Impaired phosphatidylcholine biosynthesis reduces atherosclerosis and prevents lipotoxic cardiac dysfunction in ApoE-/- mice

Abstract

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 (≈25%) in the very-low-density lipoprotein and low-density/intermediate-density lipoprotein fractions, respectively (P<0.05). Atherosclerotic lesion area was reduced by ≈30%, and aortic cholesteryl ester and cholesterol content were also reduced by ≈40% by PEMT deficiency (P<0.05). By in vivo echocardiography, we detected a ≈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. © 2011 American Heart Association. All rights reserved.