Consumption of the Fish Oil High-Fat Diet Uncouples Obesity and Mammary Tumor Growth through Induction of Reactive Oxygen Species in Protumor Macrophages

Abstract

Obesity is associated with increased risk of many types of cancer and can be induced by various high-fat diets (HFD) from different fat sources. It remains unknown whether fatty acid composition in different HFD influences obesity-associated tumor development. Here we report that consumption of either a cocoa butter or fish oil HFD induced similar obesity in mouse models. While obesity induced by the cocoa butter HFD was associated with accelerated mammary tumor growth, consumption of the fish oil HFD uncoupled obesity from increased mammary tumor growth and exhibited a decrease in pro-tumor macrophages. Compared to FA components in both HFD, n-3 FA rich in the fish oil HFD induced significant production of reactive oxygen species (ROS) and macrophage death. Moreover, A-FABP expression in the pro-tumor macrophages facilitated intracellular transportation of n-3 FA and oxidation of mitochondrial FA. A-FABP deficiency diminished n-3 FA-mediated ROS production and macrophage death in vitro and in vivo. Together, our results demonstrate a novel mechanism by which n-3 FA induce ROS-mediated pro-tumor macrophage death in an A-FABP dependent manner.

Contradictory roles of lipid metabolism in immune response within the tumor microenvironment

“…However, this phenomenon is non-universal and is largely related to the FA subtype. For example, fish oil-fed mice possess a lower percentage of pro-tumor macrophages and interleukin (IL-10) expression and higher infiltrations of B cells and CD + 8 T cells than coco butter-fed mice [ 67 ]. In addition, the enrichment of polyunsaturated fatty acids (PUSFAs), not saturated fatty acids (SFAs), exerts higher cytotoxicity on macrophages against tumor cells [ 68 ].…”

Fish oil Nano-emulsion Kills Macrophage: Ferroptosis and Autophagy Triggered by Catalase-catalysed Superoxide Eruption

“…In another in vitro study using a different murine macrophage cell line, J774, a large increase in the intracellular ROS was observed by incubation with DHA, EPA, oleic acid, linoleic acid and arachidonic acid at 100 μM for 1 h 59 , while no cytotoxicity was recorded. Furthermore, the fish oil-derived polyunsaturated n-3 fatty acids (e.g., EPA, DPA) were found to induce the death of mice bone marrow-derived macrophages at 200 μM through promoting intracellular ROS products as early as 30 mins after treatment 60 Another important conclusion we are proposing here is that CAT-triggered superoxide eruption in FONE can cause macrophage cell death through ferroptosis and autophagy, but not apoptosis. The cell death was effectively prohibited by using the ferroptosis inhibitor liproxstatin-1, which acts as a potent radical-trapping antioxidant 33 to scavenge the superoxide anions.…”

“…In another in vitro study using a different murine macrophage cell line, J774, a large increase in the intracellular ROS was observed by incubation with DHA, EPA, oleic acid, linoleic acid and arachidonic acid at 100 μM for 1 h 59 , while no cytotoxicity was recorded. Furthermore, the fish oil-derived polyunsaturated n -3 fatty acids (e.g., EPA, DPA) were found to induce the death of mice bone marrow-derived macrophages at 200 μM through promoting intracellular ROS products as early as 30 mins after treatment 60 . In general, EPA boosts cellular ROS, despite the different origin of the macrophage cells or different treatment times.…”

Effects of Dietary n–3 and n–6 Polyunsaturated Fatty Acids in Inflammation and Cancerogenesis

“…E-FABP (FABP5) has a stronger affinity for n-3 PUFAs than the others [113]. Moreover, adipose/macrophage FABP (A-FABP, FABP4) mediates ROS-mediated pro-tumor macrophage death induced by n-3 PUFAs [114].…”

“…However, it has decreased the number of pro-tumorigenic macrophages. This phenomenon was an effect of the significant ROS generation and subsequent TAM's apoptosis in the mechanism derived by adipose/macrophage-fatty acid-binding protein [114]. In the study of Liang et al, it was shown that in the case of the mice allografted with cancer androgen-sensitive prostate cancer cells fed with a high-fat diet (HFD) rich in n-3 FA TAMs proinflammatory cytokines (IL-6, TNF alpha and IL-10) and the chemoattractant protein (CCL-2) were lower expressed when compared to the animals fed an HFD based on n-6 FA [143].…”