The 18-carbon fatty acids linoleic acid (LA, omega-6) and linolenic acid (ALA, omega-3) present in intravenous lipid emulsions prevent the development of essential fatty acid deficiency. However, a high ratio of omega-6 to omega-3 fatty acids positively correlates with elevated serum inflammatory markers [
21]. The underlying reason for this observation has been ascribed to the relative pro-inflammatory effects of omega-6 fatty acids and the anti-inflammatory effects of omega-3 fatty acids (citations). LA and ALA undergo chain elongation to the omega-6 fatty acid, arachidonic acid (ARA) and omega-3 fatty acids, EPA and DHA, respectively. These fatty acids are important substrates for the production of bioactive molecules including prostaglandins and leukotrienes for ARA and EPA and the resolvins and protectins, for EPA and DHA.
ARA, EPA, and DHA are incorporated into phospholipids. In response to an environmental stimuli, they are released from the membrane via phospholipases and are substrates for the enzymes cyclooxygenases (prostaglandin synthesis) or lipoxygenases (leukotriene synthesis). ARA is converted to several different prostaglandins, but one of the more predominant variants is PGE
2. PGE
2 can stimulate inflammation though activating signaling cascades in immune cells. In mast cells, PGE
2 activates the release of histamines and interleukin-6 [
107,
108]. In helper T cells, PGE
2 facilitates differentiation into proinflammatory Th1 cells [
109] and expansion of Th17 cells [
109,
110]. Another prostaglandin metabolite of ARA is thromboxane A2 (TXA
2). In the liver, TXA
2 regulated release of tumor necrosis factor alpha (TNF-α) from resident macrophages (Kupffer cells) leads to microcirculatory dysfunction [
111]. The lipoxygenase synthesized leukotriene B4 (LTB
4) is also derived from AA. LTB
4 is a leukocyte modulator of inflammatory response. In neutrophils, LTB
4 activates chemotaxis and proinflammatory chemokine and cytokine production [
112]. Omega-3 fatty acid EPA forms similar prostaglandin and leukotriene molecules, such as PGE
3 and TXA
3 and LTB
5. EPA and ARA compete for access to the same enzymes in prostaglandin and leukotriene biosynthesis. A greater incorporation of EPA, will reduce the formation of ARA-derived prostaglandins and leukotrienes [
113,
114,
115]. Also, PGE
3 has much lower affinity for some surface receptors leading to a weaker cellular response when there is a greater concentration of EPA-derived prostaglandins [
116]. Unique to omega-3 fatty acids is the formation of resolvins and protectins. DHA forms d-series resolvins and EPA forms e-series resolvins. Resolvins have multiple anti-inflammatory properties. EPA derived resolvins downregulate leukocyte adhesion, ADP-dependent platelet activation [
117], and stimulates IL-10 production [
118]. DHA derived resolvins enhance bacterial scavenging and clearance [
119], protect against proinflammatory glutathione conjugates during oxidative stress [
120], and protect from polymorphonuclear leukocyte-mediated organ injury [
121]. Protectins can promote T cell apoptosis and resolution [
122]. Independent of the bioactive metabolites they form fatty acids may also directly initiate inflammatory processes. Palmitate, a saturated fatty acid, can bind to toll like receptor 4 (TLR4). DHA can inhibit palmitate TLR4 binding and suppress the inflammatory response [
89].
In addition to an anti-inflammatory effect, EPA and DHA have a positive effect on lipid utilization and glucose metabolism. Dietary supplementation of EPA and DHA can activate the transcription factor peroxisome proliferator activated receptor alpha (PPARα) [
123]. PPARα upregulates carnitine palmitoyltransferase 1A, which facilitates mitochondrial transport of fatty acids and pyruvate hydrogenase kinase 4, which facilitates glucose oxidation [
124]. PPARα can also decrease hepatic fibrosis caused by hepatic steatosis [
125]. In Kupffer cells, omega-3 fatty acids can increase the action of G-protein coupled receptor 120 (GPR120). GPR120 suppresses the lipogenic nuclear hormone receptor PPARγ [
71].