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Calvo et al. Omega-3 fatty acids in cardiovascular health

cholesterol to be incompatible with environments MOLECULAR MECHANISMS OF PUFAS IN
rich in highly unsaturated lipids, as observed in CARDIOVASCULAR HEALTH
phospholipid bilayers containing DHA. [33]
Chronic pro-inflammatory states
Most of the research on n-3 PUFAs in membrane The anti-inflammatory effects of n-3 PUFAs have been
models has centered around DHA. [34] This molecule widely reported. [37-40] One of the central mechanisms
is deemed unique because it contains six double is the down-regulation of the synthesis of pro-
bonds and is very flexible, with quick rearrangements inflammatory cytokines such as tumor necrosis factor
amidst multiple conformational states. [29] alpha, interleukin 6 and monocyte chemoattractant
Spectrometry studies have revealed DHA-containing protein-1 (MCP-1) [41-44] in adipose tissue. This occurs
phospholipids to form their own domains with a when EPA and DHA bind to the G-protein coupled
different arrangement in presence of sphingolipids receptor (GPR120) in macrophages and adipocytes,
and cholesterol, excluding saturated acyl chains causing its activation and internalization with
from their structure. [35] In addition, because n-3 β-arrestin-2, and forming the GPR120/β-arrestine-2
PUFAs tend to reject cholesterol, DHA-containing complex. [45] This complex is then dissociated into the
phospholipids tend to create non-raft domains which transforming growth factor beta (TGF-β) activated
may be physically separated on cell membranes. kinase 1 binding protein 1 (TAB1) that results in the
This allows proteins to more readily occupy a space inhibition of TGF-β activated kinase 1 (TAK1), and
according to its requirements in a specific domain or thus the down-regulation of the nuclear factor kappa
in amplified rafts. [36] An alternative model points out B (NF-ĸB) and the inhibition of its function. [44] Besides,
that n-3 PUFAs are probably incorporated in the rafts the incorporation of DHA to the lipid membrane
as nanodomains, forcing cholesterol out of rafts. [26] disrupts the signaling of toll-like receptor 4 (TLR-4) by
This model is also applicable to proteins within lipid impeding its translocation to the lipid raft, and inhibiting
rafts, where incorporation of n-3 PUFAs into lipid rafts the signaling pathway of MD2/TRIAP-MyD88/IRAK-
forces proteins to relocate to non-raft domains. [26] TRAF6/IKKβ [41,46,47] [Figure 2]. Also, EPA and DHA
Further research is required to fully understand the cause the down-regulation of nicotinamide adenine
biologic importance and mechanisms underlying dinucleotide phosphateoxidase, which induces the
the lateral organization of lipid microdomains in cell production of reactive oxygen species, a requirement
membranes, as well as the modulatory effects of n-3 for TLR-4 signaling. [41,42] These pathways converge in
PUFAs in this context. [32] the inhibition of NF-ĸB, diminishing the inflammatory

PGE 2 ,

Figure 1: Metabolism of n-6 and n-3 polyunsaturated fatty acids. n-3 and n-6 polyunsaturated fatty acids are derived from linoleic acid
(LA) and a-linoleic acid (ALA). Through various enzymatic reactions, LA is converted into arachidonic acid, responsible of the formation of
mainly proinflammatory PG and TX. On the other hand, ALA is converted into EPA and DHA, which derive into mostly antiinflammatory PG
and TX. PGE2: prostaglandin E2; PGD2: prostaglandin D2; PGF2a: prostaglandin F2a; PGI2: prostacyclin I2; PGE3: prostaglandin E3;
PGI3: prostacyclin I3; TX: thromboxanes; LT: leukotrienes
118 Vessel Plus ¦ Volume 1 ¦ September 26, 2017