EPA’s pleiotropic mechanisms of action: a narrative review

Figures & data

Figure 1. Cellular and Molecular Mechanisms of Atherosclerosis and the Role of EPA

Adapted with permission from Atherosclerosis, 242(1), Borow KM, Nelson JR, Mason RP. Biologic plausibility, cellular effects, and molecular mechanisms of eicosapentaenoic acid (EPA) in atherosclerosis, 357–366, copyright 2015, with permission from Elsevier [37]. ACAT = acyl CoA:cholesterol acyltransferase; Apo E = apolipoprotein E; CCR = C-C chemokine receptor; CD = clusters of differentiation; CS = connecting segment; EPA = eicosapentaenoic acid; EPA/AA = eicosapentaenoic acid/arachidonic acid ratio; HDL = high-density lipoprotein; hsCRP = high-sensitivity C-reactive protein; ICAM = intercellular adhesion molecule; IFN = interferon; IL = interleukin; iNOS = inducible nitric oxide synthase; LDL = low-density lipoprotein; LO = lipoxygenase; Lp-PLA2 = lipoprotein-associated phospholipase A2; MCP = monocyte chemotactic protein; mm-LDL = minimally modified LDL; MMP = matrix metalloproteinase; ox-LDL = oxidized LDL; RLP-C = remnant-like lipoparticle cholesterol; SMC = smooth muscle cell; Th = T helper; VCAM = vascular cell adhesion molecule.

Table 1. Effect of EPA on Lipid Markers, Inflammatory Markers, and Atherosclerotic Plaque

Parameter	Percent Change With EPA vs Placebo
TG	↓14.1–33.1
Total cholesterol	↓12.0–16.3
LDL-C	↓2.3–6.6
Non-HDL-C	↓8.6–17.7
VLDL-C	↓24.4–28.6
HDL-C	↓3.0–4.5
VLDL-TG	↓25.8–26.5
RLP-C	↓25.8–29.8
Oxidized LDL	↓6.6–13.3
Lp-PLA2	↓13.6–19.0
Apo B	↓6.7–9.3
hsCRP	↓22.0–37.6
IL-6	↓1.0–↑11.0
Total plaque	↓20
Low-attenuation plaque	↓1.2
Calcified plaque	↓16
Non-calcified plaque	↓28

Apo B = apolipoprotein B; EPA = eicosapentaenoic acid; HDL-C = high-density lipoprotein cholesterol; hsCRP = high-sensitivity C-reactive protein; IL-6 = interleukin-6; LDL-C = low-density lipoprotein cholesterol; Lp-PLA₂ = lipoprotein-associated phospholipase A₂; RLP-C = remnant-lipoprotein cholesterol; TG = triglycerides; VLDL-C = very-low-density lipoprotein cholesterol; VLDL-TG = very-low-density lipoprotein triglycerides.

Figure 2. Bioactive Metabolites of EPA

EPA is metabolized by COX and LOX enzymes to form anti-inflammatory mediators (resolvins) as well as an anti-aggregatory and vasodilatory mediator (PGI₃). Pro-aggregatory (TXA₃) and pro-inflammatory mediators (PGE₃ and LTB₅) derived from EPA are weak. COX = cyclooxygenase; EPA = eicosapentaenoic acid; HEPE = hydroxyeicosapentaenoic acid; HPEPE = hydroperoxyeicosapentaenoic acid; LOX = lipoxygenase; LT = leukotriene; PG = prostaglandin; Rv = resolvin; TX = thromboxane.

Table 2. EPA-Derived Bioactive Metabolites That Control Inflammation and Tissue Homeostasis

Name	Function
RvE1	• Inhibits neutrophil infiltration • Augments neutrophil apoptosis through phagocytosis • Enhances macrophage clearance • Downregulates inflammatory cytokines
RvE2	• Inhibits neutrophil infiltration • Enhances macrophage clearance
RvE3	• Inhibits neutrophil infiltration and migration
RvE4	• Increases macrophage efferocytosis • Inhibits neutrophil infiltration
18-HEPE	• Diminishes activation of fibroblasts • Reduces monocyte adhesion and cardiac remodeling • Improves mitochondrial function
17,18-EpETE	• Prevents mast cell degranulation • Limits adhesion of monocytes to endothelial cells • Inhibits neutrophil migration • Downregulates inflammatory cytokines
12-OH-17,18-EpETE	• Inhibits neutrophil infiltration • Diminishes neutrophil chemotaxis • Downregulates inflammatory cell accumulation

EPA = eicosapentaenoic acid; EpETE = epoxyeicosatetraenoic acid; HEPE = hydroxy-eicosapentaenoic acid; Rv = resolvin.

Figure 3. Proposed Molecular Mechanisms of Cardioprotection by Omega-3 Fatty Acids

Adapted with permission from J Cardiol, 67, Endo J, Arita M. Cardioprotective mechanism of omega-3 polyunsaturated fatty acids. J Cardiol, 22–27, copyright 2016, with permission from Elsevier [51]. Ca = calcium; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; FA = fatty acid; GPCR(GPR120) = G protein-coupled receptor 120; Na = sodium; NFκB = nuclear factor-κB; NLRP3 = NOD-like receptor family, pyrin domain containing 3; PLA2 = phospholipase A2; PPARs = peroxisome proliferator-activated receptors; TGF-β = transforming growth factor-β.

Figure 4. Lipid Interactions of EPA and Impact on Vascular Health

Schematic illustration of the proposed location of phospholipid-linked EPA in cellular membranes and lipoproteins. EPA is rapidly esterified and incorporated into lipoproteins and membrane phospholipids. Biophysical studies indicate EPA has an extended orientation that preserves membrane fluidity as well as inhibition of lipid oxidation and membrane cholesterol domain formation. Reproduced with permission from O’Connell et al. [112], Attribution-NonCommercial 4.0 International (CC BY-NC 4.0; https://creativecommons.org/licenses/by-nc/4.0/). ApoB = apolipoprotein B; EPA = eicosapentaenoic acid; IPE = icosapent ethyl; LDL = low-density lipoprotein cholesterol.

Figure 5. Icosapent Ethyl Effects on RLP-C From the MARINE and ANCHOR Studies

Reproduced with permission from Ballantyne et al. [40], Attribution-NonCommercial-NoDerivatives 4.0International (CC BY-NC-ND 4.0; https://creativecommons.org/licenses/by-nc-nd/4.0/). RLP-C = remnant-like particle cholesterol.

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Endo J, Arita M. Cardioprotective mechanism of omega-3 polyunsaturated fatty acids. J Cardiol. 2016;67(1):22–27.

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O’Connell TD, Mason RP, Budoff MJ, et al. Mechanistic insights into cardiovascular protection for omega-3 fatty acids and their bioactive lipid metabolites. Eur Heart J Suppl. 2020;22(suppl J):J3–J20.

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