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.