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 (≈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.
- phosphatidylethanolamine N-methyltransferase
- lipotoxic cardiomyopathy
- apolipoprotein E
- Received March 17, 2010.
- Revision received January 7, 2011.
- Accepted January 18, 2011.
- © 2011 American Heart Association, Inc.