Lack of Phosphatidylethanolamine N -Methyltransferase Alters Plasma VLDL Phospholipids and Attenuates Atherosclerosis in Mice

Abstract

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 ≈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 [≈45%], triacylglycerols [≈65%], cholesterol [≈58%], and cholesteryl esters [≈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.