Liver-specific deficiency of serine palmitoyltransferase subunit 2 decreases plasma sphingomyelin and increases apolipoprotein E levels.
Sphingomyelin (SM) is one of the major lipid components of plasma lipoproteins. Serine palmitoyltransferase (SPT) is the key enzyme in SM biosynthesis. Mice totally lacking in SPT are embryonic lethal. The liver is the major site for plasma lipoprotein biosynthesis, secretion, and degradation, and in this study we utilized a liver-specific knock-out approach for evaluating liver SPT activity and also its role in plasma SM and lipoprotein metabolism. We found that a deficiency of liver-specific Sptlc2 (a subunit of SPT) decreased liver SPT protein mass and activity by 95 and 92%, respectively, but had no effect on other tissues. Liver Sptlc2 deficiency decreased plasma SM levels (in both high density lipoprotein and non-high density lipoprotein fractions) by 36 and 35% (p < 0.01), respectively, and increased phosphatidylcholine levels by 19% (p < 0.05), thus increasing the phosphatidylcholine/SM ratio by 77% (p < 0.001), compared with controls. This deficiency also decreased SM levels in the liver by 38% (p < 0.01) and in the hepatocyte plasma membranes (based on a lysenin-mediated cell lysis assay). Liver-specific Sptlc2 deficiency significantly increased hepatocyte apoE secretion and thus increased plasma apoE levels 3.5-fold (p < 0.0001). Furthermore, plasma from Sptlc2 knock-out mice had a significantly stronger potential for promoting cholesterol efflux from macrophages than from wild-type mice (p < 0.01) because of a greater amount of apoE in the circulation. As a result of these findings, we believe that the ability to control liver SPT activity could result in regulation of lipoprotein metabolism and might have an impact on the development of atherosclerosis.
Li
Zhiqiang
Z
State University of New York Downstate Medical Center, Brooklyn, New York 11203, USA.
Li
Yan
Y
Chakraborty
Mahua
M
Fan
Yifan
Y
Bui
Hai H
HH
Peake
David A
DA
Kuo
Ming-Shang
MS
Xiao
Xiao
X
Cao
Guoqing
G
Jiang
Xian-Cheng
XC
D000818:Animals; D001057:Apolipoproteins E / Q000097:blood*; D015153:Blotting, Western; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D007150:Immunohistochemistry; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000097:blood; D008099:Liver / Q000166:cytology / Q000201:enzymology* / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D013058:Mass Spectrometry; D051379:Mice; D018345:Mice, Knockout; D051102:Serine C-Palmitoyltransferase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D013109:Sphingomyelins / Q000097:blood*
D001057:Apolipoproteins E; D008055:Lipids; D008074:Lipoproteins; D013109:Sphingomyelins; D002784:Cholesterol; D051102:Serine C-Palmitoyltransferase; C495090:Sptlc2 protein, mouse