Impaired Phosphatidylcholine Biosynthesis Reduces Atherosclerosis and Prevents Lipotoxic Cardiac Dysfunction in ApoE-/- Mice

Rationale: Phosphatidylcholine (PC) is the predominant phospholipid component of circulating lipoproteins. The majority of PC is formed by the choline pathway. However, approximately one-third of hepatic PC can also be synthesized by phosphatidylethanolamine N-methyltransferase (PEMT). PEMT is required for normal secretion of very-low-density lipoproteins from the liver. We hypothesized that lack of PEMT would attenuate atherosclerosis and improve myocardial function. Objective: Investigate the contribution of PEMT to atherosclerotic lesion formation and cardiac function in mice that lack apolipoprotein E. Methods and Results: Mice deficient in apolipoprotein E (Pemt(+/+)/Apoe(-/-)) and mice lacking both PEMT and apoE (Pemt(-/-)/Apoe(-/-)) were fed a chow diet for 1 year. The atherogenic lipoprotein profile of plasma of Apoe(-/-) mice was significantly improved by PEMT deficiency, with lower levels of triacylglycerol (45%) and cholesterol (approximate to 25%) in the very-low-density lipoprotein and low-density/intermediate-density lipoprotein fractions, respectively (P < 0.05). Atherosclerotic lesion area was reduced by approximate to 30%, and aortic cholesteryl ester and cholesterol content were also reduced by approximate to 40% by PEMT deficiency (P < 0.05). By in vivo echocardiography, we detected a approximate to 50% improvement in systolic function in the Pemt(-/-)/Apoe(-/-) compared with Pemt(+/+)/Apoe(-/-) mice (P < 0.05). This was accompanied by a significant reduction in cardiac triacylglycerol (34%) in mice lacking PEMT. Conclusions: These results indicate that treatment strategies aimed at inhibition of PEMT might prevent the accumulation of cardiac triacylglycerol that predisposes individuals to compromised cardiac function. (Circ Res. 2011;108:686-694.)