Highly Purified Eicosapentaenoic Acid Increases Interleukin-10 Levels of Peripheral Blood Monocytes in Obese Patients With Dyslipidemia

Abstract

OBJECTIVEIt has recently been highlighted that proinflammatory (M1) macrophages predominate over anti-inflammatory (M2) macrophages in obesity, thereby contributing to obesity-induced adipose inflammation and insulin resistance. A recent clinical trial revealed that highly purified eicosapentaenoic acid (EPA) reduces the incidence of major coronary events. In this study, we examined the effect of EPA on M1/M2-like phenotypes of peripheral blood monocytes in obese dyslipidemic patients.RESEARCH DESIGN AND METHODSPeripheral blood monocytes were prepared from 26 obese patients without and 90 obese patients with dyslipidemia. Of the latter 90 obese patients with dyslipidemia, 82 patients were treated with or without EPA treatment (1.8 g daily) for 3 months.RESULTSMonocytes in obese patients with dyslipidemia showed a significantly lower expression of interleukin-10 (IL-10), an M2 marker, than those without dyslipidemia. EPA significantly increased serum IL-10 and EPA levels, the EPA/arachidonic acid (AA) ratio, and monocyte IL-10 expression and decreased the pulse wave velocity (PWV), an index of arterial stiffness, compared with the control group. After EPA treatment, the serum EPA/AA ratio was significantly correlated with monocyte IL-10 expression. Only increases in monocyte IL-10 expression and serum adiponectin were independent determinants of a decreased PWV by EPA. Furthermore, EPA significantly increased the expression and secretion of IL-10 in human monocytic THP-1 cells through a peroxisome proliferator–activated receptor (PPAR)γ-dependent pathway.CONCLUSIONSThis study is the first to show that EPA increases the monocyte IL-10 expression in parallel with decrease of arterial stiffness, which may contribute to the antiatherogenic effect of EPA in obese dyslipidemic patients.

An Increase in the EPA/AA Ratio is Associated with Improved Arterial Stiffness in Obese Patients with Dyslipidemia

“…In addition, a sub-analysis of the JELIS and other studies suggested that a high serum EPA/AA ratio is significantly associated with a low incidence of cardiac death or myocardial infarction, and a low coronary plaque score 14,15) . We also showed that the serum EPA/AA ratio in obese patients is associated with monocyte expression of IL-10, an antiinflammatory M2 marker 16) . DHA and EPA are n-3 PUFAs, and may contribute to the prevention of atherosclerosis and inflammatory diseases 11,17) .…”

“…terol Education Program-Adult Treatment Panel Ⅲ (NCEP-ATP Ⅲ) 29) , as described previously 16) . Of the 94 obese patients with dyslipidemia, six patients were excluded for the following reasons: five patients stopped consulting our clinic and one patient withdrew consent for their participation in the study.…”

Effects of Eicosapentaenoic Acid Treatment on Epicardial and Abdominal Visceral Adipose Tissue Volumes in Patients with Coronary Artery Disease

“…However, diet-induced obesity decreased the expression of these genes in adipose tissue macrophages but increased the expression of genes encoding TNF-α and inducible nitric oxide synthase (iNOS) that are characteristic of M1 or "classically activated" macrophages 33) . In obese, dyslipidemic patients, n-3 PUFAs administration increased IL-10 expression in peripheral blood monocytes through a peroxisome proliferator-activated receptor (PPAR)-γ-dependent pathway, which indicates a shift from the M1 pro-inflammatory state to the M2-polarized state 32) . Furthermore, n-3-PUFAs inhibit Toll-like receptor 4 signaling on macrophages, which eventually suppresses adipose tissue inflammation and levels of inflammatory cytokines, including TNF-α, as well as the production of antiatherosclerotic hormones, especially adiponectin 7,34) .…”

“…Moreover, n-3 PUFAs induce a shift from the M1 pro-inflammatory macrophage state to the M2-polarized macrophage state 32) . Adipose tissue macrophages of lean mice were found to express many genes that are characteristic of M2 or "alternatively activated" macrophages, such as arginase 1 and IL-10.…”

“…Therefore, the anti-inflammatory effect of EPA might influence AVAT and EAT more strongly than SAT. cause a decrease in TNF-α production, and stimulate PPAR-γ by EPA 43,32) . Although a high n-3 PUFA intake might have moderate unfavorable effects on glucose levels and insulin sensitivity, the daily intake of approximately one gram of purified EPA appears to have negligible unfavorable effects on metabolic control in patients with type two diabetes who are at risk of developing cardiovascular diseases 53) .…”