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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1349.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

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

Yang Zhao; Brian Su; René L. Jacobs; Brian Kennedy; Gordon A. Francis; Emma Waddington; John T. Brosnan; Jean E. Vance; Dennis E. Vance

From the Group on Molecular and Cell Biology of Lipids (Y.Z., B.S., R.L.J., G.A.F., E.W., J.E.V., D.E.V.) and the Departments of Biochemistry (Y.Z., B.S., R.L.J., D.E.V.) and Medicine (G.A.F., E.W., J.E.V.), University of Alberta, Edmonton, Canada; the Department of Biochemical Molecular Biology (B.K.), Merck Frosst Centre for Therapeutic Research, Montreal, QC, Canada; and the Department of Biochemistry (J.T.B.), Memorial University of Newfoundland, St. John’s, Newfoundland.

Correspondence to Dr Dennis E. Vance, 328 Heritage Medical Research Centre, University of Alberta, Edmonton, AB T6G 2S2 Canada. E-mail dennis.vance{at}ualberta.ca

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.

Phosphatidylethanolamine N-methyltransferase (PEMT) catalyzes phosphatidylcholine biosynthesis in the liver. PEMT deficiency in LDLR-deficient mice significantly reduced plasma atherogenic lipoprotein levels and atherosclerotic lesion area, altered the phospholipid composition of hepatic apoB-containing lipoproteins, modestly decreased hepatic lipoprotein secretion, and altered the rate of lipoprotein clearance from plasma.

Key Words: phosphatidylcholine • phosphatidylethanolamine N-methyltransferase • liver • lipoproteins • LDL receptor