IRF-1 and miRNA126 Modulate VCAM-1 Expression in Response to a High-Fat Meal

Abstract

Rationale A high-fat diet accompanied by hypertriglyceridemia increases an individual’s risk for developing atherosclerosis. An early event in this process is monocyte recruitment through binding to VCAM-1 upregulated on inflamed arterial endothelium. Diets high in polyunsaturated fatty acids (PUFAs) may provide athero-protection by ameliorating this effect. Objective We investigated the acute regulation of VCAM-1 expression in human aortic endothelial cells (HAEC) in response to triglyceride-rich lipoproteins (TGRL) isolated from subjects following consumption of a high-fat meal. Methods and Results Postprandial TGRL isolated from 38 subjects were categorized as pro- or anti-atherogenic according to their capacity to alter the inflammatory response of HAEC. Pro-atherogenic TGRL increased expression of VCAM-1, ICAM-1, and E-selectin by ~20% compared to stimulation with TNFα alone, while anti-atherogenic TGRL decreased VCAM-1 expression by ~20% while still upregulating ICAM-1. The relative atherogenicity of TGRL positively correlated with particle density of TG, ApoCIII, ApoE, and cholesterol. Ω3-PUFA mimicked the effect of anti-atherogenic TGRL by down-regulating VCAM-1 expression. TGRL exerted this differential regulation of VCAM-1 by reciprocally modulating expression and activity of the transcription factor IRF-1 and expression of microRNA 126 (miR-126). Overexpression or silencing of IRF-1 or miR-126 expression recapitulated the pro- or anti-atherogenic regulation of VCAM-1. Conclusions In response to a high-fat meal, TGRL bias the inflammatory response of endothelium via transcriptional and post-transcriptional editing of VCAM-1. Subjects with an anti-inflammatory response to a high-fat meal produced TGRL that was enriched in non-esterified fatty acids, decreased IRF-1 expression, increased miR-126 activity, and diminished monocyte arrest.

Shear stress modulates VCAM-1 expression in response to TNF-α and dietary lipids via interferon regulatory factor-1 in cultured endothelium

“…Moreover, key questions remain as to how shear stress converges with diet-related factors to regulate EC function and inflammation. Motivating the present study is the finding that postprandial TGRL modulates VCAM-1 expression in an IRF-1-dependent manner (36), highlighting a potential role for IRF-1 in diet-induced inflammation and the susceptibility to atherosclerosis. We hypothesized that fluid shear stress and TGRL can each exert a distinct influence on cytokine-induced inflammation in the endothelium by directly modulating IRF-1 expression.…”

“…Human subjects were recruited according to Institutional Review Board-approved protocols at the University of California-Davis. TGRL were collected and characterized as previously described (36,44). Briefly, venous blood was collected after a 12-h overnight fast and again 3.5 h after a standardized moderately high-fat meal (1,230 calories, 42% from fat and 32% from saturated fat).…”

“…TGRL were categorized as proatherogenic (pro-TGRL) or antiatherogenic (anti-TGRL) defined by their capacity to up-or downregulate VCAM-1 surface expression, respectively, relative to TNF-␣ stimulation under static culture (36). We (36,44) have previously documented that TGRL did not elicit an increase in VCAM-1 from HAECs in the absence of TNF-␣ stimulation regardless of its atherogenic activity in its presence. Similarly, we found that TGRL alone did not mediate activation with shear alone, motivating our focus on the superposition of TGRL and cytokine.…”

“…We (36,44) have recently reported that triglyceride-rich lipoproteins (TGRL) isolated from obese and hypertriglyceridemic subjects after a high-fat meal were proatherogenic to human aortic endothelial cells (HAECs) in that they increased VCAM-1-dependent monocyte adhesion relative to TNF-␣ stimulation (36,44). In contrast, TGRL from subjects with normal serum triglycerides did not upregulate inflammation.…”

MicroRNA associated with dyslipidemia and coronary disease in humans

“…Another example of how miR may function to allow an organism to adapt to environmental changes is through diet-induced miR activity. We were unable to find any published studies describing the effect of dietary factors on miR activity and dyslipidemia performed in humans, but several in vitro and animal model studies of other conditions indicate that this relationship is plausible (23,25,29,31,47,48,53,60). Increasing interest in the implications of miRs in the area of gene-environment interactions is evidenced by the recent creation of the miREnvironment Database, which cross-references miR species with environmental risk factors and phenotypes (59).…”