Role of Hepatic PEMT and Dietary Choline in the Development of Atherosclerosis

• Author / Creator

  Zia, Yumna

• Phosphatidylethanolamine N-methyltransferase (PEMT) is a hepatic enzyme that converts phosphatidylethanolamine to phosphatidylcholine. Pemt-/- mice are protected from obesity and insulin resistance, a phenotype that is reversed with dietary choline supplementation. Additionally, PEMT deficiency reduces plasma lipids and is protective against atherosclerosis when crossed with the low-density lipoprotein receptor (Ldlr-/-) mice. Recent studies have demonstrated that choline can be metabolized by the gut microbiota into trimethylamine-N-oxide (TMAO), which is a novel risk factor for atherosclerosis. The effect of choline supplementation on the development of atherosclerosis in Pemt-/-/Ldlr-/- mice is not known. Therefore, the objective of this thesis was to determine whether reintroducing hepatic PEMT expression or dietary choline supplementation promotes atherosclerosis in Pemt-/-/Ldlr-/- mice. Pemt+/+/Ldlr-/- (SKO) and Pemt-/-/Ldlr-/- (DKO) mice were injected with an adeno-associated virus (AAV) expressing green florescent protein (GFP) or human PEMT, and fed a western diet (40% calories from fat, 0.5% cholesterol, 3g/kg choline) for 8 weeks. In a separate experiment, SKO and DKO mice were fed the western diet containing 3 or 10g/kg choline for 12 weeks. The results demonstrated that DKO mice have low plasma lipids and were protected against atherosclerosis compared to SKO mice. AAV-PEMT administration increased plasma lipids and TMAO in DKO mice. Furthermore, AAV-PEMT injected DKO mice developed atherosclerotic lesions similar to SKO mice. In the second study, choline supplementation in DKO mice did not increase atherosclerosis or plasma lipids, but did increase plasma TMAO levels. Next, we sought to investigate whether reducing dietary choline influences TMAO production and development of atherosclerosis in SKO mice. We found that reducing dietary choline attenuated atherosclerosis in SKO mice compared to mice fed a high choline diet. However, decreasing choline did not alter plasma lipids or TMAO production. In summary, this thesis focused on the role of dietary choline and PEMT enzyme in the development of atherosclerosis. We found reintroducing hepatic PEMT expression reversed the atheroprotective phenotype of DKO mice while choline supplementation did not increase atherosclerosis or plasma lipids. Our data suggests that plasma TMAO levels do not always correlate with atherosclerosis and plasma lipids. Furthermore, this is the first report suggesting that de novo choline synthesis alters TMAO metabolism. Overall this research work contributes significantly towards our understanding of the complex relationship of dietary choline, de novo choline and TMAO production and how these factors influence the development of atherosclerosis and lipid metabolism.

• Subjects / Keywords

  • Atherosclerosis
  • Choline
  • PEMT

• Graduation date

  Fall 2017

• Type of Item

  Thesis

• Degree

  Master of Science

• DOI

  https://doi.org/10.7939/R3736MJ2X

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.