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. © 2009 American Heart Association, Inc.