Changes in Triglyceride‐Rich Lipoprotein Composition in Response to a High‐Fat Meal Promote Endothelial Inflammation in Hypertriglyceridemic Subjects
Authors: Rajamani Anita , Fernandez Andrea , Simon Scott I. , Passerini Anthony G. 
Published: November 2023

Cardiovascular disease (CVD) remains the leading cause of death and disability globally, despite the realization that much of this burden is preventable. Poor diet, and associated obesity and hypertriglyceridemia (HTG), are among the principal modifiable risk factors that collectively account for > 50% of deaths due to CVD. These factors contribute to metabolic dysregulation, chronic low‐grade inflammation, and an array of stress responses, leading to endothelial dysfunction and accelerating atherosclerosis. Inflammatory responses mediated by endothelium are exacerbated by a high‐fat diet and the postprandial state, and culminate in the preferential recruitment of leukocytes to sites of nascent plaque formation via the upregulation of cell adhesion molecules (CAMs) such as VCAM‐1. The mechanisms linking unhealthy diets to the inflammation driving atherogenesis remain elusive. The prevalence of HTG as a component of the metabolic syndrome motivated us to study the atherogenicity of triglyceride‐rich lipoproteins (TGRL) isolated from human subjects after a high‐fat meal. We hypothesized that the composition of postprandial TGRL changes in proportion to the level of HTG to directly influence signaling responses in endothelium that underlie the earliest events of atherosclerosis. To study the maladaptive responses to dietary lipoproteins ex vivo, we developed a microfluidic lab‐on‐a‐chip assay, to quantify the expression of VCAM‐1 and capture of monocytes by endothelium. Our studies revealed that TGRL, isolated from human serum 3.5 hrs after a high‐fat meal challenge, primes either a pro‐ or anti‐atherogenic state in endothelium, defined as a net up‐ or down‐regulation of VCAM‐1 expression on cultured human aortic endothelial cells (HAEC) relative to inflammatory stimulation with TNFα. Pro‐inflammatory responses were associated with larger, more triglyceride‐rich particles, and correlated with subject abdominal obesity and HTG. The changes elicited by TGRL were functionally significant as they strongly correlated with flow‐dependent monocyte recruitment. To demonstrate a putative role for changes in the fatty acid (FA)‐rich triglyceride pool as a mediator of these responses, we examined TGRL from 13 subjects (ranging from pro‐ to anti‐inflammatory) for the total and non‐esterified FA (NEFA) constituents. A principle component analysis revealed discrete groupings of subjects by inflammatory phenotype. The relative abundance of NEFA provided the greatest discrimination between the samples, and implicated FA composition as a mediator of the relative inflammatory capacity of TGRL. Pro‐atherogenic changes in VCAM‐1 correlated with enrichment in the ratio of omega‐6 to omega‐3 polyunsaturated FA (PUFA). In our lab‐chip assay, the PUFA docosahexaenoic acid, eicosapentaenoic acid, and arachadonic acid significantly reduced VCAM‐1 expression by HAEC. Ongoing analysis of the bioactive metabolites of these fatty acids (oxylipins) is advancing our understanding of links between nutrition, lipid metabolism, and the earliest changes in endothelium that initiate atherosclerosis.Support or Funding InformationSupported by National Institute of Health grant HL082689 (SIS and AGP).