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. Methods and 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 approximate to 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 [approximate to 45%], triacylglycerols [approximate to 65%], cholesterol [approximate to 58%], and cholesteryl esters [approximate to 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. Conclusion-This is the first report showing that inhibition of hepatic phospholipid biosynthesis attenuates atherosclerosis. (Arterioscler Thromb Vasc Biol. 2009;29:1349-1355.)