12-Hydroxyeicosapentaenoic acid inhibits foam cell formation and ameliorates high-fat diet-induced pathology of atherosclerosis in mice

Abstract

Atherosclerosis is a chronic inflammatory disease associated with macrophage aggregate and transformation into foam cells. In this study, we sought to investigate the impact of dietary intake of ω3 fatty acid on the development of atherosclerosis, and demonstrate the mechanism of action by identifying anti-inflammatory lipid metabolite. Mice were exposed to a high-fat diet (HFD) supplemented with either conventional soybean oil or α-linolenic acid-rich linseed oil. We found that as mice became obese they also showed increased pulsatility and resistive indexes in the common carotid artery. In sharp contrast, the addition of linseed oil to the HFD improved pulsatility and resistive indexes without affecting weight gain. Histological analysis revealed that dietary linseed oil inhibited foam cell formation in the aortic valve. Lipidomic analysis demonstrated a particularly marked increase in the eicosapentaenoic acid-derived metabolite 12-hydroxyeicosapentaenoic acid (12-HEPE) in the serum from mice fed with linseed oil. When we gave 12-HEPE to mice with HFD, the pulsatility and resistive indexes was improved. Indeed, 12-HEPE inhibited the foamy transformation of macrophages in a peroxisome proliferator-activated receptor (PPAR)γ-dependent manner. These results demonstrate that the 12-HEPE-PPARγ axis ameliorates the pathogenesis of atherosclerosis by inhibiting foam cell formation.

Dietary Fish Oil Increases the Number of CD11b+CD27− NK Cells at the Inflammatory Site and Enhances Key Hallmarks of Resolution of Murine Antigen-Induced Peritonitis

“… 50 Higher concentrations of the EPA-derived HEPEs in mice fed the fish oil diet may well have contributed to the enhanced resolution response as HEPEs have been suggested to have anti-inflammatory and pro-resolving activities. 51 , 52 The lower concentrations of the AA-derived PGs, TBx 2 and HETEs could also contribute to a less pro-inflammatory environment in the fish oil fed mice to ensure proper resolution of the antigen-induced peritonitis. 53 NK cells have been shown to express high levels of 12/15-LOX in a murine model of type I diabetes 22 and could, therefore, be the source of the 12- and 15-HEPEs in the present study.…”

Intestinal microbe-dependent ω3 lipid metabolite αKetoA prevents inflammatory diseases in mice and cynomolgus macaques

“…For lipidomics, female C57BL/6J wild-type mice (6 weeks old) were purchased from Japan SLC (Hamamatsu, Japan), and were maintained for 2 months on chemically defined diets containing 4% (wt/wt) dietary oil (soybean oil or linseed oil, Oriental Yeast, Tokyo, Japan) 65 in the SPF animal facility at National Institutes of Biomedical Innovation, Health and Nutrition (NIBIOHN; Osaka, Japan). Male GF mice (ICR background), and their control ICR mice (age, 6 weeks) were purchased from Japan SLC (Hamamatsu, Japan); these mice were maintained for 2 months on chemically defined diets containing 4% (wt/wt) dietary oil (soybean oil or linseed oil) under GF or SPF conditions, respectively, at NIBIOHN and Oriental Bioservice, Inc. For contact hypersensitivity studies, female C57BL/6J wild-type mice (age, 7 weeks) were purchased from Japan SLC and maintained for 1 week before use in experiments in the SPF animal facility at NIBIOHN.…”

“…For diabetes experiments, male C57BL/6J wild-type mice (age, 8 weeks) were purchased from Japan SLC and CLEA Japan (Tokyo, Japan), and maintained in the SPF animal facility at NIBIOHN for 3–4 months on HFD composed of chemically defined materials. 65 Mice were maintained under conditions (16:8 h light/dark cycle, 22–24 °C, and 50–60% humidity), with ad libitum access to food and distilled water. Mice were euthanized by cervical dislocation under isoflurane (Forane, AbbVie, North Chicago, Illinois, USA) anesthesia.…”

Batokines: Mediators of Inter-Tissue Communication (a Mini-Review)

“…Finally, there are certain lipid-derived batokines such as 12-HEPE (12-hydroxyeicosapentaenoic acid) [21] and 12,13-diHOME [48,49] that have been described as mediators of immune cell function and/or inflammation in various other tissues [71][72][73]. For example, 12,13,-diHOME was previously described a pro-inflammatory agent with cytotoxic properties and has also been described as an inhibitor of neutrophil respiratory burst [74,75].…”

“…In a more recent study, Levan et al identified that 12,13-diHOME secreted from the gut microbiome has been reported to promote allergic inflammation in neonates and alter lipid uptake in human dendritic cells [72]. Similarly, administration of 12-HEPE resulted in inhibiting the transformation of macrophages to an inflammatory foam cell phenotype [71]. This line of evidence suggests that there might be a physiological role for BAT-derived signaling lipids to modulate circulating immune cell or tissue-specific immune cell function.…”