Sphingomyelin synthase 2 is one of the determinants for plasma and liver sphingomyelin levels in mice.
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.


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.
Liu
Jing
J
Department of Anatomy and Cell Biology, State University of New York Downstate Medical Center, 450 Clarkson Ave, Box 5, Brooklyn, NY 11203, USA.
Zhang
Hongqi
H
Li
Zhiqiang
Z
Hailemariam
Tiruneh K
TK
Chakraborty
Mahua
M
Jiang
Kailiu
K
Qiu
Daniel
D
Bui
Hai H
HH
Peake
David A
DA
Kuo
Ming-Shang
MS
Wadgaonkar
Raj
R
Cao
Guoqing
G
Jiang
Xian-Cheng
XC
D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D050197:Atherosclerosis / Q000201:enzymology / Q000517:prevention & control; D001692:Biological Transport; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage / Q000378:metabolism; D006801:Humans; D008074:Lipoproteins / Q000378:metabolism; D008099:Liver / Q000201:enzymology*; D008264:Macrophages / Q000201:enzymology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D013109:Sphingomyelins / Q000097:blood / Q000378:metabolism*; D017855:Transferases (Other Substituted Phosphate Groups) / Q000235:genetics / Q000378:metabolism*
D001057:Apolipoproteins E; D004041:Dietary Fats; D008074:Lipoproteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D013109:Sphingomyelins; D002784:Cholesterol; C455440:SGMS1 protein, human; D017855:Transferases (Other Substituted Phosphate Groups); C070186:phosphatidylcholine-ceramide phosphocholine transferase; D013108:Sphingomyelin Phosphodiesterase