on March 12, 2009
Published online before print March 12, 2009, doi: 10.1161/ATVBAHA.109.185223
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Submitted on November 16, 2008
Accepted on March 5, 2009
Sphingomyelin Synthase 2 Is One of the Determinants for Plasma and Liver Sphingomyelin Levels in Mice
Jing Liu ;
From the Department of Anatomy and Cell Biology (J.L., H.Z., Z.L., T.K.H., M.C., D.Q., R.W., X.C.J.), State University of New York Downstate Medical Center, Brooklyn, New York; the Department of Anatomy, Histology, and Embryology (H.Z.), Shanghai Medical College, Fudan; Lilly Research Laboratories (H.H.B., D.A.P., M.-S.K., G.C.), Eli Lilly & Company, Indianapolis, Indiana.
* To whom correspondence should be addressed. E-mail: XJiang{at}downstate.edu.
Background—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.
Methods and Results—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.
Conclusions—We therefore believe that regulation of liver SMS2 activity could become a promising treatment for atherosclerosis.
Key words: SMS2 knockout mice • SMS2 liver-specific transgenic mice • plasma sphingomyelin • plasma lipoproteins • plasma cholesterol