The role docosapentaenoic acid omega-3 plays in controlling lipid metabolism and inflammation associated with obesity, atherosclerosis, and neurodegenerative disease
Pepper-Yowell, Amanda Rae
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Macrophages play a key role in inflammation associated with obesity and atherosclerosis. Additionally, obesity, cardiovascular disease, and chronic inflammation associated with both diseases are risk factors for neural degenerative diseases. Omega-3 (n-3) fatty acids are known to down-regulate inflammation. Much of the research conducted on n-3 fatty acids and inflammation have focused on eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) due to their high availability and easy extraction from fish oil. Research on docosapentaenoic acid n-3 (DPAn3), the intermediate of EPA and DHA is newly emerging and still very limited in scope due to the high cost of DPAn3 and thus, low availability. The low-density lipoprotein receptor knock-out (LDLr-/-) mouse is a great model for researching atherosclerosis, and diseases for which hyperlipidemia is a risk factor due to the inability of this mouse to clear low-density lipoprotein from circulation. Feeding a high fat, high cholesterol diet to this mouse model exacerbates hyperlipidemia and increases deposition of cholesterol in peripheral tissues, namely the aorta. These mice were fed an atherogenic diet consisting of 20% fat, and 0.15% cholesterol, with 3.5% of the fatty acids replaced with 1) milk fat from the base diet, or omega-3 fatty acids as follows: 2) DHA, 3) DPAn3, 4) EPA, 5) Lovaza®, and 6) OmegaActiv®. Mice were fed their respective diets for 20 weeks then blood lipid profiles, aortic cholesterol, adipocyte inflammation, brain lipid profiles, and neural inflammation were measured. Supplementing an atherogenic diet with n-3 fatty acids decreased total serum cholesterol (~200 mg/dL), cholesterol deposition in the aorta (~100 μg/mg protein), and circulating triglyceride (~100 mg/dL), but had no effect on low density lipoprotein cholesterol or serum glucose. Inflammation in visceral adipose tissue was reduced by n-3 fatty acid supplementation, as evident by reduced mRNA concentrations of interleukin-6 (60-98% decrease) and protein concentrations of tumor necrosis factor-α (33% decrease). In addition, all omega-3 fatty acid treatments equally ameliorated inflammation in the hippocampus and microvessel of the brain. Macrophages play a key role in moderating inflammation in all of the aforementioned diseases. Monocytes from the THP-1 cell line were differentiated into macrophages and used to determine the effects of various saturated, monounsaturated and polyunsaturated fatty acids alone or in combination on lipopolysaccharide-stimulated eicosanoid and cytokine release. The cells supplemented with EPA had the greatest effect on ameliorating cytokine release, but supplementing cells with DPAn3 and DHA were more potent than EPA at decreasing prostaglandin E2 release (90% decrease). Supplementing macrophages with arachidonic acid increased prostaglandin release exponentially (18 to 67 times control) which likely negatively fed back and inhibited pro-inflammatory cytokine release by these cells. Co-incubation of THP-1 cells with arachidonic acid and EPA at varying ratios for 3 concentrations of arachidonic acid revealed an interaction between the ratio of arachidonic acid to EPA and the concentration of arachidonic acid for stimulated PGE2 and IL6 release. Overall, n-3 fatty acid supplementation alone or in combination decreased inflammation associated with chronic inflammatory diseases. Supplementation with DPAn3 could decrease inflammation better than DHA, acting similarly to EPA, or could increase incorporation of DHA into tissues better than EPA, acting similarly to DHA. This data suggests that the total amount of very long chain omega-3 fatty acids in the diet is equally important as the ratio of n-6 to n-3 fatty acids in the diet, namely the ratio of arachidonic acid to EPA due to the ability of these fatty acids to increase or decrease inflammation, respectively.