, NY 11203, USA.
Arteriosclerosis Thrombosis and Vascular Biology (Impact Factor: 6). 04/2009; 29(6):850-6. DOI: 10.1161/ATVBAHA.109.185223
Source: PubMed


It has been proposed that plasma sphingomyelin (SM) plays a very important role in plasma lipoprotein metabolism and atherosclerosis. Sphingomyelin synthase (SMS) is the last enzyme for SM de novo biosynthesis. Two SMS genes, SMS1 and SMS2, have been cloned and characterized.
To evaluate the in vivo role of SMS2 in SM metabolism, we prepared SMS2 knockout (KO) and SMS2 liver-specific transgenic (LTg) mice and studied their plasma SM and lipoprotein metabolism. On a chow diet, SMS2 KO mice showed a significant decrease in plasma SM levels (25%, P<0.05), but no significant changes in total cholesterol, total phospholipids, or triglyceride, compared with wild-type (WT) littermates. On a high-fat diet, SMS2 KO mice showed a decrease in plasma SM levels (28%, P<0.01), whereas SMS2LTg mice showed a significant increase in those levels (29%, P<0.05), but no significant changes in other lipids, compared with WT littermates. Atherogenic lipoproteins from SMS2LTg mice displayed a significantly stronger tendency toward aggregation after mammalian sphingomyelinase treatment, compared with controls. Moreover, SMS2 deficiency significantly increased plasma apoE levels (2.0-fold, P<0.001), whereas liver-specific SMS2 overexpression significantly decreased those levels (1.8-fold, P<0.01). Finally, SMS2 KO mouse plasma promoted cholesterol efflux from macrophages, whereas SMS2LTg mouse plasma prevented it.
We therefore believe that regulation of liver SMS2 activity could become a promising treatment for atherosclerosis.

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    • "SMS1 and SMS2 are expressed in a variety of tissues and cells with different ratio. SMS1 is mainly expressed in macrophages [18], while SMS2 is mainly expressed in the liver [19]. It is reported that SMS1 and SMS2 expression is positively correlated with SM levels in cells and lipid rafts [20], [21], [22]. "
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    ABSTRACT: Sphingomyelin synthase (SMS) plays an important role in plasma atherogenic lipoprotein metabolism, inflammation, and the development of atherosclerosis. To understand whether the impaired apoB secretion and inflammation response is a direct result from lack of SMS activity, in this study, we prepared a series of compounds that inhibit SMS activity. Further, we characterized Dy105, the most potent inhibitor. We found that Dy105 treatment significantly reduces SM levels in SM-rich microdomain on cell membranes. Moreover, we found that SMS inhibition reduces apoB secretion in a human hepatoma cell line and reduces the activation of NFκB and p38, a MAP kinase, in bone marrow derived macrophages. These studies provided further evidence that SMS activity regulates atherogenic lipoprotein metabolism and inflammatory responses. Pharmacologic inhibition of SMS may be a new therapy for atherosclerosis by reducing apoB secretion, and reducing inflammation.
    Full-text · Article · Jul 2014 · PLoS ONE
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    • "When our group cloned the pig SGMS1 gene, we observed a high intestinal expression [43], and we have now found that its intestinal expression increases postprandially. Recently, genetic manipulation of sphingomyelin synthases 1 and 2 has been proved to regulate plasma sphingomyelin levels [44], [45]. Likewise, several environmental conditions have been found to modified plasma sphingomyelin (SM). "
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    ABSTRACT: The present study was designed to verify the influence of acute fat loading on high density lipoprotein (HDL) composition, and the involvement of liver and different segments of small intestine in the changes observed. To address these issues, rats were administered a bolus of 5-ml of extra-virgin olive oil and sacrificed 4 and 8 hours after feeding. In these animals, lipoproteins were analyzed and gene expressions of apolipoprotein and HDL enzymes were assessed in duodenum, jejunum, ileum and liver. Using this experimental design, total plasma and HDL phospholipids increased at the 8-hour-time-point due to increased sphingomyelin content. An increase in apolipoprotein A4 was also observed mainly in lipid-poor HDL. Increased expression of intestinal Apoa1, Apoa4 and Sgms1 mRNA was accompanied by hepatic decreases in the first two genes in liver. Hepatic expression of Abcg1, Apoa1bp, Apoa2, Apoe, Ptlp, Pon1 and Scarb1 decreased significantly following fat gavage, while no changes were observed for Abca1, Lcat or Pla2g7. Significant associations were also noted for hepatic expression of apolipoproteins and Pon1. Manipulation of postprandial triglycerides using an inhibitor of microsomal transfer protein -CP-346086- or of lipoprotein lipase -tyloxapol- did not influence hepatic expression of Apoa1 or Apoa4 mRNA. All these data indicate that dietary fat modifies the phospholipid composition of rat HDL, suggesting a mechanism of down-regulation of hepatic HDL when intestine is the main source of those particles and a coordinated regulation of hepatic components of these lipoproteins at the mRNA level, independently of plasma postprandial triglycerides.
    Full-text · Article · Jan 2013 · PLoS ONE
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    • "We employed ICR liver homogenate as SMS enzyme resource in this study in hopes the result of this in vitro assay might be close to that of in vivo. It has been reported that regulation of liver SMS activity could become a promising treatment for atherosclerosis (Liu et al. 2009). The liver and small intestine are the major places for the production of plasma SM. "
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    ABSTRACT: Sphingomyelin synthase (SMS) is a key enzyme for the synthesis of mammalian sphingomyelin. SMS plays diverse roles in physiology and pathology, thus, it could be a useful disease marker and/or drug target. We report here a novel and sensitive method for SMS activity measurement. Using a HPLC column (C18-RP), SMS activity was monitored by measuring a decrease of the fluorescent substrate C6-4-nitrobenzo-2-oxa-1,3-diazole (NBD)-ceramide (C6-NBD-Cer) and increase of the product (C6-NBD-SM). Time- and protein-dependent formation of C6-NBD-SM was investigated and enzyme kinetics was determined [Km = 7.49 ± 0.48 µM (C6-NBD-Cer) and Vmax = 27.86 ± 0.73fmol/h/mg homogenate protein]. This method is feasible, rapid, accurate, and highly reproducible, and suitable for quantifying SMS enzyme activity in SMS inhibitor screening studies. A known SMS inhibitor, D609, was employed to evaluate the assay and its IC50 value has been determined.
    Full-text · Article · Aug 2012 · Analytical Letters
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