Abstract
Elevated triglyceride-rich lipoproteins (TGRL) in circulation is a risk factor for atherosclerosis. TGRL from subjects consuming a high saturated fat test meal elicited a variable inflammatory response in TNFα-stimulated endothelial cells (EC) that correlated strongly with the polyunsaturated fatty acid (PUFA) content. This study investigates how the relative abundance of oxygenated metabolites of PUFA, oxylipins, is altered in TGRL postprandially, and how these changes promote endothelial inflammation. Human aortic EC were stimulated with TNFα and treated with TGRL, isolated from subjects’ plasma at fasting and 3.5 hrs postprandial to a test meal high in saturated fat. Endothelial VCAM-1 surface expression stimulated by TNFα provided a readout for atherogenic inflammation. Concentrations of esterified and non-esterified fatty acids and oxylipins in TGRL were quantified by mass spectrometry. Dyslipidemic subjects produced TGRL that increased endothelial VCAM-1 expression by ≥35%, and exhibited impaired fasting lipogenesis activity and a shift in soluble epoxide hydrolase and lipoxygenase activity. Pro-atherogenic TGRL were enriched in eicosapentaenoic acid metabolites and depleted in esterified C18-PUFA-derived diols. Abundance of these metabolites was strongly predictive of VCAM-1 expression. We conclude the altered metabolism in dyslipidemic subjects produces TGRL with a unique oxylipin signature that promotes a pro-atherogenic endothelial phenotype.
Highlights
Disorders of metabolism are accompanied by an elevated systemic inflammatory state that accelerates the progression of atherosclerotic cardiovascular disease (CVD), the leading cause of death and disability in our society[1,2]
To evaluate the capacity of triglyceride-rich lipoproteins (TGRL) to mediate an inflammatory response in arterial endothelium, we examined a cohort of 39 subjects, characterizing each individual by their anthropometric, lipid, and metabolic characteristics, fasting and 3.5 hrs after the high fat test meal (Supplementary Table S1)
cytochrome P450s (CYP) activity (EPA) Overall COX activity soluble epoxide hydrolase (sEH)-derived diols and LOX-derived alcohols in response to the meal compared to normolipidemic subjects. We investigated whether these subjects exhibited differences in the activity of enzymes including LOX, COX, CYP, and sEH that could account for the observed range in ex vivo VCAM-1 response
Summary
Disorders of metabolism are accompanied by an elevated systemic inflammatory state that accelerates the progression of atherosclerotic cardiovascular disease (CVD), the leading cause of death and disability in our society[1,2]. We showed that TGRL isolated from subjects after a standardized fast food breakfast meal high in saturated fat, can prime either a pro- or anti-atherogenic state, defined as a net up- or down-regulation of VCAM-1 expression in TNFα-stimulated human aortic endothelial cells (HAEC)[15,16,17,18]. In these studies, the level of VCAM-1 expression was strongly associated with the relative capacity to induce recruitment of monocytes from healthy subjects assessed in TNFα-inflamed HAEC16. Fatty acids and oxylipins are found in both esterified (bound) and non-esterified (free) pools in TGRL, and can be released by the action of lipases or upon receptor-mediated uptake by endothelial cells (EC)[21]
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