The role of dietary choline on atherosclerosis development

  • Author / Creator
    Aldana Hernandez, Paulina
  • Choline, as an essential nutrient, is needed for a variety of biological processes such as phospholipid synthesis, cell-membrane signaling, lipoprotein secretion, acetylcholine biosynthesis, and one-carbon metabolism. In the North American population diet the two most common forms of choline in foods are phosphatidylcholine (PC) and free-choline (FC). The recommended adequate intake (AI) is 550 and 425 mg/d for men and women, respectively. However, it has been reported that choline intake is below the AI in various populations and it has been recommended to increase the consumption of foods that are rich in choline. During the last decade epidemiological studies have suggested that consumption of choline rich foods (specifically PC from animal source) might increase cardiovascular disease (CVD) risk. Excess dietary choline is metabolized by gut microorganisms to trimethylamine (TMA) and then is further oxidized in the liver to form trimethylamine N-oxide (TMAO). It has been proposed that TMAO might enhance atherosclerosis development and be a biomarker for CVD risk. Therefore, the objective of this thesis was to understand the role of dietary choline supplementation on atherosclerosis development.
    We conducted a series of feeding trials to investigate whether the form of dietary choline, free choline or PC supplementation influences atherosclerosis development in atherogenic mouse models. It was observed that in Ldlr-/- mice, dietary supplementation with choline or TMAO increased plasma TMAO levels by 1.6- and 4-fold, respectively after 8 wk. Meanwhile, after 16 wk there was an increase of 2-fold at TMAO supplementation. In Apoe-/- mice, plasma TMAO levels were significantly (p<0.05) different only between choline and betaine supplemented for 12 wk. However, following the dietary intervention for 28 wk in this mouse model, TMAO levels were significantly (p<0.05) increased in choline and TMAO groups compared to controls, 1.8 and 1.5-fold respectively. These dietary interventions did not alter atherosclerosis or plasma cholesterol levels in either mouse model.
    Surprisingly, in Ldlr-/- mice PC supplementation reduced atherosclerotic lesions (p<0.05) while having 2-fold higher plasma TMAO levels compared with both control and choline supplemented diets (p<0.05). At fasting state, PC supplementation decreased (p<0.05) plasma VLDL-C and APOB48, and increased (p<0.05) plasma HDL-C. However, VLDL secretion was not affected by dietary treatment. In spleen and peripheral blood immune cell phenotypes there were no differences in the proportion of T and B cells subsets and macrophages along with the activation markers that they express including ICAM-1. Nevertheless, we observed lower (p<0.05) levels of circulating pro-atherogenic chemokines in the PC supplemented group. This study suggests that increased dietary PC intake does not induce a pro-atherogenic phenotype.
    In parallel a randomized controlled crossover in healthy men was performed. We examined the effect of standardized breakfasts containing different dietary amounts, forms, and sources of choline on postprandial choline and TMAO metabolism in healthy men. The high choline meals (~360 mg of choline) provided to the participants did not impact postprandial TMA, TMAO, choline response. However, plasma TMAO levels were increased (p<0.05) after 0.5 and 1 h of consuming a high free-choline breakfast compared to high PC breakfasts.
    Overall, it was concluded that dietary choline supplementation did not enhance atherosclerosis despite increasing plasma TMAO levels. Surprisingly, dietary PC supplementation reduced atherosclerotic development. In healthy men, it was showed that a single high choline meal did not alter the postprandial TMAO response.

  • Subjects / Keywords
  • Graduation date
    Fall 2021
  • Type of Item
  • Degree
    Doctor of Philosophy
  • DOI
  • 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.