Critical Reviews in Food Science and Nutrition

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Omega-3 pleiad: The multipoint anti-inflammatory

strategy

Ellencristina da Silva Batista, Susana Castelo Branco Ramos Nakandakari,

Adelino Sanchez Ramos da Silva, José Rodrigo Pauli, Leandro Pereira de
Moura, Eduardo Rochete Ropelle, Enilton A. Camargo & Dennys Esper Cintra

To cite this article: Ellencristina da Silva Batista, Susana Castelo Branco Ramos Nakandakari,
Adelino Sanchez Ramos da Silva, José Rodrigo Pauli, Leandro Pereira de Moura, Eduardo
Rochete Ropelle, Enilton A. Camargo & Dennys Esper Cintra (2022): Omega-3 pleiad: The
multipoint anti-inflammatory strategy, Critical Reviews in Food Science and Nutrition, DOI:
10.1080/10408398.2022.2146044

To link to this article: https://doi.org/10.1080/10408398.2022.2146044

Published online: 16 Nov 2022.

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Critical Reviews in Food Science and Nutrition
https://doi.org/10.1080/10408398.2022.2146044

Review

Omega-3 pleiad: The multipoint anti-inflammatory strategy

Ellencristina da Silva Batistaa,b,c,d*, Susana Castelo Branco Ramos Nakandakarib,c*, Adelino Sanchez
Ramos da Silvae, José Rodrigo Paulic,f, Leandro Pereira de Mouraf, Eduardo Rochete Ropellec,f, Enilton A.
Camargoa,g and Dennys Esper Cintrab,c,h
a
Graduate Program of Health Sciences (PPGCS), Federal University of Sergipe, Aracaju, Sergipe, Brazil; bNutritional Genomics Laboratory,
LabGeN, School of Applied Sciences, UNICAMP, São Paulo, Brazil; cNutrigenomics and Lipids Research Center, CELN, School of Applied
Sciences, UNICAMP, São Paulo, Brazil; dNutrition Department, Federal University of Sergipe, Lagarto, Sergipe, Brazil; eSchool of Physical
Education and Sport, University of São Paulo – USP, Ribeirão Preto, São Paulo, Brazil; fLaboratory of Molecular Biology of Exercise, School of
Applied Sciences, UNICAMP, São Paulo, Brazil; gDepartment of Physiology, Federal University of Sergipe, São Cristóvão, Sergipe, Brazil; hOCRC
– Obesity and Comorbidities Research Center, UNICAMP, São Paulo, Brazil

ABSTRACT KEYWORDS
Omega 3 (ω3) fatty acids have been described since the 1980s as promising anti-inflammatory Omega 3; inflammation;
substances. Prostaglandin and leukotriene modulation were exhaustively explored as the main chronic diseases; GPR120;
reason for ω3 beneficial outcomes. However, during the early 2000s, after the human genome cellular signaling; nutrigenomics
decoding advent, the nutrigenomic approaches exhibited an impressive plethora of ω3 targets,
now under the molecular point of view. Different G protein-coupled receptors (GPCRs) recognizing
ω3 and its derivatives appear to be responsible for blocking inflammation and insulin-sensitizing
effects. A new class of ω3-derived substances, such as maresins, resolvins, and protectins, increases
ω3 actions. Inflammasome disruption, the presence of GPR120 on immune cell surfaces, and
intracellular crosstalk signaling mediated by PPARγ compose the last discoveries regarding the
multipoint anti-inflammatory targets for this nutrient. This review shows a detailed mechanistic
proposal to understand ω3 fatty acid action over the inflammatory environment in the background
of several chronic diseases.

Introduction receptor (Hirasawa et al. 2005) their homologs, together

During the 1970s, Dyerberg and Bang (1979) noticed the
existing paradox between Danish and Greenlandic popula-
tions related to cardiovascular disease incidence. Although
the total fat consumption was the same among these pop-
ulations, coronary disease was less significant among
Greenlandic Inuit Eskimos. For the first time, they showed
the influence of marine sources of omega-3 (ω3) fatty acids
on hemostatic function and platelets of Inuits and the par-
ticipation of thromboxane A3, derived from ω3 after cyclo-
oxygenase action, increasing the time of bleeding (Bang,
Dyerberg, and Hjøorne 1976; Dyerberg et al. 1978; Dyerberg
and Bang 1979).
Throughout the 1980s, the hypothesis for eicosanoid
modulation by ω3 was maintained and reinforced in vitro
(Croset et al. 1988) and in vivo, with animals (Adan et al.
1999; Tashijan et al. 1984) and humans (Payan et al. 1986;
Singer et al. 1990), until the 2000s. With the advent of
molecular approaches after human genome decoding, several
new signaling pathways were established for biological com-
pounds, natural substances, or xenobiotics. However, the
molecular mechanisms of action of ω3 stagnated for a long
time. Currently, science has deciphered the specific ω3
with nodal intracellular proteins, responsive structures,
nuclear receptors, genes, metabolites, particular conditions,
and other determinants involved in ω3 anti-inflammatory
abilities or even their side effects (Bagger et al. 2020; Downie
et al. 2019; Hirasawa et al. 2005; Ishitani et al. 2003; Oh
et al. 2010; Poreba et al. 2017; Yang, 2014).
Thus, this review focuses on the multitude of
anti-inflammatory molecular mechanisms targeted by ω3
fatty acids and their new potential for use in experimental
and clinical studies related to chronic diseases with the
low-grade proinflammatory state as background.
ω3 and prostaglandins: an old relationship
The ratio between ω3 and ω6 fatty acid intake needs to be
considered in the context of inflammation, as ω6 intake is
considered pro-inflammatory when it is ten times higher
than ω3 (10:1) due to the ability of ω6 (linoleic [C18:2] and
arachidonic [C20:4]) to be efficiently converted to prosta-
glandins from even series (i.e., PGE2, PGI2, and TXA2).
Interestingly, eicosapentaenoic acid (EPA – C20:5) competes
with arachidonic for cyclo-oxygenases reducing its action

CONTACT Dennys Esper Cintra dcintra@yahoo.com

*These authors work equally.
© 2022 Taylor & Francis Group, LLC
2 E. DA SILVA BATISTA ET AL.
on arachidonic (DiNicolantonio, Okeefe 2019). Despite it,
and considering the optimal ω6:ω3 ratio (5:1), Simopoulos
(2016) described a very discrepant ratio for western coun-
tries, approximately 20:1. Nonetheless, some societies far
exceed this value, reaching more than 50:1 (Udipi et al. 2006).
ω3 alters eicosanoid profile generation in a class of less
reactive prostaglandins and more effective leukotrienes.
Prostaglandins such as PGE2 (Prostaglandin E2) and PGI2
(Prostacyclin I2) as well as TXA2 (Thromboxane A2), are
the classical mediators of cardinal symptoms of inflamma-
tion, such as pain, heat, rubor, and tumescence, which
increase vasodilatation, bronchoconstriction, platelet aggre-
gation, polymorphonuclear cell recruitment, and other effects
(Esser-von Bieren 2019; Mastalerz et al. 2019). These medi-
ators are generated predominantly from arachidonic acid,
an ω6 fatty acid, after COX1 (Cyclooxygenase 1) action – a
constitutive enzyme – or mainly after COX2 (Cyclooxygenase
2) – an enzyme that rapidly emerges after tissue aggression
(Esser-von Bieren 2019; Kain wt al. 2018). However, from
ω3, a mild alteration in the structure of these eicosanoids
can enormously change their functions. PGE3 (Prostaglandin
E3) and PGI3 (Prostaglandin I3) diminish vasodilatation,
while TXA3 (Thromboxane A3) markedly increases platelet
antiaggregant effects, leading to an increased time of bleed-
ing (Dyerberg, Bang 1979). These effects, shown in several
studies, encouraged medical societies to prescribe ω3 fatty
acids mainly in poststroke and heart attacks (Bang, Dyerberg,
and Hjøorne 1976; Bhatt et al. 2019a; Bhatt et al. 2019b;
Croset et al. 1988; Dyerberg, Bang 1979; Dyerberg et al.
1978; Payan et al. 1986; Singer et al. 1990).
The neglected role of alpha-linolenic (C18:3) ω3
fatty acid
The most relevant ω3 members considered over the years
in the classical nutritional sciences literature were EPA and
docosahexaenoic acid (DHA – C22:6), while alpha-linolenic
acid (ALA – C18:3) was practically neglected (Arterburn,
Hall, and Oken 2006). This fact could be attributed to the
low grade of C18:3 bioconversion to longer fatty acids (C20:5
and C22:6) in mammals (Arterburn, Hall, and Oken 2006),
and it has few biological activities compared to EPA and
DHA. In baboon neonates receiving oral doses of 13 C-labeled
ALA or DHA for two weeks, the bioconversion from ALA
to DHA was different for each tissue tested. In the brain,
only 0.23% of DHA was preformed from ALA compared to
1.71% of those treated directly with DHA, while in tissues
such as the liver or erythrocytes, this ratio reached up to
60% (Su et al. 1999). Demar Jr et al. (2006) found a low
rate of DHA bioconversion in the brains of rats receiving
ALA. In contrast, Sinclair, Guo, and Abedin (2022) showed
DHA incorporation in the retina of guinea pigs proportion-
ally to the ALA content in the diet. The difference is that
retina cells are essentially composed of neuron cells (Dátilo
et al. 2018).
If the ALA bioconversion to elongated fatty acids is gov-
erned by delta-5/6 desaturases (Zhang, Kothapalli, and
Brenna 2016), it is plausible that the gene expression of
these enzymes works in a tissue-dependent manner (Figure
6B). As a confounding factor, delta-5 and delta-6 enzymes
also act in the linoleic fatty acid (C18:2 [ω6]) bioconversion
route, becoming a competitive process between these fatty
acids, which needs to be considered (Picklo, Murphy 2016).
Reductions in dietary ω3 result in an increased ability of
the liver to elongate and desaturate ω3 fatty acids, whereas
the brain is not responsive to dietary levels (Demar et al.
2005). This evidences that ω3 and ω6 fatty acid metabolism
regulation is more complex than a trivial competition by
the substrates, once this process is regulated by the genetic
background as well (Barceló-Coblijn, 2009; Demar et al.
2005; Zhang, Kothapalli, and Brenna 2016).
The metabolic effects of derived products from ALA or
other ω3 fatty acids are essential to be noticed. For example,
in a randomized double-blind crossover study, Gabbs et al.
(2021) treated twelve healthy volunteers with 4 g of ALA or
DHA capsules for 28 days to measure oxylipin production.
Oxylipins are biologically active lipids formed from PUFAs
released from membrane phospholipids by phospholipase
A2 and oxygenated by COX (Cycloxygenases), ALOX
(Lipoxygenases), and cytochrome P450 enzymes (An, Kim,
and Oh 2021). After 28 days, ALA supplementation doubled
ALA blood concentrations; however, without effects on ALA
oxylipins. Also, DHA supplementation tripled both DHA
and its oxylipins, showing a more active cytochrome metab-
olism associated with DHA (Gabbs et al. 2021). This data
demonstrates that each nutrient has a specific role.
Nutrigenomic approaches have been decisive enlarging the
understanding of each nutrient. EPA and DHA were always
referenced as the main ω3 species associated with increased
bleeding time.
Recently, the same role was shown for ALA; however,
using a different mechanism. While EPA and DHA influ-
ence the time of bleeding through TXA3 prostaglandin
modulation, ALA changes the gene expression of adhesion
molecules such as intercellular adhesion molecule-1 (ICAM),
vascular cell adhesion molecule-1 (VCAM), and von
Willebrand Factor (vWF) (Stivala et al. 2022). The gene
expression of ICAM and VCAM is coordinated by NFkB
(nuclear factor-kappa B), a transcription factor considered
a masterpiece of proinflammatory genes. Holy et al. (2011)
showed that dietary ALA could reduce endothelial cell
activation by downregulating MAPK (Mitogen-Activated
Protein Kinase) pathways and the nuclear translocation of
NFkB. A more detailed ALA role associated with inflam-
mation was understood after discovering the GPR120 and
GPR40 receptors, which recognize several unsaturated fatty
acids and ALA (Cintra et al. 2012; Oliveira et al. 2015).
Thus, the demonstration of ALA influencing health and
disease was only at the beginning; however, its potential
for use needs to be reconsidered, once its natural sources
are abundant. The oils from chia seed and flaxseed have
approximately 50–60% ALA in their composition, making
these oils or seeds a very attractive food due to the low
cost compared to EPA or DHA capsules (Cintra et al. 2006;
Knez et al. 2019). The molecular mechanism by which ALA
coordinates the inflammatory process will be shown ahead.

The interpretative transition from prostaglandins
to NFkB pathway as ω3-molecular targets
The lipid influence debates related to prostaglandins and
inflammation have crossed the decades. In 2003, some dif-
ferent hypotheses were proposed for the anti-inflammatory
effects of ω3 once COX2 gene expression was discovered to
be regulated by transcription factors such as NFkB, CREB
(Cyclic-AMP Response Element-Binding Protein), and C/EBP
(CCAAT Enhancer-Binding Protein) (Park et al. 2005).
Posttranscriptionally, the COX2 protein structure can be
directly affected by the iNOS (inducible Nitric Oxide
Synthase) protein, which nitrosylates and intensifies COX2
activation (Kim, Huri, and Snyder 2005). Each step of COX2
regulation can be used as a potential ω3-therapeutic target.
In 2003, Komatsu et al. (2003) showed a reduction in iNOS
expression and its main product, nitric oxide (NO), after
macrophage cell line (RAW264) DHA incubation. Then, ω3
fatty acids probably decrease prostaglandins due to iNOS
inactivation. However, if iNOS gene expression is partially
encoded by NFkB (Park et al. 2005), iNOS inhibition by ω3
may be an indirect activity.
Different studies have shown the disruption of NFkB
signaling after ω3 treatment in several conditions, such as
leukemia (Fahrmann et al. 2013), neuronal damage (Yang
et al. 2014), and sickle cell disease (Daak et al. 2015), among
others. Sinha et al. (2004) postulated preliminary evidence
that ω3 could induce Ikk (Inhibitor Kappa Kinase) inhibi-
tion, an upstream NFkB protein (Spenser et al. 2013).
Low-grade inflammation modulated by fats
The NFkB proinflammatory end-products are controlled by
both TLR2/4 (Toll-Like Receptors 2 and 4) and cytokine
receptors such as TNFα (Tumor Necrosis Factor-α), IL
(Interleukin) 1β, and IL6 pathways. In the context of car-
diometabolic risk, proinflammatory stimuli are triggered by
the connection between saturated fatty acids and TLRs,
mainly TLR4 (Huang et al. 2012). Despite the TLR-saturated
fat binding has become a classical system explaining inflam-
matory signaling beginning, it might be questionable.
Lancaster et al. (2018) showed that saturated fatty acids
could trigger inflammation, not precisely through TLR4, but
through its downstream pathway. Using bone marrow-derived
macrophages, they showed that saturated fatty acids inter-
nally “pre-prepare” the cell for inflammation using
TLR4-associated proteins (MyD88 and others). The inflam-
mation was induced by saturated fatty acid even in the
absence of TLR4 (Tlr4-KO-/- cells). On the opposite, Sutter
et al. (2016) showed the ablation of pro-inflammatory stimuli
induced by saturated fat in the liver of Tlr4 KO mice. Using
biophysical approaches, Kang and Lee (2011) demonstrated
the exact position of the structural binding site for saturated
lipids. For a while, all scientific evidence strongly suggests
the TLR4 or its surrounding proteins system is the primary
conductor of inflammation induced by saturated fats.
The pernicious amount of saturated fatty acids can be
provided from its excessive intake during de novo lipogenesis
converting the excess of carbohydrates and proteins or
Critical Reviews in Food Science and Nutrition 3
during the hypermetabolic context, followed by high amounts
of saturated free fatty acids released from adipose tissue
directly to the bloodstream. Although these mentioned con-
ditions are commonly associated with an “obesogenic sce-
nario,” different circumstances can interfere with the fatty
acids released from adipose or other tissues. For instance,
cold exposition (Chen et al. 2022), gender (Hames et al.
2015), exercise (de Melo et al. 2022). severe fasting (Marks
et al. 2015; Raclot 2003), parenteral nutrition (Guthrie 2022),
drugs (Yu et al. 2022), burning injury, lipodystrophy, and
cachexia (Vegiopoulos, Rohm, and Herzig 2017) are distinct
examples of fatty acids release.
Saturated fats bind and activate TLR4 (Huang et al. 2012),
a transmembrane innate immunity receptor that recruits
MyD88 (Myeloid Differentiation Primary Response 88 Protein)
in juxtaposition. These connected proteins attract IRAK4
(interleukin-1 receptor-associated kinase 4), which associates
with and phosphorylates a similar protein, IRAK1, inducing
TRAF6 (TNF Receptor-Associated Factor 6) recruitment and
activation. The activated IRAK1 and TRAF6 complex is dis-
sociated from this large protein conglomerate and migrates
until the inoperant TAK1 (Transforming Growth Factor-β-
Activated Kinase 1) activates it (Adhikari, Xu, and Chen 2007).
Juxtaposed to TAK1, IRAK1 and TRAF6 recruit the proteins
TAB1/2 (Transforming Growth Factor-Beta Activated Kinase
1 binding protein 1/2) to TAK1. TAB proteins induce TAK1
ubiquitination through the activation of UBC3 and UEV1A
(Ubiquitin Ligases), which allows TAK1 phosphorylation and
activation (Adhikari, Xu, and Chen 2007; Shi, Kehrl 2010;
Mihaly, Morioka 2014) (Figure 1A). As shown above, the
relative novelty in the ω3 anti-inflammatory mechanism is
related specifically to this molecular nodus. Once after TAK1
phosphorylation, it phosphorylates and activates IKK (Inhibitor
of Kappa Kinase), activating the canonical NFkB pathway (Oh
et al. 2010; Figure 1B and C).
Parallel to TLR signaling, signals from cytokine receptors
can enlarge the proinflammatory stimulus. When activated
by its ligands, at the base of cytokine receptors, TRAF2/6
(TNF Receptor-Associated Factor 2/6) is attached and acti-
vated, transducing the signaling to TAK1 (Ishitani et al.
2003; Figure 1B). Therefore, the signals from TLR or cyto-
kine receptors culminate at the same point. The most evi-
denced ω3 action is attributed to anti-inflammatory ability
more than antihypertensive, anti-thrombogenic, or hypoli-
pemiant actions. However, part of this ability is due to its
recently deorphanized receptor, GPR120.
G protein-coupled receptors recognize and
mediate anti-inflammatory ω3 actions
In 2005, the GPR120, a GPCR (G protein-coupled receptor),
was partially deorphanized as a long-chain fatty acid recep-
tor. However, there are many ligands as possibilities, with
an extensive range of fatty acids, among 16 to 24 carbons
(Hirasawa et al. 2005). In elegant work, despite the vast
range among GPR120 activators, Oh et al. (2010) established
a binding rank associated with GPR120 activation. DHA is
the most significant fatty acid bound, followed by palmitoleic
4 E. DA SILVA BATISTA ET AL.

Figure 1. Pro-inflammatory signaling transduction disrupted by GPR120 receptor. (A) High amounts of saturated fatty acids activate TLR4 which transduces its
signaling to the intracellular medium coupling the accessory protein MyD88, attracting IRAK1/4 and TRAF6 proteins to form a structural conglomerate. After,
IRAK1 and TRAF6 migrate to TAK1, recruiting Tab1/2 proteins, which phosphorylate TAK1 through ubiquitinases support. (B) Cytokines such as TNFα and IL1β
activate their receptors and intracellular TRAF2 protein conduct the receptor signals until to TAK1 protein, reinforcing the proinflammatory signaling. (C) The
confluence between TLR and cytokine receptors culminates in the canonical signaling mediated by Ikk until NFkB which induces the gene transcription of
several pro-inflammatory targets. (D) The GPR120 receptor recognizes all species of ω3 recruiting the βArr2. The βArr2 trajectory removes both Tab1/2 (dashed
red arrows) from TLR4 and cytokine cascades, disrupting the multiple proinflammatory signalings by blocking the TAK1 phosphorylation (continuous red line).
All 3D molecules are originals from Homo sapiens.

(C16:1 [ω7]), oleic (C18:1 [ω9]), and EPA fatty acids (Oh
et al. 2010). The demonstration of the inability of saturated
fatty acids and ω6 family members to activate GPR120 was
as important as the discovery itself. The significance of this
work goes further once they showed detailed downstream
anti-inflammatory mechanisms coordinated by ω3. In
HEK293 cells treated with DHA, the βarr2 (beta-Arrestin
2) protein was immediately attracted to GPR120. During
the βArr2 trajectory to GPR120, βArr2 “arrests” TAB1 and
TAB2 proteins from the TAK1 node, disrupting TLR, TNF,
and IL1 cascades (Oh et al. 2010; Figure 1D).
Interestingly, ω3 from vegetable oils (ALA [C18:3]) was
also able to activate the GPR120 receptor and its down-
stream signaling (Figure 1D). Cintra et al. (2012) treated
obese mice for two months with diets containing ALA from
flaxseed oil. Systemic low-grade inflammation was controlled
in the central nervous system. The ALA crossed the
blood-brain barrier and reached the hypothalamus. The
authors acutely infused purified ALA directly into the rodent
hypothalamus to guarantee that the observed phenomenon
was carried out by ALA, but not by some other diet com-
pound or metabolic interference. Using immunoprecipitation
approaches, the authors attributed the effects to the con-
nection between GPR120 and βarr2 followed by a relation-
ship between βarr2 and TAB1/2 proteins (Cintra et al. 2012).
The presence and functionality of GPR120 have already
been demonstrated in several tissues, such as the liver (Oh
et al. 2010; Oliveira et al. 2015), skeletal muscle (Oliveira
et al. 2015), adipose tissue (Oliveira et al. 2015), retina
(Dátilo et al. 2018), aorta (Moura-Assis et al. 2018), and
hypothalamus (Cintra et al. 2012). In the liver, muscle, and
adipose tissue of obese mice treated with a diet containing
ALA, the improvement in metaflammation status was
attributed to GPR120 action in all of these tissues (Oliveira
et al. 2015). Additionally, there was a significant amelioration
in global glucose homeostasis, followed by an improvement
in fasting serum glucose and insulin (Oliveira et al. 2015).
In practical terms, due to the similar ability to provide
GPR120 activation mediated by both ω3 members (ALA,
EPA, and DHA), interest in ALA fatty acid therapeutic use
has been growing (Stivala et al. 2022).
GPR40 was deorphanized by Itoh et al. (2003), showing
several fatty acids as possible ligands, including oleic fatty
acid. Oh et al. (2010) tested a synthetic and specific GPR120
agonist, GW9508, which also can activate GPR40 due to
the 10% shared homology between these receptors. Obese
mice treated with ω3 or ω9 diets showed a cross-activation
between GPR120 and GPR40, probably due to their homol-
ogy. The GPR40 downstream mechanism associated with
blocking inflammation is also partially mediated by βArr2
(Oliveira et al. 2015). Nevertheless, the action or potency
of these receptors appears to be tissue-specific. Oliveira
et al. (2015) showed a more pronounced activity of both
GPR120 and GPR40 receptors in skeletal muscle than in
liver or adipose tissue. It appears to be a relevant open
avenue for further explorations related to controlling
 Critical Reviews in Food Science and Nutrition 5

glucose metabolism and insulin resistance. These receptors
are also relevantly expressed in beta-pancreatic cells (Wu
et al. 2021), influencing insulin secretion. Synthetic GPR120
and GPR40 agonists are currently being tested in clinical
randomized controlled trials, together with the
anti-inflammatory exploration hypothesis (Marcinak et al.
2017; Mauricio et al. 2017).
Notably, the anti-inflammatory GPR120-dependent mech-
anism begins when ω3 is connected to GPR120, which is
still outside the cell (Oh et al. 2010). When βArr2 binds to
the C-terminal GPR120, the inflammatory cascade is dis-
rupted (Figure 1E). Then, βArr2 internalizes GPR120 and
its consecutive agonists (Figure 2A). From now on, ω3 fatty
acids can follow their classical attributed physiological
actions (Figure 2B), such as retina and myelin sheath coat-
ing, cell membrane constitution and fluidity, prostaglandin
formation, and many other essentialities (Miles et al. 2004).
Still using GPCR-βarr2 protein aggregation, ω3 fatty acids
can interfere with inflammatory signaling by disrupting a
system known as the inflammasome (Figure 3).

Figure 2. The ω3 internalization mediated by GPR120 receptor. (A) After binding to GPR120, the ω3 fatty acids are internalized together with their receptor.
This process is mediated by βArr2 which drags the receptor and its ligand into the cell. (B) Once inside the cell, ω3 can assume distinct routes, many of them
also involved in inflammation interruption. For example, the generation of odd series prostaglandins, which counteractive the proinflammatory ω6 prostaglandins
from even series. ω3 molecules could be bioconverted in SPMs mediators such as resolvins, protectins, and maresins that show a powerful action blocking
inflammation. (C) The last pathway shows the ω3 ability in to directly activate the PPARγ, which inactivates the NFkB protein, avoiding its migration to the
nucleus. All 3D molecules are originals from Homo sapiens.

Figure 3. Inflammasome activation. (A) NLRP3 molecules produced from TLR or cytokine cascades are connected to ASC and Casp1 proteins to form the first
part of the inflammasome. (B) These three proteins are oligomerized multiple times until to form a nodal structure. (C) The inflammasome. (D) Once structured,
the inflammasome cleavages the immature IL1 β and IL18 to mature proteins, increasing the inflammatory tonus. All 3D molecules are originals from Homo
sapiens.
6 E. DA SILVA BATISTA ET AL.
The inflammasome disruption mediated by ω3
Inflammasomes are cytoplasmic multiprotein complexes that
respond to PAMPs or DAMPs (pathogen-associated or
damage-associated molecular patterns). Inflammasome struc-
ture formation is essential to maintain or increase inflam-
mation and is responsible for making interleukins IL1β and
IL18 mature, which are pre-translated from NFkB signaling
(Figure 1C). Once mature, IL1β and IL18 are secreted out-
side the cell. Studies have offered a glimpse into the sophis-
ticated mechanisms by which inflammasomes respond to
danger and secretion of IL1β and IL18 and the therapeutic
ω3 capacity (Martínez-Micaelo et al. 2016; Mortimer et al.
2016; Shen et al. 2017; Williams-Bey et al. 2014; Yan et al.
2013). PAMPS, such as LPS (lipopolysaccharides), activates
TLR4 and NFkB canonical signaling, which transcribes sev-
eral proinflammatory-related genes, such as TNFα, IL1β,
IL6, IL18, iNOS, COX2, NLRP3 (NACHT, LRR, and PYD
Domains-Containing Protein 3), and the anti-inflammatory
IL10 (Liu et al. 2017; Figure 1C). When the inflammatory
tonus is increased, NLRP3 is recruited to bind to ASC
(apoptosis-associated speck-like CARD-domain containing
protein) and Casp1 (Caspase 1) proteins, assembling the
first inflammasome masterpiece (Agostini et al. 2004;
Compan et al. 2015; Figure 3A). The NLRP3-ASC-Casp1
aggregate undergoes subsequent oligomerization (Figure 3B)
to form the final inflammasome complex (Figure 3C), which
begins the IL1β and IL18 cleavages (Figure 3D). Both inter-
leukins can reach the bloodstream or through autocrine
signaling, contributing to redundant or perpetual inflamma-
tory signaling (Agostini et al. 2004; Compan et al. 2015).
The ω3 fatty acids partially inhibit inflammasome acti-
vation by disarming the original signaling from the saturated
fat/LPS-TLR4 cascade, which decreases NFkB and its prod-
uct, NLRP3 (Martínez-Micaelo et al. 2016; Figure 4).
Interestingly, ω3 could interfere differently with the inflam-
masome structure. Inhibition of NLRP3 and consequently
Casp1 activation was shown in different models through
GPR120/GPR40-βArr2 binding to NLRP3 (Mo et al. 2020;
Williams-Bey et al. 2014; Yan et al. 2013). βArr2 sequesters
NLRP3 from the inflammasome structure and disassembles
the entire structure (Figure 4A). Willians-Bey et al. (2014)
demonstrated that GPR120 rather than GPR40 is the relevant
ω3 receptor involved in limiting inflammation and likely
inflammasome activation in mouse (bone marrow-derived
macrophages) and human (THP1) macrophages. In addition,
the deletion of βArr2 partially inhibited ω3 effects, suggest-
ing that other mechanisms independent of GPR120/40 and
βArr2 might be involved in inhibiting the activation of the
NLRP3 inflammasome (Yan et al. 2013).
The NLRP3 inflammasome and IL1β have been linked to
obesity and its metabolic complications in murine models
induced by a high-fat diet (Vandanmagsar et al. 2011; Youm
et al. 2011) and obese humans (Quezada et al. 2021; Unamuno
et al. 2021). Recently, Unamuno et al. (2021) found that the
NLRP3 inflammasome was strikingly involved in IL1β pro-
duction in adipose tissue. Quezada et al. (2021) did not support
an increase in the hepatic levels of NLRP3 components in
patients with cardiometabolic risk. They did not correlate
Figure 4. GPR120 activation elicits the inflammasome disruption. (A) GPR120
anti-inflammatory response involves βArr2 activation which sequesters NLRP3
proteins (red arrows) disrupting inflammasome structure, reducing a matured
form of IL1β and IL18 (B). (C) GPR120/βArr2 axis blocks NFkB activity (dashed
red line - βArr2 blocks NFkB in an indirect form) which is the transcriptional
factor responsible for NLRP3 gene expression. All 3D molecules are originals
from Homo sapiens.
hepatic NLRP3 inflammasome components with insulin resis-
tance, inflammation, or morphological damage in the liver of
patients (Quezada et al. 2021). Notably, these authors carried
out an indirect inflammasome activity determination. In indi-
viduals severely obese (BMI > 50 kg/m2) and with NASH
(nonalcoholic steatohepatitis), NLRP3 inflammasome activation
was observed in hepatic tissue (Wree et al. 2014).
Increasing evidence suggests that ω3 PUFAs can poten-
tially decrease the activity of the NLRP3 inflammasome in
many types of cells, such as macrophages, hepatocytes, and
adipocytes (Martínez-Micaelo et al. 2016; Mortimer et al.
2016; Shen et al. 2017; Yan et al. 2013). The reduction in
inflammasome signaling was shown in a recent study in
which Lovaza®(3,6 g of EPA and DHA) treatment for 8 weeks
in obese humans reduced NLRP3 inflammasome and Casp1,
IL1β, and IL18 gene expression in adipose tissue and cir-
culating levels of IL18 (Lee, Midgette, and Shah 2019). In
a randomized controlled trial (Satoh et al. 2014), 60 patients
with coronary artery disease (CAD) showed NLRP3 inflam-
masome levels (gene expression measured in mononuclear
PBMC cells) higher than in the non-CAD group, with a
higher correlation between NLRP3 and IL1β and IL18 in
the bloodstream. Patients who randomly received 8 months
of treatment with atorvastatin or rosuvastatin, showed sig-
nificantly reduced NLRP3 levels. Despite pharmacogenomics
showing new molecular pathways for FDA-approved drugs,
the nutrigenomics perspective of disrupting the inflammaso-
mal structure mediated by a nutrient is an exciting and
novel possibility to be tested in several chronic diseases with
low-grade inflammation as a background (Satoh et al. 2014).

Intracellular ω3 anti-inflammatory signaling
The anti-inflammatory mechanism mediated by GPCRs
induced by ω3 is strongly involved in the ability of βArr2
to sequester TAB1/2 and NLRP3 with ω3 still outside the
cell. GPCRs (GPR120 and GPR40) contribute to ω3 inter-
nalization, although there are many other mechanisms of
ω3 uptake (Oh et al. 2010; Oliveira et al. 2015). Different
membrane receptors and mechanisms (Figure 5) are involved
in ω3 cell absorption, such as the flip-flop hypothesis
(Gurtovenko, Vattulainen 2007), FABP (Fatty Acid-Binding
Protein) (Liu et al. 2010), FATP (Fatty Acid Transporter
Protein-1) (Ochiai et al. 2017), CD36 (Cluster of
Differentiation 36) or synonymously SR-B2 (Scavenger
Receptor B2) (29), and MFSD2A (Major Facilitator
Superfamily Domain-Containing 2 A) (Duc, Kim, and Chung
2015.). Both FABP and FATP are superfamily receptors;
however, the high ω3 affinity/specificity is related to FABP2
and FATP1, respectively (Liu et al. 2010, Pishva et al. 2012).
Once inside the cell, ω3 could exhibit different ways to
interfere with proinflammatory signaling through its protein
interaction or after its metabolic derivation.
Unlike protein-protein interactions, understanding the
lipid-protein connection remains methodologically challeng-
ing, relying only on indirect tests. The “lipidation” is chal-
lenging to visualize, and all tests are estimative or
circumcircles. It is attributed to ω3 fatty acids and direct
protein connections, which are responsible for its intracel-
lular anti-inflammatory activities, representing ω3 nonge-
nomic signaling.
The anti-inflammatory ω3 actions mediated by
PPARγ
Peroxisome proliferator-activated receptors (PPARs) are
ligand-activated transcription factors of the nuclear hormone
receptor superfamily, and PPAR-gamma (PPARγ) is the cen-
tral transcriptional regulator of lipid metabolism. Thus, the
broad spectrum of PPARγ action, such as glucose
Figure 5. Intracellular ω3 uptake. Several ω3 receptors were described to promote its absorption. (A) GPCRs (GPR120 and GPR40), (B) FATP1 (fatty acid trans-
porter protein-1), (C) FABP2 (fatty acid-binding protein-2). ω3 internalization involves different membrane receptors and mechanisms, including (D) CD36 (cluster
of differentiation 36), (E) MFSD2A (major facilitator superfamily domain-containing 2A), and the flip-flop mechanism.
Critical Reviews in Food Science and Nutrition 7
homeostasis control (Tanaka et al. 2020), cardiovascular
functions (Tanaka et al. 2020), energy expenditure (Risérus
et al. 2008), liver lipid metabolism in nonalcoholic steato-
hepatitis (Francque et al. 2021, Lefere et al. 2020), modu-
lation of innate immunity (Lefere et al. 2020), and NFkB
signaling blockade (Zhao, Wang, and Guo 2016; Figures 2C
and 6A), is not surprising. It is also attributed to fatty acid
PPAR modulation, which is widely proven to affect gene
expression and protein content; however, it is early to alle-
viate direct PPAR agonism by fatty acids.
In the studies from Kliewer et al. (1997), Magee et al.
(2012), and Yamada et al. (2014), luciferase assays were
carried out to suggest the ω3-PPARγ connection and its
downstream effects. Magee et al. (2012) tested EPA
anti-inflammatory action in TNFα-injured C2C12 muscle
cells, suggesting a direct EPA effect on PPARγ blocking
NFkB signaling. Interestingly, Yamada et al. (2014) showed
that both EPA and its metabolites are PPARγ agonists, rein-
forcing the previous data that PPARγ is a relevant NFkB
blocker. Under ALOX enzyme action (ALOX5, 12, and 15),
EPA is derived in several leukotrienes from the HEPE
(Hydroxy Eicosapentaenoic Acid) family (Schulze et al.
2020). In this work, all tested HEPEs (HEPE5, HEPE8,
HEPE9, HEPE12, and HEPE18) were able to induce PPARγ
activation; however, HEPE8 and HEPE9 were the most
potent EPA-derived metabolite PPARγ activators (Yamada
et al. 2014; Figure 6A).
The ω3 fatty acids can follow different intracellular met-
abolic routes tracking specific enzyme systems. For example,
the hydroxy-lipidic mediators derived from EPA and DHA
after oxidative metabolisms in the P450 system, such as
17S-hydroxyDHA (17-HDHA) (González‐Périz et al. 2006;
Neuhofer et al. 2013) and protectin D1, can also act as
PPARγ ligands (González‐Périz et al. 2006). However, other
metabolites derived from ω3 fatty acids can use different
anti-inflammatory strategies independently of PPARγ acti-
vation. From the P450 system or ALOX enzymes, resolvins,
protectins, and maresins configure a new species of potent
ω3-derived anti-inflammatory metabolites using different
mechanisms (Figure 6B).
8 E. DA SILVA BATISTA ET AL.

Figure 6. The anti-inflammatory action of ω3-derived compounds. (A) EPA could be derived in several HEPE (hydroxy eicosapentaenoic acid) compounds. All
of them appear to have anti-inflammatory potentials, however, the HEPE8 and HEPE9 show described mechanisms of action, which activate PPARγ, direct (red
line) blocking NFkB, including EPA proper. (B) During the ω3 elongation and desaturation cascade, from EPA and DHA several new molecules can be derived.
EPA could be derived in odd series prostaglandins from the COX2 (Cyclooxygenase 2) enzyme. From P450 proteins (Cyp450), EPA can be derived in 18-hydroxy
eicosapentaenoic acid and resolvins (RvE1/E2). Also, three lipoxygenases could derivates EPA in active metabolites such as lipoxins, from lipoxygenases 12 and
15 (ALOX12/15), and leukotrienes of odd series, from lipoxygenase 5 (ALOX5). DHA could be derived in 14-HpDHA (14-hydroperoxide intermediate DHA) and
maresins MaR1/2 by lipoxygenase 12 (ALOX12) and 17-HpDHA (17-hydroperoxide intermediate DHA) and protectins (PD1 and NPD1) from lipoxygenase 15
(ALOX15). 17-hydroperoxide intermediate DHA could be converted into hydroxy docosahexaenoic acid by ALOX5. (C) Membrane receptor FPR2 recognizes RvD1
which blocks (dashed red lines) the pro-inflammatory signaling in the three hypothesized targets: IRAK1, TRAF6, and IkBα. (D) A GPCR receptor GPR32 which
also recognizes the RvD1, recruiting βArr2 that disarms proinflammatory cascades mediated by TLR4 and cytokine receptors. All 3D molecules are originals
from Homo sapiens.

Resolvins, protectins, and maresins
After internalization, some ω3 molecules are metabolized
into an extensive range of substances, as previously
described, such as prostaglandins and leukotrienes, derived
from COX and ALOX enzymes (Schulze et al. 2020;
Figures 2B and 6A). Other ω3-EPA molecules are derived
in epoxyns by the P450 system, called E-resolvins 1/2
(RvE1 and RvE2) by hydroxylases (CYP4A and CYP4F)
(Schulze et al. 2020), which shows a powerful
anti-inflammatory role. From ALOX5 metabolism, resolvins
can also be generated from DHA (RvD1 to RvD6) (Schulze
et al. 2020). Serhan et al. (2002) first described the exis-
tence and activity of resolvins. Since this, different ω3
metabolites have been described by Serhan’s group. In
2003, they identified the first member of a new category
of substances derived from DHA, the “protectins,” repre-
sented by the 10,17S-docosatrienoic acid, which was later
renamed neuroprotectin D1 (NPD1) (Mukherjee et al.
2004). In 2004, NPD1 was isolated, identified, and

characterized as derived from DHA after ALOX15 metab-
olism, including protectin D1 (PD1), another essential
member of the protectin class (Hansen, Dalli, and Serhan
2017). Last, in 2009, maresins (MaR) derived from DHA
under ALOX12 metabolism were identified to have sig-
nificant anti-inflammatory properties in macrophages
(Serhan et al. 2009). This metabolic route was evidenced
in macrophages, which gave meaning to the maresin
nomenclature “macrophages mediators in resolving inflam-
mation” (Serhan et al. 2009). Together, all resolvins, pro-
tectins, and maresins are collectively termed specialized
pro-resolving mediators (Serhan 2017) (Figure 6B).
Several mechanisms of action have been proposed to
explain the anti-inflammatory role attributed to each
pro-resolving mediator. Until now, the primary highlighted
mechanism involves the interaction between resolvins and
the ALX/FPR2 (Lipoxin A4 Receptor/Formyl Peptide
Receptor 2) receptor, a GPCR member, at the 3rd extracel-
lular loop (Bena et al. 2012). Recently, after FPR2 receptor
activation by RvD1, the receptor probably interacts with
IRAK1 or TRAF6 proteins, blocking the signal before reach-
ing the NFkB transcription factor (Liu et al. 2020; Figure
6C). It is very fascinating and biologically relevant to the
explicit demonstration of the mechanism of action. Although
in this work (Liu et al. 2020) the authors were relatively in
doubt between IRAK1 and TRAF6 proteins as a FPR2 target,
IRAK1/TRAF6 work side-by-side, with the spectrum of
action being very delimited. A specific nutrient can act on
multiple protein targets. Thus, Wang et al. (Wang et al.
2011) showed the ability of RvD1 to reduce IkBα degrada-
tion. IkBα acts as an anchor for the P50/P65 (NFkB) protein,
and its degradation allows continuous proinflammatory sig-
naling, releasing NFkB to the nucleus (Figure 6C). Thus,
RvD1 appears to act as an anti-inflammatory substance
working at different points in the same pathway, highlighting
its potential. To reinforce this point of view, Krishnamoorthy
et al. (2010) identified GPR32 as another RvD1 recognizer
that uses the intracellular βArr2 protein to transduce part
of its signal (34) (Figure 6D). As mentioned before, βArr2
mediates the anti-inflammatory response induced by GPR120,
an ω3 receptor, amplifying the RvD1 anti-inflammatory
specter (DeMar et al. 2006).
Receptors for protectins are still being described. GPR37
is considered an orphan receptor; however, its affinity for
protectin NPD1 was recently postulated as a possible medi-
ator of several NPD1 properties, mainly anti-inflammation
(Bang et al. 2014) (Figure 7A). Bang and colleagues reported
that GPR37, expressed by macrophages but not microglia,
contributes to the resolution of inflammatory pain. The
absence of GPR37 makes macrophages unable to produce
IL10, even under NPD1 stimuli, and the lagging macrophagic
transition from a pro- to anti-inflammatory profile delays
tissue repair (Bang et al. 2014). In the recent work published
by Mikroulis et al. (2022), a gripping PD1 action was
described as regulating the seizures induced by high GABA
neuron excitability (Mikroulis et al. 2022). During epilepsy
pathogenesis, neuroinflammation is increased, and IL1β and
TNFα are the ictogenic cytokines, leading to the worst
Critical Reviews in Food Science and Nutrition 9
Figure 7. The macrophage profile is controlled by ω3 and its derived com-
pounds. During the proinflammatory stage, the immune cell release several
proteins such as TNFα, IL1β, iNOS, NLRP3, and many others, including the
inflammasome assembling. (A) Protectins such as NPD1 (neuroprotection D1)
bind in the GPR37 receptor, which induces the gene transcription of the potent
anti-inflammatory interleukin, IL10. (B) Once inside the cell, the maresin “MaR1”
migrates to the nucleus binding to the nuclear receptor RORE (ROR-[retinoic
acid-related orphan receptor alpha (RORα)] Response Element) that also induces
the IL10 gene transcription. (C) Once activated by ω3, βArr2 recruited and
activated by GPR120 block several proinflammatory proteins (dash red line –
indirectly through TAK1 inhibition), direct (continuous red line) disarm inflam-
masome, indirect (blue dashed lines) activate the anti-inflammatory proteins
such as arginase 1 Arg1), chemokine 13 (CXCL13), transforming growth
factor-beta (TGFβ) and IL10. All these actions induce the anti-inflammatory
profile adopted by macrophages, resolving the inflammation. All 3D molecules
are originals from Homo sapiens.
prognosis characterized by seizures (Frigerio et al. 2018).
Despite PD1 controlling the inflammation and IL1β protein
content (Frigerio et al. 2018), the authors (Mikroulis et al.
2022) noticed that the seizures were contained in an inde-
pendent form of inflammation, suggesting different signalings
coordinating different phenomena. There are no identified
PD1 receptors, but in this work, treatment with a Gi inhibitor
completely abolished the neuroprotective PD1 action, sug-
gesting a GPCR as its receptor (Mikroulis et al. 2022).
Although maresins appear to act as potent protective medi-
ators of macrophage function, promoting acute inflammation
resolution and tissue regeneration (Hwang et al. 2019), there
are no well-established mechanisms. Recent and exciting dis-
coveries shine a light on MaR1 pathway possibilities. After
intracellular generation, some MaR1 molecules migrate to the
nucleus and activate a nuclear retinoic acid-related orphan
receptor alpha (RORα), binding to the RORE (ROR-Response
Element), which drives the complex (MaR1-RORα) to gene
target regions (Han et al. 2019; Figure 7B). The transcript
products are related to anti-inflammatory proteins such as
IL10 and TGFβ (transforming growth factor-beta) (Han et al.
2019). MaR1 molecules are also released from cells, and LGR6
(Leucine-Rich Repeat-Containing G Protein-Coupled Receptor
6) was recently described as its receptor. LGR6 is widely
expressed in various mouse and human tissues and induces
phagocytosis, efferocytosis, chemotaxis, and a distinct
10 E. DA SILVA BATISTA ET AL.
phosphorylation pathway coordinated by ERK (Extracellular
Signal-Regulated Kinase) (Chiang et al. 2019). Chiang et al.
also demonstrated the ability of MaR1 to recruit the βArr2
protein to the LGR6 base, evoking possible anti-inflammatory
MaR1 effects through the βArr2 downstream cascade (Chiang
et al. 2019).
In a proinflammatory context, MaR1 appears to firmly
resolve it due to induced macrophage polarization to a more
anti-inflammatory profile (CD11c-CD206+). Thus, MaR1 is
an indirect IL10- and TGFβ-inducible factor secreted by
CD206+ macrophages (Chiang et al. 2019). In a NASH
model, Han et al. (2019) showed that the improvement in
liver status was not provided by DHA activating GPR120
but through its derived, MaR1, preventing the progression
of high-fat diet-induced NASH in a RORα-dependent man-
ner. Thus, the confluence between extra and intracellular
signaling mediated by MaR1 composes significant
anti-inflammatory resources.
The evidence of these lipid mediators in humans is still
scarce, considering the methodological difficulties in access-
ing the measurements of resolvins, protectins, and maresins.
Some randomized and controlled studies have shown the
bioconversion process from ω3 food sources. Polus et al.
(2016) observed that a three-month supplementation with
1.8 g ω3 (EPA and DHA) in obese women significantly
increased plasma RvD1 and RvD2. Mas et al. (2016) showed
in a double-blind, placebo-controlled intervention that the
8 weeks of 4 g/d (1840 mg EPA and 1520 mg DHA) ω3 sup-
plementation in patients with chronic kidney disease
increased the plasma levels of RvD1 and the pathway pre-
cursors 18-HEPE (E-series resolvin from EPA) and 17-HDHA
(D-series resolvin from DHA). In obese and insulin-resistant
mice supplemented with flaxseed oil (ALA – C18:3 source),
the EPA, DHA, resolvin RvE1, RvE2, RvD2, and RvD6 levels
were increased, regulating the proinflammatory IL2, TNFα
and IFNγ cytokines and upregulating IL4 and IL10 produc-
tion by macrophages from adipose tissue (Bashir et al. 2019).
The macrophage as the conductor
From the nutritional point of view, ω3 fatty acids have been
described for a long time as the leading macrophage action
influencer (Leslie et al. 1985; Spencer et al. 2013). Several
reasons are attributable to this, such as the individual nutri-
tional status related to the ω6:ω3 ratio, the intracellular
macrophage signaling mediated by PPARγ among other
molecules, and pro-resolvins, as mentioned above. However,
during the last decade, GPR120 has been described in sev-
eral studies as being expressed on the surface of macro-
phages (Figure 7C). Interestingly, GPR120 is expressed on
the surface of tissue cells and immune cells (macrophages
and dendritic cells) (Feng et al. 2021).
For the first time, Raptis et al. (2014) showed GPR120
expressed on the Kupffer cell surface in mice under hepatic
ischemia-reperfusion injury, and an exaggerated inflamma-
tory response was attenuated after Omegaven® (parenteral
ω3 nutrition) treatment. Once GPR120 was identified as a
possible effector protein, its gene silencing (siRNA) showed
the ablation of ω3 action after treatment, marked by non-
transition between pro- and anti-inflammatory macrophage
profiles (Raptis et al. 2014)). A similar observation was
noticed by Oliveira et al. (2015) when liver steatohepatitis
was restored in obese and insulin-resistant mice after flax-
seed oil diet treatment. GPR120 was identified on the
hepatocyte and Kupffer cell surfaces and bound to the βArr2
protein after treatment (Oliveira et al. 2015). In another
experiment, both human macrophages (THP1) derived from
foam cells and lineage (Raw 264.7) were treated with a
GPR120-synthetic agonist (GW9508), and showed increased
expression of ABCA1 and ABCG1 (ATP-binding cassette
transporters), increasing cholesterol efflux after GPR120
activation (Ann et al. 2020). In obese and knockout LDLr
(low-density lipoprotein receptor) mouse models, Moura-Assis
et al. (2018) identified GPR120 in endothelial cells and on
the surface of infiltrating macrophages in the intimal layer
of the aortic wall (Moura-Assis et al. 2018). This last dis-
covery is fascinating once the cardiovascular benefits attrib-
utable to ω3 fatty acids, since its first demonstration
(Dyerberg, Bang 1979), could be induced by different mech-
anisms, such as switching the macrophage profile (Figure 7).
There is still a wide range of miscellaneous signaling
pathways associated with the anti-inflammatory effects of
ω3 in an attempt to orchestrate macrophages. Interestingly,
many of the above-described mechanisms could also interact
and be counteractive in the cells. For example, GPR120 has
a close relationship with PPARγ, and knowledge of this
interaction is another crucial issue for better understanding
the complex metabolic reactions that appear to modulate.
GPR120 is a direct PPARγ target gene in adipocytes, but
not in macrophages, and its induction by rosiglitazone
enables thiazolidinediones to potentiate the effects of the
GPR120 agonist. In addition, PPARγ activity is maintained
by activated GPR120, which increases the production of
15dPGJ2 and blocks ERK, a PPARγ inhibitor (Paschoal et al.
2020). Not only marine ω3 species (EPA and DHA) act at
these proposed molecular points. Kumar et al. (2016) showed
that the ALOX15 ALA metabolites (13-S-HPOTrE and
13-S-HOTrE) are natural PPARγ ligands, leading to the
blocking of NLRP3 and the inflammasome, followed by its
downstream signaling molecules, such as Casp1 and IL1β
(Kumar et al. 2016).
ω3 is not a panacea: adverse effects of ω3
supplementation
There is a high interest of all members of society (citizens,
public health administrators, pharmaceutical companies, etc.)
in finding strategies to control inflammation. Both levels (high
or low) of inflammation are the basis for almost all disease
development. As shown, ω3 fatty acids have many actions,
counteracting inflammation in a multipoint strategy. Then, if
ω3 is so potent, why is it still not considered in the leading
international guidelines? Many questions could be detailed,
such as the absence of recommended dose of consumption,
the quality of the oil from capsules, the ideal blend between
EPA: DHA or its isolated consumption, the ALA bioconversion

to longer ω3 species, the FADS (fatty acid desaturase) muta-
tion dispersion among populations, the quality of experimental
and clinical studies design, the compliance of the study
funders, and because it is a nutrient, not a medication.
Notwithstanding, some side effects need to be considered.
There is no established UL (Upper Level) for ω3 intake.
It is assumed that supplementation in clinical practice is safe
due to the literature’s scarce evidence of toxic effects. On the
other hand, not all intervention studies describe adverse or
side effects. Most clinical trials do not prepare concise or
reasonable reports showing adverse events (Abdelhamid et al.
2018, Alvarez Campano et al. 2019). The most commonly
reported adverse event was gastrointestinal upset (Downie
et al. 2019; Poreba et al. 2017). A significant concern with
ω3 supplementation would be the bleeding risk (Dyerberg,
Bang 1979). However, it is still unknown whether the anti-
platelet effect per se could be transposed into increased clin-
ical risk for patients (Bagger et al. 2020; Jeansen et al. 2018).
In the clinical trials with large sample sizes such as JELIS
(Yokoyama et al. 2007) and REDUCE-IT (Bhatt et al. 2019b)
studies, increased bleeding was observed using EPA alone
over approximately 5 years. In JELIS, 1.8 g of EPA was tested
in Japanese patients with hypercholesterolemia using statins
(Yokoyama et al. 2007). In the REDUCE-IT study, patients
with elevated triglycerides on statins received 4 g/d of highly
purified EPA ethyl ester (icosapent ethyl) (Bhatt et al.
2019a). In the REDUCE-IT study (Bhatt et al. 2019a), there
are reports that ω3 supplementation could cause atrial fibril-
lation, which was also achieved in the STRENGTH trial
(Nicholls et al. 2020). STRENGTH was conducted in 13.078
patients receiving statins and 4 g/d of ω3 carboxylic acid
(75% EPA and DHA) over a 3.2-year average follow-up
(Nicholls et al. 2020). Unexpectedly, no change in the risk
of atrial fibrillation was observed in the VITAL-AF study,
which used 840 mg/d of marine ω3 fatty acids (EPA-DHA;
1.2:1 ratio) for 5.3 years, carried out in patients with no
prior history of cardiovascular disease (Albert et al. 2021).
These findings suggest that the risk of atrial fibrillation is
higher with increasing ω3 dose, especially EPA.
Given the high natural amount of DHA in neurons, it is
hypothesized that its supplementation would have a neuro-
protective effect. However, the maxim of “the greater, the
better” does not apply in this case either. The opposite has
been observed as a worsening cognitive function in the
elderly (Danthiir et al. 2018; Naderali E, Naderali M-M,
Abubakari 2014) and throughout the life of animals’ off-
spring supplemented with ω3 in pregnancy and lactation,
as well as a reduced life expectancy (Church et al. 2008;
Church et al. 2010). In an animal model for amyotrophic
lateral sclerosis, worsening of brain cell damage was observed
with EPA supplementation (Yip et al. 2013). The association
between ω3 supplementation and ethanol intake in animals
worsened nonalcoholic fatty liver disease through an
increased inflammatory response by reducing IL4 and
anti-inflammatory macrophages (Feng et al. 2021; Li et al.
2017). Although still not established, it seems necessary to
define an ω3 intake limit beyond which the beneficial capac-
ity of these fatty acids would be extrapolated, leading to
adverse effects. Further clinical trials are needed to address
Critical Reviews in Food Science and Nutrition 11
this possibility, as ω3 is generally safe and well-tolerated but
not free of adverse effects.
Limitations
Still are several limitations related to the ω3 mechanisms
of action and the applicability of findings in humans. Lipids
are non-crystallizable substances, which turns impossible
until now, the optical methods to binding studies. The cur-
rent methods in the literature only surround lipid action
measurements. The incorrect placebo adoption in studies
with cells, mice, and humans promote several biases. The
results found in studies using ω6 sources (safflower, sun-
flower, and corn oil) can overestimate the ω3 benefits, and
ω9 (olive oil) can underestimate it. Undisputedly, the wrong
dose definitions are a bottleneck in this area. Many studies,
using large cohorts claim the benefits of using, for example,
4 grams of ω3. However, they used 4 capsules with 1 gram
of oil each, but less than 2 grams of ω3 fatty acid in the
total. The fatty acid profile determination previously to the
experimentations needs to be obligatory. When the study
hits this aim, it might fail on non-checked adulterated prod-
ucts; frequently found on the market. Science must overcome
these questions to promote more realistic practice applica-
tions based on these interesting molecular mechanisms find-
ings. Finally, the gene variations associated with GPR120,
FADS, and other genes participating in omega-3 metabolism
will need to be investigated to understand if there are prone
or less responsive people to omega-3 fatty acids usage.
Conclusion
The molecular sciences provided new exploratory instru-
mentals that enabled inside-the-cell pathway understanding.
The most explored nutrient in nutritional sciences now has
a plethora of mechanistic possibilities. By targeting receptors
on the surface cells, managing macrophage polarization,
disrupting the multiple proinflammatory intracellular cas-
cades, or disassembling the inflammasome structure on both
tissue and immune cells, omega-3 fatty acids show their
impressive versatile action. Nonetheless, it is necessary to
understand why this enormous anti-inflammatory signal
convergence is not translated into clinical significance. The
nutrigenomic approaches still have a long way to determine
the omega-3 ideal dose, treatment duration, the balance
between omega-3 and omega-6 ingestion, and tissue-specific
bioconversion from short (ALA) to long-chain species (EPA
and DHA). Regardless, the science surrounding omega-3
anti-inflammatory investigation leaves a legacy with new
proposed targets that enable other nutrients or even drugs
to be intelligently designed.
Acknowledgments
We thank the Research Collaboratory for Structural Bioinformatics –
Protein Data Bank (RCSB-PDB) and AlphaFold Protein Structure
Database for the free use of tridimensional protein structures. We also
thank all the members of the Nutritional Genomics Lab for their helpful
12 E. DA SILVA BATISTA ET AL.
discussions. EAC thanks to CNPq (Brazilian National Council for
Scientific and Technological Development) for the scientific productivity
fellowship (CNPq: 315369/2021-3). S.C.B.R.N and D.E.C thanks to “São
Paulo Research Foundation – FAPESP,” by grants 2020/13443-1,
2019/13168-3 and 2019/13210-0, and CNPq: 312970/2022-6, which sup-
port all scientific investigations at the laboratory.
Disclosure statement
The authors are not aware of any affiliations, memberships, funding,
or financial holdings that might be perceived as affecting the objectivity
of this review.
Funding
The author(s) reported there is no funding associated with the work
featured in this article.
References
Abdelhamid, A. S., T. J. Brown, J. S. Brainard, P. Biswas, G. C. Thorpe,
H. J. Moore, K. H. Deane, F. K. AlAbdulghafoor, C. D. Summerbell,
H. V. Worthington, et al. 2018. Omega-3 fatty acids for the prima-
ry and secondary prevention of cardiovascular disease. Cochrane
Database of Systematic Reviews 7 (7):CD003177. doi:
10.1002/14651858.CD003177.pub4.
Adan, Y., K. Shibata, M. Sato, I. Ikeda, and K. Imaizum. 1999. Effects
of docosahexaenoic and eicosapentaenoic acid on lipid metabolism,
eicosanoid production, platelet aggregation and atherosclerosis in
hypercholesterolemic rats. Bioscience, Biotechnology, and Biochemistry
63 (1):111–9. doi: 10.1271/bbb.63.111.
Adhikari, A., M. Xu, and Z. J. Chen. 2007. Ubiquitin-mediated acti-
vation of TAK1 and IKK. Oncogene. 26 (22):3214–26. doi: 10.1038/
sj.onc.1210413.
Agostini, L., F. Martinon, K. Burns, M. F. McDermott, P. N. Hawkins,
and J. Tschopp. 2004. NALP3 forms an IL-1β-processing inflam-
masome with increased activity in muckle-wells autoinflammatory.
Immunity. 20 (3):319–25. doi: 10.1016/s1074-7613(04)00046-9.
Albert, C. M., N. R. Cook, J. Pester, M. V. Moorthy, C. Ridge, J. S.
Danik, B. Gencer, H. K. Siddiqi, C. Ng, H. Gibson, et al. 2021.
Effect of marine omega-3 fatty acid and vitamin D supplementation
on incident atrial fibrillation: A randomized clinical trial. JAMA
325 (11):1061–73. doi: 10.1001/jama.2021.1489.
Alvarez Campano, C. G., M. J. Macleod, L. Aucott, and F. Thies. 2019.
Marine-derived n-3 fatty acids therapy for stroke. Cochrane Database
Systematic Reviews 26 (6):CD012815.
An, J. U., S. E. Kim, and D. K. Oh. 2021. Molecular insights into lip-
oxygenases for biocatalytic synthesis of diverse lipid mediators.
Progress in Lipid Research 83:101110. doi: 10.1016/j.plipres.2021.101110.
An, T., X. Zhang, H. Li, L. Dou, X. Huang, Y. Man, X. Zhang, T.
Shen, G. Li, J. Li, et al. 2020. GPR120 facilitates cholesterol efflux
in macrophages through activation of AMPK signaling pathway. The
FEBS Journal 287 (23):5080–95. doi: 10.1111/febs.15310.
Arterburn, L. M., E. B. Hall, and H. Oken. 2006. Distribution, inter-
conversion, and dose response of n − 3 fatty acids in humans. The
American Journal of Clinical Nutrition 83 (Suppl 6):1467S–76S. doi:
10.1093/ajcn/83.6.1467S.
Bagger, H., M. Hansson, T. Kander, and U. Schött. 2020. Synergistic
platelet inhibition between Omega-3 and acetylsalicylic acid dose
titration; an observational study. BMC Complementary Medicine and
Therapies 20 (1):1–9. doi: 10.1186/s12906-020-02990-9.
Bang, H. O., J. Dyerberg, and N. Hjøorne. 1976. The composition of
food consumed by Greenland Eskimos. Acta Medica Scandinavica
200 (1-2):69–73. doi: 10.1111/j.0954-6820.1976.tb08198.x.
Bang, S., Y. Xie, Z. Zhang, Z. Wang, Z. Xu, and R. Ji. 2018. GPR37
regulates macrophage phagocytosis and resolution of inflammatory
pain. The Journal of Clinical Investigation 128 (8):3568–82. doi:
10.1172/JCI99888.
Barceló-Coblijn, G, and E. J. Murphy. 2009. Alpha-linolenic acid and
its conversion to longer chain n-3 fatty acids: Benefits for human
health and a role in maintaining tissue n-3 fatty acid levels. Progress
in Lipid Research 48 (6):355–74. doi: 10.1016/j.plipres.2009.07.002.
Bashir, S., Y. Sharma, D. Jairajpuri, F. Rashid, M. Nematullah, and F.
Khan. 2019. Alteration of adipose tissue immune cell milieu towards
the suppression of inflammation in high fat diet fed mice by flax-
seed oil supplementation. PLoS One 14 (10):e0223070. doi: 10.1371/
journal.pone.0223070.
Bena, S., V. Brancaleone, J. M. Wang, M. Perretti, and R. J. Flower.
2012. Annexin A1 interaction with the FPR2/ALX receptor:
Identification of distinct domains and downstream associated sig-
naling. The Journal of Biological Chemistry 287 (29):24690–7. doi:
10.1074/jbc.M112.377101.
Bhatt, D. L., P. G. Steg, M. Miller, E. A. Brinton, T. A. Jacobson, S.
B. Ketchum, R. T. Doyle, Jr, R. A. Juliano, L. Jiao, C. Granowitz,
et al. 2019a. Cardiovascular risk reduction with icosapent ethyl for
hypertriglyceridemia. The New England Journal of Medicine 380
(1):11–22. doi: 10.1056/NEJMoa1812792.
Bhatt, D. L., P. G. Steg, M. Miller, E. A. Brinton, T. A. Jacobson, S.
B. Ketchum, R. T. Doyle, Jr, R. A. Juliano, L. Jiao, C. Granowitz,
REDUCE-IT Investigators, et al. 2019b. Effects of icosapent ethyl
on total ischemic events: From REDUCE-IT. Journal of the American
College of Cardiology 73 (22):2791–802. doi: 10.1016/j.jacc.2019.02.032.
Chen, Y., Z. Wu, S. Huang, X. Wang, S. He, L. Liu, Y. Hu, L. Chen,
P. Chen, S. Liu, et al. 2022. Adipocyte IRE1α promotes PGC1α
mRNA decay and restrains adaptive thermogenesis. Nature
Metabolism 4 (9):1166–84. doi: 10.1038/s42255-022-00631-8.
Chiang, N., S. Libreros, P. C. Norris, X. D. Rosa, and C. N. Serhan.
2019. Maresin 1 activates LGR6 receptor promoting phagocyte im-
munoresolvent functions. The Journal of Clinical Investigation 129
(12):5294–311. doi: 10.1172/JCI129448.
Church, M. W., K.-L. C. Jen, J. I. Anumba, D. A. Jackson, B. R. Adams,
and J. W. Hotra. 2010. Excess omega-3 fatty acid consumption by
mothers during pregnancy and lactation caused shorter life span
and abnormal ABRs in old adult offspring. Neurotoxicology and
Teratology 32 (2):171–81. doi: 10.1016/j.ntt.2009.09.006.
Cintra, D. E. C., A. V. Costa, C. G. Peluzio M do, S. L. P. Matta, M. T.
C. Silva, and N. M. B. Costa. 2006. Lipid profile of rats fed high-fat
diets based on flaxseed, peanut, trout, or chicken skin. Nutrition
(Burbank, Los Angeles County, Calif.) 22 (2):197–205. doi: 10.1016/j.
nut.2005.09.003.
Cintra, D. E., E. R. Ropelle, J. C. Moraes, J. R. Pauli, J. Morari, C. T.
Souza, R. Grimaldi, M. Stahl, J. B. Carvalheira, M. J. Saad, et al. 2012.
Unsaturated fatty acids revert diet-induced hypothalamic inflammation
in obesity. PloS One 7 (1):e30571. doi: 10.1371/journal.pone.0030571.
Compan, V., F. Martín-Sánchez, A. Baroja-Mazo, G. López-Castejón,
A. I. Gomez, A. Verkhratsky, D. Brough, and P. Pelegrín. 2015.
Apoptosis-associated speck-like protein containing a CARD forms
specks but does not activate caspase-1 in the absence of NLRP3
during macrophage swelling. Journal of Immunology (Baltimore, Md.:
1950) 194 (3):1261–73. doi: 10.4049/jimmunol.1301676.
Croset, M., A. Sala, G. Folco, and M. Lagarde. 1988. Inhibition by
lipoxygenase products of TXA2-like responses of platelets and vas-
cular smooth muscle. Biochemical Pharmacology 37 (7):1275–80.
doi: 10.1016/0006-2952(88)90782-4.
Daak, A. A., A. Y. Elderdery, L. M. Elbashir, K. Mariniello, J. Mills,
G. Scarlett, M. I. Elbashir, and K. Ghebremeskel. 2015. Omega 3
(n-3) fatty acids down-regulate nuclear factor-kappa B (NF-κB) gene
and blood cell adhesion molecule expression in patients with ho-
mozygous sickle cell disease. Blood Cells, Molecules & Diseases 55
(1):48–55. doi: 10.1016/j.bcmd.2015.03.014.
Danthiir, V., D. E. Hosking, T. Nettelbeck, A. D. Vincent, C. Wilson,
N. O’Callaghan, E. Calvaresi, P. Clifton, and G. A. Wittert. 2018.
An 18-mo randomized, double-blind, placebo-controlled trial of
DHA-rich fish oil to prevent age-related cognitive decline in cog-
nitively normal older adults. The American Journal of Clinical
Nutrition 107 (5):754–62. doi: 10.1093/ajcn/nqx077.

Dátilo, M. N., M. R. Sant’Ana, G. P. Formigari, P. B. Rodrigues, L. P.
de Moura, A. S. R. da Silva, E. R. Ropelle, J. R. Pauli, and D. E.
Cintra. 2018. Omega-3 from flaxseed oil protects obese mice against
diabetic retinopathy through GPR120 receptor. Scientific Report 8
(1):14318.
de Melo, D. G., C. P. Anaruma, K. C. da Cruz Rodrigues, R. M.
Pereira, T. D. P. de Campos, R. S. Canciglieri, C. O. Ramos, D. E.
Cintra, E. R. Ropelle, A. S. R. da Silva, et al. 2022. Strength train-
ing alters the tissue fatty acids profile and slightly improves the
thermogenic pathway in the adipose tissue of obese mice. Scientific
Reports 2812 (1):6913. doi: 10.1038/s41598-022-10688-w.
Demar, J. C., Jr, K. Ma, L. Chang, J. M. Bell, and S. I. Rapoport. 2005.
Alpha-Linolenic acid does not contribute appreciably to docosahex-
aenoic acid within brain phospholipids of adult rats fed a diet
enriched in docosahexaenoic acid. Journal of Neurochemistry 94
(4):1063–76. doi: 10.1111/j.1471-4159.2005.03258.x.
DeMar, J. C., K. Ma, J. M. Bell, M. Igarashi, D. Greenstein, and S. I.
Rapoport. 2006. One generation of n-3 polyunsaturated fatty acid
deprivation increases depression and aggression test scores in rats.
Journal of Lipid Research 47 (1):172–80. doi: 10.1194/jlr.M500362-JLR200.
DiNicolantonio, J. J, and J. OKeefe. 2019. Importance of maintaining
a low omega-6/omega-3 ratio for reducing platelet aggregation,
coagulation and thrombosis. Open Heart 6 (1):e001011. doi: 10.1136/
openhrt-2019-001011.
Doege, H, and A. Stahl. 2006. Protein-mediated fatty acid uptake:
Novel insights from in vivo models. Physiology (Bethesda, Md.)
21:259–68. doi: 10.1152/physiol.00014.2006.
Downie, L. E., S. M. Ng, K. B. Lindsley, and E. K. Akpek. 2019.
Omega-3 and omega-6 polyunsaturated fatty acids for dry eye dis-
ease. The Cochrane Database of Systematic Reviews 12 (12):CD011016.
doi: 10.1002/14651858.CD011016.pub2.
Duc, N. M., H. R. Kim, and K. Y. Chung. 2015. Structural mechanism
of G protein activation by G protein-coupled receptor. European
Journal of Pharmacology 763 (Pt B):214–22. doi: 10.1016/j.ej-
phar.2015.05.016.
Dyerberg, J, and H. O. Bang. 1979. Haemostatic function and platelet
polyunsaturated fatty acids in Eskimos. The Lancet 314 (8140):433–
5. doi: 10.1016/S0140-6736(79)91490-9.
Dyerberg, J., H. O. Bang, E. Stoffersen, S. Moncada, and J. R. Vane.
1978. Eicosapentaenoic acid and prevention of thrombosis and ath-
erosclerosis? Lancet (London, England) 2 (8081):117–9. doi: 10.1016/
s0140-6736(78)91505-2.
Emre, C., L. E. Arroyo-García, K. V. Do, B. Jun, M. Ohshima, S. G.
Alcalde, M. L. Cothern, S. Maioli, P. Nilsson, E. Hjorth, et al. 2022.
Intranasal delivery of pro-resolving lipid mediators rescues memo-
ry and gamma oscillation impairment in App NL-G-F/NL-G-F mice.
Communications Biology 5 (1):245. doi: 10.1038/s42003-022-03169-3.
Esser-von Bieren, J. 2019. Eicosanoids in tissue repair. Immunology
and Cell Biology 97 (3):279–88. doi: 10.1111/imcb.12226.
Fahrmann, J. F., O. F. Ballester, G. Ballester, T. R. Witte, A. J. Salazar,
B. Kordusky, K. G. Cowen, G. Ion, D. A. Primerano, G. Boskovic,
et al. 2013. Inhibition of nuclear factor kappa B activation in
early-stage chronic lymphocytic leukemia by omega-3 fatty acids.
Cancer Investigation 31 (1):24–38. doi: 10.3109/07357907.2012.743553.
Feng, C., L. Li, Q. Li, K. Switzer, M. Liu, S. Han, and B. Zheng. 2021.
Docosahexaenoic acid ameliorates autoimmune inflammation by
activating GPR120 signaling pathway in dendritic cells. International
Immunopharmacology 97:107698. doi: 10.1016/j.intimp.2021.107698.
Francque, S. M., P. Bedossa, V. Ratziu, Q. M. Anstee, E. Bugianesi, A.
J. Sanyal, R. Loomba, S. A. Harrison, R. Balabanska, L. Mateva,
et al. 2021. A Randomized, Controlled Trial of the Pan-PPAR
Agonist Lanifibranor in NASH. The New England Journal of Medicine
385 (17):1547–58. doi: 10.1056/NEJMoa2036205.
Frigerio, F., G. Pasqualini, I. Craparotta, S. Marchini, E. A. van Vliet,
P. Foerch, C. Vandenplas, K. Leclercq, E. Aronica, L. Porcu, et al.
2018. n-3 Docosapentaenoic acid-derived protectin D1 promotes
resolution of neuroinflammation and arrests epileptogenesis. Brain:
A Journal of Neurology 141 (11):3130–43. doi: 10.1093/brain/awy247.
Gabbs, M., P. Zahradka, C. G. Taylor, and H. M. Aukema. 2021. Time
course and sex effects of α-linolenic acid-rich and DHA-rich
Critical Reviews in Food Science and Nutrition 13
s­ upplements on human plasma oxylipins: A randomized double-blind
crossover trial. The Journal of Nutrition 151 (3):513–22. doi: 10.1093/
jn/nxaa294.
González-Périz, A., A. Planagumà, K. Gronert, R. Miquel, M.
López-Parra, E. Titos, R. Horrillo, N. Ferré, R. Deulofeu, V. Arroyo,
et al. 2006. Docosahexaenoic acid (DHA) blunts liver injury by
conversion to protective lipid mediators: Protectin D1 and 17S‐hy-
droxy‐DHA. FASEB Journal: Official Publication of the Federation
of American Societies for Experimental Biology 20 (14):2537–9. doi:
10.1096/fj.06-6250fje.
Gurtovenko, A. A, and I. Vattulainen. 2007. Molecular mechanism for
lipid flip-flops. The Journal of Physical Chemistry. B 111 (48):13554–
9. doi: 10.1021/jp077094k.
Guthrie, G. 2022. Parenteral nutrition associated hepatic steatosis and
NAFLD intersect at AMPK. Cellular and Molecular Gastroenterology
and Hepatology 14 (3):724–5. doi: 10.1016/j.jcmgh.2022.06.005.
Hames, K. C., C. Koutsari, S. Santosa, N. C. Bush, and M. D. Jensen.
2015. Adipose tissue fatty acid storage factors: Effects of depot, sex
and fat cell size. International Journal of Obesity (2005) 39 (6):884–
7. doi: 10.1038/ijo.2015.10.
Han, Y. H., K. O. Shin, J. Y. Kim, D. B. Khadka, H. J. Kim, Y. M.
Lee, W. J. Cho, J. Y. Cha, B. J. Lee, and M. O. Lee. 2019. A ma-
resin 1/ROR α/12-lipoxygenase autoregulatory circuit prevents in-
flammation and progression of nonalcoholic steatohepatitis. The
Journal of Clinical Investigation 129 (4):1684–98. doi: 10.1172/
JCI124219.
Hansen, T. V., J. Dalli, and C. N. Serhan. 2017. The novel lipid me-
diator PD1n-3 DPA: An overview of the structural elucidation,
synthesis, biosynthesis and bioactions. Prostaglandins & Other Lipid
Mediators 133:103–10. doi: 10.1016/j.prostaglandins.2017.06.003.
Hirasawa, A., T. Hara, S. Katsuma, T. Adachi, and G. Tsujimoto. 2008.
Free fatty acid receptors and drug discovery. Biological &
Pharmaceutical Bulletin 31 (10):1847–51. doi: 10.1248/bpb.31.1847.
Hirasawa, A., K. Tsumaya, T. Awaji, S. Katsuma, T. Adachi, M. Yamada,
Y. Sugimoto, S. Miyazaki, and G. Tsujimoto. 2005. Free fatty acids
regulate gut incretin glucagon-like peptide-1 secretion through
GPR120. Nature Medicine 11 (1):90–4. doi: 10.1038/nm1168.
Holy, E. W., M. Forestier, E. K. Richter, A. Akhmedov, F. Leiber, G.
G. Camici, P. Mocharla, T. F. Lüscher, J. H. Beer, and F. C. Tanner.
2011. Dietary α-linolenic acid inhibits arterial thrombus formation,
tissue factor expression, and platelet activation. Arteriosclerosis,
Thrombosis, and Vascular Biology 31 (8):1772–80. doi: 10.1161/
ATVBAHA.111.226118.
Huang, S., Rutkowsky, J. M. Snodgrass, R. G. Ono-Moore, K. D.
Schneider, D. A. Newman, J. W. Adams, S. H. Hwang, and D. H.
S. 2012. Saturated fatty acids activate TLR-mediated proinflamma-
tory signaling pathways. Journal of Lipid Research 53 (9):2002–13.
doi: 10.1194/jlr.D029546.
Hwang, S.-M., G. Chung, Y. H. Kim, and C.-K. Park. 2019. The role
of maresins in inflammatory pain: Function of macrophages in
wound regeneration. International Journal of Molecular Sciences 20
(23):5849. doi: 10.3390/ijms20235849.
Ishitani, T., G. Takaesu, J. Ninomiya-Tsuji, H. Shibuya, R. B. Gaynor,
and K. Matsumoto. 2003. Role of the TAB2-related protein TAB3
in IL-1 and TNF signaling. The EMBO Journal 22 (23):6277–88.
doi: 10.1093/emboj/cdg605.
Itoh, Y., Y. Kawamata, M. Harada, M. Kobayashi, R. Fujii, S. Fukusumi,
K. Ogi, M. Hosoya, Y. Tanaka, H. Uejima, et al. 2003. Free fatty
acids regulate insulin secretion from pancreatic β cells through
GPR40. Nature 422 (6928):173–6. doi: 10.1038/nature01478.
Jeansen, S., Witkamp, R. F. Garthoff, J. A. Helvoort, A. Van, and
Calder, P. C. 2018. Fish oil LC-PUFAs do not affect blood coagu-
lation parameters and bleeding manifestations: Analysis of 8 clini-
cal studies with selected patient groups on omega-3-enriched med-
ical nutrition. Clinical Nutrition (Edinburgh, Scotland) 37 (3):948–57.
doi: 10.1016/j.clnu.2017.03.027.
Kain, V., K. A. Ingle, M. Kachman, H. Baum, G. Shanmugam, N. S.
Rajasekaran, M. E. Young, and G. V. Halade. 2018. Excess ω-6
fatty acids influx in aging drives metabolic dysregulation, electro-
cardiographic alterations, and low-grade chronic inflammation.
14 E. DA SILVA BATISTA ET AL.
American Journal of Physiology. Heart and Circulatory Physiology
314 (2):H160–H169. doi: 10.1152/ajpheart.00297.2017.
Kang, J. Y, and J. O. Lee. 2011. Structural biology of the Toll-like
receptor family. Annual Review of Biochemistry 80:917–41. doi:
10.1146/annurev-biochem-052909-141507.
Kim, S. F., D. A. Huri, and S. H. Snyder. 2005. Medicine: Inducible
nitric oxide synthase binds, S-nitrosylates, and activates
cyclooxygenase-2. Science (New York, N.Y.) 310 (5756):1966–70. doi:
10.1126/science.1119407.
Kliewer, S. A., S. S. Sundseth, S. A. Jones, P. J. Brown, G. B. Wisely,
C. S. Koble, P. Devchand, W. Wahli, T. M. Willson, J. M. Lenhard,
et al. 1997. Fatty acids and eicosanoids regulate gene expression
through direct interactions with peroxisome proliferator-activated
receptors α and γ. Proceedings of the National Academy of Sciences
of the United States of America 94 (9):4318–23. doi: 10.1073/
pnas.94.9.4318.
Knez Hrnčič, M., M. Ivanovski, D. Cör, and Ž. Knez. Ž 2019. Chia
seeds (Salvia hispanica L.): An overview-phytochemical profile, iso-
lation methods, and application. Molecules 25 (1):11. doi: 10.3390/
molecules25010011.
Komatsu, W., K. Ishihara, M. Murata, H. Saito, and K. Shinohara.
2003. Docosahexaenoic acid suppresses nitric oxide production and
inducible nitric oxide synthase expression in interferon-γ plus
lipopolysaccharide-stimulated murine macrophages by inhibiting the
oxidative stress. Free Radical Biology & Medicine 34 (8):1006–16.
doi: 10.1016/s0891-5849(03)00027-3.
Krishnamoorthy, S., A. Recchiuti, N. Chiang, S. Yacoubian, C. H. Lee,
R. Yang, N. A. Petasis, and C. N. Serhan. 2010. Resolvin D1 binds
human phagocytes with evidence for proresolving receptors.
Proceedings of the National Academy of Sciences of the United States
of America 107 (4):1660–5. doi: 10.1073/pnas.0907342107.
Kumar, N., G. Gupta, K. Anilkumar, N. Fatima, R. Karnati, G. V.
Reddy, P. V. Giri, and P. Reddanna. 2016. 15-Lipoxygenase metab-
olites of α-linolenic acid, [13-(S)-HPOTrE and 13-(S)-HOTrE], me-
diate anti-inflammatory effects by inactivating NLRP3 inflammasome.
Scientific Report 18 (6):31649.
Lancaster, G. I., K. G. Langley, N. A. Berglund, H. L. Kammoun, S.
Reibe, E. Estevez, J. Weir, N. A. Mellett, G. Pernes, J. R. W. Conway,
et al. 2018. Evidence that TLR4 is not a receptor for saturated
fatty acids but mediates lipid-induced inflammation by reprogram-
ming macrophage metabolism. Cell Metabolism 27 (5):1096–110.e5.
doi: 10.1016/j.cmet.2018.03.014.
Lee, K. R., Y. Midgette, and R. Shah. 2019. Fish oil derived omega 3
fatty acids suppress adipose NLRP3 inflammasome signaling in
human obesity. Journal of the Endocrine Society 3 (3):504–15. doi:
10.1210/js.2018-00220.
Lefere, S., T. Puengel, J. Hundertmark, C. Penners, A. K. Frank, A.
Guillot, K. de Muynck, F. Heymann, V. Adarbes, E. Defrêne, et al.
2020. Differential effects of selective- and pan-PPAR agonists on
experimental steatohepatitis and hepatic macrophages. Journal of
Hepatology 73 (4):757–70. doi: 10.1016/j.jhep.2020.04.025.
Leslie, C. A., W. A. Gonnerman, M. D. Ullman, K. C. Hayes, C.
Franzblau, and E. S. Cathcart. 1985. Dietary fish oil modulates
macrophage fatty acids and decreases arthritis susceptibility in mice.
The Journal of Experimental Medicine 162 (4):1336–49. doi: 10.1084/
jem.162.4.1336.
Li, X.-J., Y.-M. Mu, Q.-F. Qin, Z.-X. Zeng, Y.-S. Li, W. K. Zhang, H.-
B. Tang, G.-H. Tian, and H.-C. Shang. 2017. Chronic high-dosage
fish oil exacerbates gut–liver axis injury in alcoholic steatohepatitis
in mice: The roles of endotoxin and IL-4 in Kupffer cell polarization
imbalance. Toxicology Research 6 (5):611–20. doi: 10.1039/c7tx00037e.
Liu, G. J., T. Tao, H. Wang, Y. Zhou, X. Gao, Y. Y. Gao, C. H. Hang,
and W. Li. 2020. Functions of resolvin D1-ALX/FPR2 receptor in-
teraction in the hemoglobin-induced microglial inflammatory re-
sponse and neuronal injury. Journal of Neuroinflammation 17 (1):239.
doi: 10.1186/s12974-020-01918-x.
Liu, R. Z., R. Mita, M. Beaulieu, Z. Gao, and R. Godbout. 2010. Fatty
acid binding proteins in brain development and disease. The
International Journal of Developmental Biology 54 (8-9):1229–39.
doi: 10.1387/ijdb.092976rl.
Liu, T., L. Zhang, D. Joo, and S.-C. Sun. 2017. NF-κB signaling in
inflammation. Signal Transduction and Targeted Therapy 2 (1):17023.
doi: 10.1038/sigtrans.2017.23.
Magee, P., S. Pearson, J. Whittingham-Dowd, and J. Allen. 2012. PPARγ
as a molecular target of EPA anti-inflammatory activity during
TNF-α-impaired skeletal muscle cell differentiation. The Journal of
Nutritional Biochemistry 23 (11):1440–8. doi: 10.1016/j.jnut-
bio.2011.09.005.
Marcinak, J., C. Cao, D. Lee, and Z. Ye. 2017. Fasiglifam for glycemic
control in patients with type 2 diabetes: A phase 3, placebo-controlled
study. Diabetes, Obesity & Metabolism 19 (12):1714–21. doi: 10.1111/
dom.13004.
Marks, K. A., P. M. Marvyn, J. J. Henao, R. M. Bradley, K. D. Stark,
and R. E. Duncan. 2015. Fasting enriches liver triacylglycerol with
n-3 polyunsaturated fatty acids: Implications for understanding the
adipose-liver axis in serum docosahexaenoic acid regulation. Genes
& Nutrition 10 (6):39. doi: 10.1007/s12263-015-0490-2.
Martínez-Micaelo, N., N. González-Abuín, M. Pinent, A. Ardévol, and
M. Blay. 2016. Dietary fatty acid composition is sensed by the
NLRP3 inflammasome: Omega-3 fatty acid (DHA) prevents NLRP3
activation in human macrophages. Food & Function 7 (8):3480–7.
doi: 10.1039/c6fo00477f.
Mas, E., A. Barden, V. Burke, L. J. Beilin, G. F. Watts, R. C. Huang,
I. B. Puddey, A. B. Irish, and T. A. Mori. 2016. A randomized
controlled trial of the effects of n-3 fatty acids on resolvins in
chronic kidney disease. Clinical Nutrition (Edinburgh, Scotland) 35
(2):331–6. doi: 10.1016/j.clnu.2015.04.004.
Mastalerz, L., K. E. Tyrak, M. Ignacak, E. Konduracka, F. Mejza, A.
Ćmiel, M. Buczek, A. Kot, K. Oleś, and M. Sanak. 2019. Prostaglandin
E2 decrease in induced sputum of hypersensitive asthmatics during
oral challenge with aspirin. Allergy 74 (5):922–32. doi: 10.1111/
all.13671.
Mauricio, D., L. Meneghini, J. Seufert, L. Liao, H. Wang, L. Tong, A.
Cali, P. Stella, P. Carita, and K. Khunti. 2017. Glycaemic control
and hypoglycaemia burden in patients with type 2 diabetes initiat-
ing basal insulin in Europe and the USA. Diabetes, Obesity &
Metabolism 19 (8):1155–64. doi: 10.1111/dom.12927.
Mihaly, S. R., J. Ninomiya-Tsuji, and S. Morioka. 2014. TAK1 control
of cell death. Cell Death and Differentiation 21 (11):1667–76. doi:
10.1038/cdd.2014.123.
Mikroulis, A., M. Ledri, G. Ruffolo, E. Palma, G. Sperk, J. Dalli, A.
Vezzani, and M. Kokaia. 2022. Lipid mediator n-3 docosapentae-
noic acid-derived protectin D1 enhances synaptic inhibition of hip-
pocampal principal neurons by interaction with a G-protein-coupled
receptor. FASEB Journal: Official Publication of the Federation of
American Societies for Experimental Biology 36 (3):e22203. doi:
10.1096/fj.202101815R.
Miles, E. A., T. Banerjee, M. M. B. W. Dooper, L. M. Rabet, Y. M. F.
Graus, and P. C. Calder. 2004. The influence of different combina-
tions of g -linolenic acid, stearidonic acid and EPA on immune
function in healthy young male subjects. The British Journal of
Nutrition 91 (6):893–903. doi: 10.1079/BJN20041131.
Mo, Z., C. Tang, H. Li, J. Lei, L. Zhu, L. Kou, H. Li, S. Luo, C. Li,
W. Chen, et al. 2020. Eicosapentaenoic acid prevents inflammation
induced by acute cerebral infarction through inhibition of NLRP3
inflammasome activation. Life Sciences 242:117133. doi: 10.1016/j.
lfs.2019.117133.
Mortimer, L., F. Moreau, J. A. MacDonald, and K. Chadee. 2016.
NLRP3 inflammasome inhibition is disrupted in a group of
auto-inflammatory disease CAPS mutations. Nature Immunology 17
(10):1176–86. doi: 10.1038/ni.3538.
Moura-Assis, A., M. S. Afonso, V. de Oliveira, J. Morari, G. A. Dos
Santos, M. Koike, A. M. Lottenberg, R. Ramos Catharino, L. A.
Velloso, A. Sanchez Ramos da Silva, et al. 2018. Flaxseed oil rich
in omega-3 protects aorta against inflammation and endoplasmic
reticulum stress partially mediated by GPR120 receptor in obese,
diabetic and dyslipidemic mice models. The Journal of Nutritional
Biochemistry 53:9–19. doi: 10.1016/j.jnutbio.2017.09.015.
Mukherjee, P. K., V. L. Marcheselli, C. N. Serhan, and N. G. Bazan. 2004.
Neuroprotectin D1: A docosahexaenoic acid-derived docosatriene

­rotects human retinal pigment epithelial cells from oxidative stress.
p Raclot, T. 2003. Selective mobilization of fatty acids from adipose
Proceedings of the National Academy of Sciences of the United States of
America 101 (22):8491–6. doi: 10.1073/pnas.0402531101.
Naderali, E., M.-M. Naderali, and A.-R. Abubakari. 2014. Omega-3
fatty acid supplementation and cognitive function: Are smaller dos-
ages more beneficial? International Journal of General Medicine 7
(7):463–73. doi: 10.2147/IJGM.S67065.
Neuhofer, A., M. Zeyda, D. Mascher, B. K. Itariu, I. Murano, L. Leitner,
E. E. Hochbrugger, P. Fraisl, S. Cinti, C. N. Serhan, et al. 2013.
Impaired local production of proresolving lipid mediators in obe-
sity and 17-HDHA as a potential treatment for obesity-associated
inflammation. Diabetes 62 (6):1945–56. doi: 10.2337/db12-0828.
Nicholls, S. J., A. M. Lincoff, M. Garcia, D. Bash, C. M. Ballantyne,
P. J. Barter, M. H. Davidson, J. J. P. Kastelein, W. Koenig, D. K.
McGuire, et al. 2020. Effect of high-dose omega-3 fatty acids vs
corn oil on major adverse cardiovascular events in patients at high
cardiovascular risk: The STRENGTH randomized clinical trial. JAMA
324 (22):2268–80. doi: 10.1001/jama.2020.22258.
Ochiai, Y., Y. Uchida, S. Ohtsuki, M. Tachikawa, S. Aizawa, and T.
Terasaki. 2017. The blood-brain barrier fatty acid transport protein
1 (FATP1/SLC27A1) supplies docosahexaenoic acid to the brain,
and insulin facilitates transport. Journal of Neurochemistry 141
(3):400–12. doi: 10.1111/jnc.13943.
Oh, D. Y., S. Talukdar, E. J. Bae, T. Imamura, H. Morinaga, W. Fan,
P. Li, W. J. Lu, S. M. Watkins, and J. M. Olefsky. 2010. GPR120 Is
an omega-3 fatty acid receptor mediating potent anti-inflammatory
and insulin-sensitizing effects. Cell 142 (5):687–98. doi: 10.1016/j.
cell.2010.07.041.
Oliveira, V., R. Marinho, D. Vitorino, G. A. Santos, J. C. Moraes, N.
Dragano, A. Sartori-Cintra, L. Pereira, R. R. Catharino, A. S. R. da
Silva, et al. 2015. Diets containing α-linolenic (ω3) or oleic (ω9)
fatty acids rescues obese mice from insulin resistance. Endocrinology
156 (11):4033–46. doi: 10.1210/en.2014-1880.
Paschoal, V. A., E. Walenta, S. Talukdar, A. R. Pessentheiner, O.
Osborn, N. Hah, T. J. Chi, G. L. Tye, A. M. Armando, R. M. Evans,
et al. 2020. Positive reinforcing mechanisms between GPR120 and
PPARγ modulate insulin sensitivity. Cell Metabolism 31 (6):1173–88.
e5. doi: 10.1016/j.cmet.2020.04.020.
Payan, D. G., M. Y. Wong, T. Chernov-Rogan, F. H. Valone, W. C.
Pickett, V. A. Blake, W. M. Gold, and E. J. Goetzl. 1986. Alterations
in human leukocyte function induced by ingestion of eicosapentae-
noic acid. Journal of Clinical Immunology 6 (5):402–10. doi: 10.1007/
BF00915380.
Picklo, M. J, and E. J. Murphy. 2016. A high-fat, high-oleic diet, but
not a high-fat, saturated diet, reduces hepatic α-linolenic acid and
eicosapentaenoic acid content in mice. Lipids 51 (5):537–47. doi:
10.1007/s11745-015-4106-9.
Pishva, H., M. Amini, M. R. Eshraghian, S. Hosseini, and S. A.
Mahboob. 2012. Effects of EPA supplementation on plasma fatty
acids composition in hypertriglyceridemic subjects with FABP2 and
PPARα genotypes. Journal of Diabetes and Metabolic Disorders 11
(1):25. doi: 10.1186/2251-6581-11-25.
Polus, A., B. Zapala, U. Razny, A. Gielicz, B. Kiec-Wilk, M.
Malczewska-Malec, M. Sanak, C. E. Childs, P. C. Calder, and A.
Dembinska-Kiec. 2016. Omega-3 fatty acid supplementation influ-
ences the whole blood transcriptome in women with obesity, asso-
ciated with pro-resolving lipid mediator production. Biochimica et
Biophysica Acta 1861 (11):1746–55. doi: 10.1016/j.bbalip.2016.08.005.
Poreba, M., M. Mostowik, A. Siniarski, R. Golebiowska-Wiatrak, K. P.
Malinowski, M. Haberka, E. Konduracka, J. Nessler, A. Undas, and
G. Gajos. 2017. Treatment with high-dose n-3 PUFAs has no effect
on platelet function, coagulation, metabolic status or inflammation
in patients with atherosclerosis and type 2 diabetes. Cardiovascular
Diabetology 16 (1):50. doi: 10.1186/s12933-017-0523-9.
Quezada, N., I. Valencia, J. Torres, G. Maturana, J. Cerda, J. P. Arab,
J. J. Fuentes, C. Pinto, D. Turiel, and V. Cortés. 2021. Insulin re-
sistance and liver histopathology in metabolically unhealthy subjects
do not correlate with the hepatic abundance of NLRP3 inflam-
masome nor circulating IL-1β levels. BMJ Open Diabetes Research
& Care 9 (1):e001975. doi: 10.1136/bmjdrc-2020-001975.
Critical Reviews in Food Science and Nutrition 15
tissue triacylglycerols. Progress in Lipid Research 42 (4):257–88. doi:
10.1016/s0163-7827(02)00066-8.
Raptis, D. A., P. Limani, J. H. Jang, U. Ungethüm, C. Tschuor, R. Graf,
B. Humar, and P. A. Clavien. 2014. GPR120 on Kupffer cells me-
diates hepatoprotective effects of ω3-fatty acids. Journal of Hepatology
60 (3):625–32. doi: 10.1016/j.jhep.2013.11.006.
Risérus, U., D. Sprecher, T. Johnson, E. Olson, S. Hirschberg, A. Liu,
Z. Fang, P. Hegde, D. Richards, L. Sarov-Blat, et al. 2008. Activation
of peroxisome proliferator – activated receptor (PPAR)δ promotes
reversal of multiple metabolic abnormalities, reduces oxidative stress,
and increases fatty acid oxidation in moderately obese men. Diabetes
57 (2):332–9. doi: 10.2337/db07-1318.
Satoh, M., T. Tabuchi, T. Itoh, and M. Nakamura. 2014. NLRP3 in-
flammasome activation in coronary artery disease: Results from
prospective and randomized study of treatment with atorvastatin
or rosuvastatin. Clinical Science 126 (3):233–41. doi: 10.1042/
CS20130043.
Schulze, M. B., A. M. Minihane, R. N. M. Saleh, and U. Risérus. 2020.
Intake and metabolism of omega-3 and omega-6 polyunsaturated
fatty acids: Nutritional implications for cardiometabolic diseases.
The Lancet. Diabetes & Endocrinology 8 (11):915–30. doi: 10.1016/
S2213-8587(20)30148-0.
Serhan, C. N. 2017. Treating inflammation and infection in the 21st
century: New hints from decoding resolution mediators and mech-
anisms. FASEB Journal: Official Publication of the Federation of
American Societies for Experimental Biology 31 (4):1273–88. doi:
10.1096/fj.201601222R.
Serhan, C. N., S. Hong, K. Gronert, S. P. Colgan, P. R. Devchand, G.
Mirick, and R. L. Moussignac. 2002. Resolvins: A family of bioac-
tive products of omega-3 fatty acid transformation circuits initiated
by aspirin treatment that counter proinflammation signals. The
Journal of Experimental Medicine 196 (8):1025–37. doi: 10.1084/
jem.20020760.
Serhan, C. N., R. Yang, K. Martinod, K. Kasuga, P. S. Pillai, T. F.
Porter, S. F. Oh, and M. Spite. 2009. Maresins: Novel macrophage
mediators with potent antiinflammatory and proresolving actions.
The Journal of Experimental Medicine 206 (1):15–23. doi: 10.1084/
jem.20081880.
Shen, L., Y. Yang, T. Ou, C. C. Key, S. H. Tong, R. C. Sequeira, J. M.
Nelson, Y. Nie, Z. Wang, E. Boudyguina, et al. 2017. Dietary PUFAs
attenuate NLRP3 inflammasome activation via enhancing macro-
phage autophagy. Journal of Lipid Research 58 (9):1808–21. doi:
10.1194/jlr.M075879.
Shi, C. S, and J. H. Kehrl. 2010. TRAF6 and A20 regulate lysine
63-linked ubiquitination of Beclin-1 to control TLR4-induced au-
tophagy. Science Signaling 3 (123):ra42. doi: 10.1126/scisig-
nal.2000751.
Simopoulos, A. P. 2016. An increase in the omega-6/omega-3 fatty
acid ratio increases the risk for obesity. Nutrients 8 (3):128. doi:
10.3390/nu8030128.
Sinclair, A. J., X. F. Guo, and L. Abedin. 2022. Dietary Alpha-Linolenic
Acid Supports High Retinal DHA Levels. Nutrients 14 (2):301. doi:
10.3390/nu14020301.
Singer, P., W. Jaeger, I. Berger, H. Barleben, M. Wirth, E.
Richter-Heinrich, S. Voigt, and W. Gödicke. 1990. Effects of dietary
oleic, linoleic, and α-linolenic acids on blood pressure, serum lipids,
lipoproteins and the formation of eicosanoid precursors in patients
with mild essential hypertension. Journal of Human Hypertension 4
(3):227–33.
Sinha, S., G. Perdomo, N. F. Brown, and R. M. O’Doherty. 2004. Fatty
acid-induced insulin resistance in L6 myotubes is prevented by
inhibition of activation and nuclear localization of nuclear factor
κB. The Journal of Biological Chemistry 279 (40):41294–301. doi:
10.1074/jbc.M406514200.
Spencer, M., B. S. Finlin, R. Unal, B. Zhu, A. J. Morris, L. R. Shipp,
J. Lee, R. G. Walton, A. Adu, R. Erfani, et al. 2013. Omega-3 fatty
acids reduce adipose tissue macrophages in human subjects with
insulin resistance. Diabetes 62 (5):1709–17. doi: 10.2337/db12-1042.
16 E. DA SILVA BATISTA ET AL.
Stivala, S., S. Gobbato, N. Bonetti, G. G. Camici, T. F. Lüscher, and
J. H. Beer. 2022. Dietary alpha‐linolenic acid reduces platelet acti-
vation and collagen‐mediated cell adhesion in sickle cell disease
mice. Journal of Thrombosis and Haemostasis: JTH 20 (2):375–86.
doi: 10.1111/jth.15581.
Su, H. M., L. Bernardo, M. Mirmiran, X. H. Ma, T. N. Corso, P. W.
Nathanielsz, and J. T. Brenna. 1999. Bioequivalence of dietary
α-linolenic and docosahexaenoic acids as sources of docosahexaenoate
accretion in brain and associated organs of neonatal baboons. Pediatric
Research 45 (1):87–93. doi: 10.1203/00006450-199901000-00015.
Sutter, A. G., A. P. Palanisamy, J. H. Lench, S. Esckilsen, T. Geng, D.
N. Lewin, L. A. Cowart, and K. D. Chavin. 2016. Dietary saturat-
ed fat promotes development of hepatic inflammation through
toll-like receptor 4 in mice. Journal of Cellular Biochemistry 117
(7):1613–21. doi: 10.1002/jcb.25453.
Park, S. W., M. W. Sung, D. S. Heo, H. Inoue, S. H. Shim, and K. H.
Kim. 2005. Nitric oxide upregulates the cyclooxygenase-2 expression
through the cAMP-response element in its promoter in several
cancer cell lines. Oncogene 24 (44):6689–98. doi: 10.1038/sj.
onc.1208816.
Tanaka, H., F. Soga, K. Tatsumi, Y. Mochizuki, H. Sano, H. Toki, K.
Matsumoto, J. Shite, H. Takaoka, T. Doi, et al. 2020. Positive effect
of dapagliflozin on left ventricular longitudinal function for type 2
diabetic mellitus patients with chronic heart failure. Cardiovascular
Diabetology 19 (1):6. doi: 10.1186/s12933-019-0985-z.
Tashjian, A. H., E. F. Voelkel, D. R. Robinson, and L. Levine. 1984.
Dietary menhaden oil lowers plasma prostaglandins and calcium in
mice bearing the prostaglandin-producing HSDM1 fibrosarcoma.
The Journal of Clinical Investigation 74 (6):2042–8. doi: 10.1172/
JCI111627.
Udipi, S., S. Karandikar, R. Mukherjee, S. Agarwal, and P. Ghugre. 2006.
Variations in fat and fatty acid intakes of adult males from three
regions of India. Indian Journal of Public Health 50 (3):179–86.
Unamuno, X., J. Gómez-Ambrosi, B. Ramírez, A. Rodríguez, S. Becerril,
V. Valentí, R. Moncada, C. Silva, J. Salvador, G. Frühbeck, et al. 2021.
NLRP3 inflammasome blockade reduces adipose tissue inflammation
and extracellular matrix remodeling. Cellular & Molecular Immunology
18 (4):1045–57. doi: 10.1038/s41423-019-0296-z.
Vandanmagsar, B., Y. H. Youm, A. Ravussin, J. E. Galgani, K. Stadler,
R. L. Mynatt, E. Ravussin, J. M. Stephens, and V. D. Dixit. 2011.
The NLRP3 inflammasome instigates obesity-induced inflammation
and insulin resistance. Nature Medicine 17 (2):179–88. doi: 10.1038/
nm.2279.
Vegiopoulos, A., M. Rohm, and S. Herzig. 2017. Adipose tissue:
Between the extremes. The EMBO Journal 36 (14):1999–2017. doi:
10.15252/embj.201696206.
Wang, B., X. Gong, J. Y. Wan, L. Zhang, Z. Zhang, H. Z. Li, and S.
Min. 2011. Resolvin D1 protects mice from LPS-induced acute lung
injury. Pulmonary Pharmacology & Therapeutics 24 (4):434–41. doi:
10.1016/j.pupt.2011.04.001.
Williams-Bey, Y., C. Boularan, A. Vural, N. N. Huang, I. Y. Hwang,
C. Shan-Shi, and J. H. Kehrl. 2014. Omega-3 free fatty acids suppress
macrophage inflammasome activation by inhibiting NF-κB activation
and enhancing autophagy. PloS One 9 (6):e97957. doi: 10.1371/
journal.pone.0097957.
Wree, A., M. D. McGeough, C. A. Peña, M. Schlattjan, H. Li, M. E.
Inzaugarat, K. Messer, A. Canbay, H. M. Hoffman, and A. E.
Feldstein. 2014. NLRP3 inflammasome activation is required for
fibrosis development in NAFLD. Journal of Molecular Medicine
(Berlin, Germany) 92 (10):1069–82. doi: 10.1007/s00109-014-1170-1.
Wu, C. T., K. I. Hilgendorf, R. J. Bevacqua, Y. Hang, J. Demeter, S.
K. Kim, and P. K. Jackson. 2021. Discovery of ciliary G
protein-coupled receptors regulating pancreatic islet insulin and
glucagon secretion. Genes & Development 35 (17–18):1243–55. doi:
10.1101/gad.348261.121.
Yamada, H., E. Oshiro, S. Kikuchi, M. Hakozaki, H. Takahashi, and
K. I. Kimura. 2014. Hydroxyeicosapentaenoic acids from the Pacific
krill show high ligand activities for PPARs. Journal of Lipid Research
55 (5):895–904. doi: 10.1194/jlr.M047514.
Yan, Y., W. Jiang, T. Spinetti, A. Tardivel, R. Castillo, C. Bourquin, G.
Guarda, Z. Tian, J. Tschopp, and R. Zhou. 2013. Omega-3 fatty
acids prevent inflammation and metabolic disorder through inhibi-
tion of NLRP3 inflammasome activation. Immunity 38 (6):1154–63.
doi: 10.1016/j.immuni.2013.05.015.
Yang, R. H., J. Lin, X. H. Hou, R. Cao, F. Yu, H. Q. Liu, A. L. Ji, X.
N. Xu, L. Zhang, and F. Wang. 2014. Effect of docosahexaenoic acid
on hippocampal neurons in high-glucose condition: Involvement of
PI3K/AKT/nuclear factor-κB-mediated inflammatory pathways.
Neuroscience 274:218–28. doi: 10.1016/j.neuroscience.2014.05.042.
Yip, P. K., C. Pizzasegola, S. Gladman, M. L. Biggio, M. Marino, M.
Jayasinghe, F. Ullah, S. C. Dyall, A. Malaspina, C. Bendotti, et al.
2013. The omega-3 fatty acid eicosapentaenoic acid accelerates dis-
ease progression in a model of amyotrophic lateral sclerosis. PLoS
One 8 (4):e61626. doi: 10.1371/journal.pone.0061626.
Yokoyama, M., H. Origasa, M. Matsuzaki, Y. Matsuzawa, Y. Saito, Y.
Ishikawa, S. Oikawa, J. Sasaki, H. Hishida, H. Itakura, et al. 2007.
Effects of eicosapentaenoic acid on major coronary events in hy-
percholesterolaemic patients (JELIS): A randomised open-label,
blinded endpoint analysis. Lancet (London, England) 369 (9567):1090–
8. doi: 10.1016/S0140-6736(07)60527-3.
Yu, D., M. Zou, Q. Pan, Y. Song, M. Li, X. Zhang, Y. Zhou, X. Wang,
and L. Guo. 2022. Effects of liraglutide or lifestyle interventions
combined with other antidiabetic drugs on abdominal fat distribu-
tion in people with obesity and type 2 diabetes mellitus evaluated
by the energy spectrum ct: A prospective randomized controlled
study. Frontier Endocrinology 13:951570.
Zhang, J. Y., K. S. D. Kothapalli, and J. T. Brenna. 2016. Desaturase
and elongase-limiting endogenous long-chain polyunsaturated fatty
acid biosynthesis. Current Opinion Clinical. Nutrition Metabolism
Care 19 (2):103–10.
Zhao, N., L. Wang, and N. Guo. 2016. α-Linolenic acid increases the
G0/G1 switch gene 2 mRNA expression in peripheral blood mono-
nuclear cells from obese patients: A pilot study. Lipids in Health
and Disease 15:36. doi: 10.1186/s12944-016-0207-6.