Lack of phosphatidylethanolamine N-methyltransferase alters plasma VLDL phospholipids and attenuates atherosclerosis in mice.
OBJECTIVE
Impaired hepatic phosphatidylcholine (PC) synthesis lowers plasma lipids. We, therefore, tested the hypothesis that lack of phosphatidylethanolamine N-methyltransferase (PEMT), a hepatic enzyme catalyzing PC biosynthesis, attenuates the development of atherosclerosis.


RESULTS
Mice deficient in both PEMT and low-density lipoprotein receptors (Pemt(-/-)/Ldlr(-/-) mice) were fed a high-fat/high-cholesterol diet for 16 weeks. Atherosclerotic lesion area was approximately 80% lower (P<0.01) in Pemt(-/-)/Ldlr(-/-) mice than in Pemt(+/+)/Ldlr(-/-) mice, consistent with the atheroprotective plasma lipoprotein profile (ie, significant reduction in very low-density lipoprotein [VLDL]/intermediate-density lipoprotein/low-density lipoprotein-associated phospholipids [approximately 45%], triacylglycerols [approximately 65%], cholesterol [approximately 58%], and cholesteryl esters [approximately 68%]). Plasma apoB was decreased by 40% to 60%, whereas high-density lipoprotein levels were not altered. In addition, PEMT deficiency reduced plasma homocysteine by 34% to 52% in Pemt(-/-)/Ldlr(-/-) mice. The molar ratio of PC/phosphatidylethanolamine in nascent VLDLs produced by Pemt(-/-)/Ldlr(-/-) mice was lower than in VLDLs in Pemt(+/+)/Ldlr(-/-) mice. Furthermore, deletion of PEMT modestly reduced hepatic VLDL secretion in Ldlr(-/-) mice and altered the rate of VLDL clearance from plasma.


CONCLUSIONS
This is the first report showing that inhibition of hepatic phospholipid biosynthesis attenuates atherosclerosis.
Zhao
Yang
Y
Department of Biochemistry, University of Alberta, Edmonton, Canada.
Su
Brian
B
Jacobs
René L
RL
Kennedy
Brian
B
Francis
Gordon A
GA
Waddington
Emma
E
Brosnan
John T
JT
Vance
Jean E
JE
Vance
Dennis E
DE
D000818:Animals; D001055:Apolipoproteins B / Q000097:blood; D050197:Atherosclerosis / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*; D002784:Cholesterol / Q000097:blood; D002788:Cholesterol Esters / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D006710:Homocysteine / Q000097:blood; D007700:Kinetics; D053419:Lipoproteins, IDL / Q000097:blood; D008077:Lipoproteins, LDL / Q000097:blood; D008079:Lipoproteins, VLDL / Q000097:blood*; D008099:Liver / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010713:Phosphatidylcholines / Q000097:blood*; D050918:Phosphatidylethanolamine N-Methyltransferase / Q000172:deficiency* / Q000235:genetics; D010714:Phosphatidylethanolamines / Q000097:blood; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D014280:Triglycerides / Q000097:blood
D001055:Apolipoproteins B; D002788:Cholesterol Esters; D053419:Lipoproteins, IDL; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D010713:Phosphatidylcholines; D010714:Phosphatidylethanolamines; D011973:Receptors, LDL; D014280:Triglycerides; D006710:Homocysteine; D002784:Cholesterol; D050918:Phosphatidylethanolamine N-Methyltransferase