Date of Award
Fall 2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Molecular, Cellular, and Developmental Biology
First Advisor
Rodeheffer, Matthew
Abstract
Cardiovascular diseases (CVDs) are the number one killer of people worldwide, of which coronary heart disease, which is mainly due to atherosclerosis, is the main contributor to death. Nonetheless, the etiology of atherosclerosis remains poorly understood. It is universally accepted that dietary fat influences atherosclerosis, however, the role of specific fats is not well-understood. Despite the widely-held perception that saturated fats drive atherosclerotic CVDs while monounsaturated fats are protective, there have been numerous studies from human and mice that do not fit with this prevailing narrative. Thus, despite the importance of dietary fats in CVDs, the exact effects remain controversial and there is a substantial gap in knowledge about how specific dietary fats drive atherosclerotic CVDs. In my thesis work, I systematically dissect the role of dietary fats in atherosclerosis using an unbiased diet screen. Mice were fed a series of custom isocaloric high-fat diets (HFDs), which differed only in the fat source, for 12 weeks and atherosclerosis progression was assessed. I found that dietary fat composition significantly influences the extent of atherosclerosis. Lipidomic analysis of the diets revealed that atherosclerosis correlates with only two dietary fatty acids: C16:0, palmitic acid (PA) and C18:1 n-9, oleic acid (OA). This unbiased approach, for the first time, elucidates precisely that it is not fatty acids per se, but dietary PA and OA that play critical roles in atherosclerosis. Leveraging the correlative relationship, I characterized the atherosclerotic plaque morphology developed in mice fed the high-OA and high-PA diets, which indicates differential regulation of lesional macrophage apoptosis based on dietary fat composition despite comparable plaque size. This suggests that dietary PA and OA drive atherosclerosis by different mechanisms. In vitro transcriptome analysis of fatty acid-treated macrophages revealed that PA and OA induce two separate pathways that are known to be involved in human atherosclerosis, with PA inducing macrophage colony stimulating factor (M-CSF, or CSF1) and OA downregulating liver X receptor (LXR). While both CSF1 and LXR pathways are known to affect atherosclerosis, their roles in response to dietary PA and OA are unknown. Therefore, I determine the role of PA and OA-induced pathways in atherosclerosis by targeting these pathways in vivo both individually and in combination in the context of high-PA and high-OA diets. I found that the efficacy of targeting each pathway individually is diet-dependent, supporting the central premise that there are two independent diet-induced atherosclerotic pathways. Incredibly, given that PA and OA are always present together in the diet and in vivo, targeting both OA and PA-induced pathways simultaneously is found to have a profound, synergistic effect on ameliorating atherosclerosis. Together, these data indicate that there are two separate dietary fatty acid-induced pathways that drive atherosclerosis.
Recommended Citation
Wang, Zenan, "The Role Of Dietary Fats In Driving Atherosclerosis" (2023). Yale Graduate School of Arts and Sciences Dissertations. 1107.
https://elischolar.library.yale.edu/gsas_dissertations/1107
