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Role of fish oil in human health and possible mechanism to reduce the
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Role of fish oil in human health and
possible mechanism to reduce the
inflammation

Mohammed S. Ellulu, Huzwah Khaza’ai,

Yehia Abed, Asmah Rahmat, Patimah
Ismail & Yazan Ranneh

Inflammopharmacology
Experimental and Therapeutic Studies

ISSN 0925-4692

Inflammopharmacol
DOI 10.1007/s10787-015-0228-1

1 23
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 Author's personal copy
Inflammopharmacol
DOI 10.1007/s10787-015-0228-1
REVIEW
Role of fish oil in human health and possible mechanism to reduce
the inflammation
Mohammed S. Ellulu • Huzwah Khaza’ai •
Yehia Abed • Asmah Rahmat •
Patimah Ismail • Yazan Ranneh
Received: 29 November 2014 / Accepted: 20 January 2015
Ó Springer Basel 2015
Abstract The roles of Omega-3 FAs are inflammation
antagonists, while Omega-6 FAs are precursors for in-
flammation. The plant form of Omega-3 FAs is the short-
chain a-linolenic acid, and the marine forms are the long-
chain fatty acids: docosahexaenoic acid and eicosapen-
taenoic acid. Omega-3 FAs have unlimited usages, and
they are considered as omnipotent since they may benefit
heart health, improve brain function, reduce cancer risks
and improve people’s moods. Omega-3 FAs also have
several important biological effects on a range of cellular
functions that may decrease the onset of heart diseases and
reduce mortality among patients with coronary heart dis-
ease, possibly by stabilizing the heart’s rhythm and by
reducing blood clotting. Some review studies have de-
scribed the beneficial roles of Omega-3 FAs in
cardiovascular diseases (CVDs), cancer, diabetes, and
other conditions, including inflammation. Studies of the
effect of Omega-3 FAs gathered from studies in diseased
and healthy population. CVDs including atherosclerosis,
coronary heart diseases, hypertension, and metabolic syn-
drome were the major fields of investigation. In studies of
obesity, as the central obesity increased, the level of adi-
pocyte synthesis of pro-inflammatory cytokines like tumor
M. S. Ellulu (&)
A. Rahmat
Y. Ranneh
Department of Nutrition and Dietetics, Faculty of Medicine
and Health Sciences, Universiti Putra Malaysia,
43400 Serdang, Selangor, Malaysia
e-mail: mohdsubhilulu@gmail.com
H. Khaza’ai
P. Ismail
Department of Biomedical Science, Faculty of Medicine
and Health Sciences, Universiti Putra Malaysia,
43400 Serdang, Selangor, Malaysia
Y. Abed
Faculty of Public Health, Al Quds University, Gaza, Palestine
Inflammopharmacology
necrosis factor alpha (TNF-a) and interleukin 6 (IL-6) were
increased and the level of anti-inflammatory adiponectin
was decreased indicating a state of inflammation. The level
of C reactive protein (CRP) synthesized from hepatocyte is
increased by the influence of IL-6. CRP can be considered
as a marker of systemic inflammation associated with in-
creased risks of CVDs. In molecular studies, Omega-3 FAs
have direct effects on reducing the inflammatory state by
reducing IL-6, TNF-a, CRP and many other factors. While
the appropriate dosage along with the administrative du-
ration is not known, the scientific evidence-based
recommendations for daily intake are not modified.
Keywords Omega-3 fatty acids

Polyunsaturated fatty acids
Inflammation
Mechanism

Metabolic syndrome
Obesity
Cardiovascular diseases

Cancer
Interleukin 6
C reactive protein
Introduction
Omega-3 fatty acids are dietary essentials of polyun-
saturated fatty acids (PUFAs) (Simopoulos 2002). The
plant form of Omega-3 FAs is a short-chain fatty acid a-
linolenic acid obtained from plant oil, including leafy
vegetables, walnuts, soy bean oil, canola oil and flaxseed
oil (Jenkins and Josse 2008). The marine forms of Omega-
3 FAs are the long-chain fatty acids: docosahexaenoic acid
(DHA) and eicosapentaenoic acid (EPA) and they obtained
from seafood, fishes and algae (Brenna et al. 2009).
Chemically, fatty acids are hydrocarbon chains with a
carboxyl (–COOH) at one end and a methyl group (–CH3)
at the other. Fatty acids vary in length, degree of un-
saturation (Stryer 1995), and location of double bonds
(Lichtenstein and Jones 2001). Fatty acids in which the first
123
 Author's personal copy
double bonds occur three carbons from methyl end are
called Omega-3 FAs and are symbolized as (x-3 or n-3)
fatty acids (Lichtenstein and Jones 2001).
Omega-3 FAs are considered important fatty acids, be-
cause they are vital for normal metabolism (Benatti et al.
2004). DHA, the most abundant Omega-3 FAs in most
tissues, is in higher concentration in the myocardium,
retina, and brain, and is essential for proper functioning of
these tissues and growth (Jump 2002; Lee and Lip 2003).
Different classes of lipids in the body contain Omega-3
FAs. For instance, EPA is found in cholesterol esters,
triglycerides, and phospholipids, whereas DHA is existed
mostly in phospholipids (Simopoulos 1991).
The human body can convert about 5 % of a-linolenic
acid to EPA; the blood level of EPA is not witnessed to be
raised during the consumption of a-linolenic acid (Jenkins
and Josse 2008) because humans lack the D12- and D15-
desaturases enzymes necessary to insert a double bond at the
Omega-3 of an FA carbon chain (Adkins and Kelley 2010).
The dietary intake of Omega-3 FAs in the recent report of the
Food and Agriculture Organization (FAO) has recom-
mended a dose of 0.250 gm/day of EPA plus DHA for adult
males and non-pregnant/non-lactating adult females, but
with insufficient evidence to set a specific minimum intake of
either EPA or DHA alone (FAO/WHO 2010). The upper
value of acceptable macronutrient distribution range for EPA
plus DHA consumption has been set at 2 gm/day due to
experimental evidence indicating that high supplement in-
takes of Omega-3 FAs could increase lipid peroxidation and
reduce cytokine production (Rangel-Huerta et al. 2012).
Currently, Omega-3 FAs may have unlimited usages for
the treatment of different diseases, which could be consid-
ered as omnipotent since they may benefit heart health, brain
function, reduce some cancer risk, and improve people’s
moods. Omega-3 FAs have several important biological ef-
fects on a range of cellular functions that may reduce the
onset of heart diseases and reduce mortality among patients
with coronary heart disease, possibly by stabilizing the
heart’s rhythm and by reducing blood clotting (Jenkins and
Josse 2008). In animal short-term clinical trials, increased
intake of fish oil improves multiple indexes of hemodynamic
and cardiac function, including blood pressure, systemic
vascular resistance, and myocardial efficiency (Peoples et al.
2008), and provides antifibrotic and anti-inflammatory ef-
fects that could decrease long-term atrial remodeling (Duda
et al. 2009; Nodari et al. 2011).
Reviews
Many researchers reviewed studies that linked Omega-3
FAs with health conditions or specific diseases; they
demonstrated outstanding results for many conditions. The
123
M. S. Ellulu et al.
most important reviews are related to the cardiovascular
diseases (CVDs). The major data about the effect of
Omega-3 FAs have collected from randomized controlled
trials (RCTs) and cohort intervention or assessment, where
the objective criteria in selecting subjects evaluated indi-
vidually (Hooper et al. 2006).
Cardiovascular diseases
The strongest and most established body of science for the
marine Omega-3 FAs is in relation to cardiovascular
health. In addition to a lower risk of cardiovascular disease
(CVD) risk, research has also linked Omega-3 FAs to
improved heart rhythms, and a reduced risk of a second
heart attack (O’Keefe et al. 2006). Review of Omega-3
FAs does have cardiovascular benefits such as improved
vascular tone, heart rate, blood lipid levels, blood pressure,
and reduced hardening of the arteries (Stark et al. 2008).
The protection against CVD was assumed by lowering
blood pressure and heart rate, reducing serum triglycerides,
thrombotic tendency, inflammation, and arrhythmias, and
improving endothelial function, insulin sensitivity,
paraoxonase concentrations, and plaque stability (Bhatna-
gar and Durrington 2003; Thies et al. 2003, Geelen et al.
2004; Din et al. 2004). In the following review studies,
Omega-3 FAs linked to CVDs and some of them have
assumed the significant relationship while others did not
detect the relation.
Rizos et al. (2012) reviewed 20 studies, reporting cases
of deaths, cardiac deaths, sudden deaths, myocardial in-
farctions, and strokes. A statistically significant association
was not observed with all-cause mortality when all sup-
plement studies were considered. Overall conclusion,
PUFA supplementation was not associated with a lower
risk of all-cause mortality, cardiac death, sudden death,
myocardial infarction, or stroke based on relative and ab-
solute measures of association.
Chowdhury et al. (2012) reviewed 26 prospective cohort
studies and 12 RCTs with aggregate data on non-overlap-
ping people and cerebrovascular outcomes were included.
They indicated moderate, inverse associations of fish
consumption and Omega-3 FAs with cerebrovascular risk.
Through cohort studies, the pooled relative risk (RR) for
cerebrovascular disease for 2–4 servings a week versus B1
servings a week was 0.94 (95 % CI 0.90–0.98) and for C5
servings a week versus 1 serving a week was 0.88 (95 % CI
0.81–0.96). In the RCTs, the RR for cerebrovascular dis-
ease in Omega-3 FAs supplement compared with the
control group in primary prevention trials was 0.98 (95 %
CI 0.89–1.08) and in secondary prevention trials was 1.17
(95 % CI 0.99–1.38).
Delgado-Lista et al. (2012) concluded that Omega-3 FAs
are effective in reducing risks and preventing cardiovascular
 Author's personal copy
Role of fish oil in human health
events, cardiac death and coronary events, especially in
persons with high cardiovascular risk. Among 21 of the 452
pre-selected studies, they found an overall decrease in risk of
suffering a cardiovascular event of any kind of 10 %
OR = 0.90 (95 % CI 0.85–0.96, P \ 0.001), a 9 % decrease
in risk of cardiac death OR = 0.91 (95 % CI 0.83–0.99,
P \ 0.03), a decrease in coronary events (fatal and non-fatal)
of 18 % OR = 0.82 (95 % CI 0.75–0.90, P \ 0.001), and a
trend to lower total mortality 5 % reduction of risk;
OR = 0.95 (95 % CI 0.89–1.02, P \ 0.15).
Marik and Varon (2009) reviewed 11 RCTs’ studies in-
cluded patients after recent myocardial infarction, those with
an implanted cardioverter defibrillator, and patients with
heart failure, peripheral vascular disease, and hypercholes-
terolemia. The average dose of EPA/DHA was 1.8 ± 1.2
gm/day and the mean duration of follow-up was
2.2 ± 1.2 years. This meta-analysis demonstrates that di-
etary supplementation with fish oil Omega-3 FAs for a year
or longer significantly reduces the risk of cardiovascular
deaths, sudden cardiac death, all-cause mortality, and non-
fatal cardiovascular events. The benefit appeared to depend
on the patient’s risk stratification with a reduction in deaths in
high-risk patients and a reduction in nonfatal cardiovascular
events in moderate risk patients. This observation likely re-
flects the fact that the number of deaths in the moderate risk
group was very low, while these patients are at a higher risk
of developing nonfatal cardiovascular events related to
progressive atherosclerotic disease.
Hooper et al. (2006) reviewed 18 RCTs provided data
on cardiovascular events. The meta-analysis showed no
definite effect of Omega-3 FAs on cardiovascular events,
but confidence intervals were wide (0.95 % CI 0.82–1.12)
and inconsistency was high (I2 = 65 %). Removing studies
at moderate or high risk of bias reduced but did not remove
inconsistency (1.09, 0.87–1.37; 570 events; I2 = 49 %).
Cohort studies also provided no strong evidence that
Omega-3 FAs protect against cardiovascular events.
Type-2 diabetes
Wu et al. (2012) collected 16 studies based on objective cri-
teria, including cohorts comprising individuals and cases of
incident DM. The inclusion criteria depended on evaluating
the circulating PUFAs after dietary intake and relating the
condition with incidence of DM. The overall pooled findings
did not support either major harms or benefits of fish/seafood
or EPA ? DHA on development of DM, and suggest that
ALA may be associated with modestly lower risk.
Cancer
Levels of EPA influence many physiological processes, in-
cluding calcium transport across cell membranes,
angiogenesis, apoptosis, cell proliferation, and immune cell
function (Johnson 2002). These processes are integral to the
immune system and hence the pathogenesis of autoimmune
diseases such as arthritis, systemic lupus erythematous, and
asthma, as well as cancer. Epidemiological studies have
suggested that groups of people who consume diets high in
Omega-3 FAs may experience a lower prevalence of some
types of cancer (Takezaki et al. 2003).
Gerber (2012) designed a systemic review to determine
whether there exists any progress in the evaluation of the
causal relationship between dietary PUFAs and cancers
since the previous FAO/OMS expert consultation and
whether it is possible to propose preventive and/or adjuvant
therapeutic recommendations. The review concluded
prospective and case–control observational studies in ad-
dition to RCTs. Observational studies on colorectal,
prostate and breast cancers only provided limited evidence
suggesting a possible role of PUFAs in cancer prevention
because of insufficient homogeneity of the observations.
The role of PUFAs as adjuvant might be considered of
possible use, in view of the RCT on lung cancers.
MacLean et al. (2006) designed a systematic review study
to review the effect of Omega-3 FAs on cancer incidence and
treatment. Study gathered different types of cancer studies like
lung, colorectal, breast, bladder, ovarian, pancreatic, and
prostate cancers. Studies of breast cancer demonstrated major
lack of relationship with PUFAs either from dietary sources or
supplementation, 7 estimates did not have a significant asso-
ciation, 3 were for decreased risk RR (0.68–0.72) and one for
increasing the incidence RR (1.47, 95 % CI 1.10–1.98).
Studies of colorectal cancer identified just one study that de-
creased risk RR (0.49, 95 % CI 0.27–0.89) and 17 estimated
without association. Regarding lung cancer, in one study, fish
consumption was associated with a reduced risk of lung cancer
RR (0.32, 95 % CI 0.13–0.76), in another study, fish con-
sumption was associated with an increased risk of lung cancer
RR (3.0, 95 % CI 1.2–7.3). In other 4 studies, no significant
association was found between fish intake and lung cancer
incidence or death from lung cancer. For other types of cancer,
similar results showed no association between intake of
PUFAs either from dietary sources or supplements with
pancreatic, bladder, ovarian and prostatic cancers.
Hooper et al. (2006) have also reviewed 10 RCTs re-
lated to incidence of cancer; 391 diagnoses of cancer or
death from cancer occurred in 17,433 participants. They
found no evidence that Omega-3 FAs had an effect on the
incidence of cancer (1.07: 0.88–1.30) and there was no
inconsistency (I2 = 0 %). 5 trials and seven events re-
mained on sensitivity analysis. Seven cohort studies
provided data on cancer (832 events in the highest and
lowest quantiles), and meta-analysis found no effect of
high versus low intake of Omega-3 FAs (1.02: 0.87–1.19;
I2 = 21 %).
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M. S. Ellulu et al.

Depression control treatment, which were included. Beneficial changes

By year of 2020, depressive disorder will be the second
leading cause of disability worldwide and first in devel-
oping countries based on World Health Organization
(WHO) report (Murray and Lopez 1997). Based on the
epidemiologic studies, societies with a high consumption
of fish, which contains high amounts of PUFAs, appear to
have a lower prevalence of major depressive disorder
(Tanskanen et al. 2001).
Lin and Su (2007) selected ten double-blind placebo-
controlled studies in patients with mood disorders receiv-
ing Omega-3 PUFAs with the treatment period lasting
4 weeks or longer which were included. After pooling the
results of the included studies (329 participants), the re-
searchers found a significant antidepressant effect of
Omega-3 FAs. Likewise, they significantly improved de-
pression in patients with clearly defined depression or with
bipolar disorder.
Non-alcoholic fatty liver disease
Non-alcoholic fatty liver disease (NAFLD) is characterized
by increased hepatic fat accumulation in individuals not
consuming excessive alcohol and represents a spectrum of
disease ranging from simple steatosis to non-alcoholic
steatohepatitis (Sanyal et al. 2010). In Western populations,
the prevalence of NAFLD may exceed 30 % (Browning
et al. 2004) and can be as high as 88 % in the obese
(Angulo 2007). NAFLD is independently associated with
coronary heart disease (Targher and Arcaro 2007) insulin
resistance (Chitturi et al. 2002) and type II diabetes (Yu-
nianingtias and Volker 2006).
Parker et al. (2012) gathered data from 9 eligible stud-
ies, involving 355 individuals given either Omega-3 FAs or
in liver fat favoured Omega-3 FAs treatment. A benefit of
Omega-3 FAs compared to control was also observed for
aspartate aminotransferase (AST). There was a trend to-
wards favouring Omega-3 FAs treatment on alanine
aminotransferase (ALT) but this was not significant. Sub-
analyses of only RCTs showed a significant benefit for
Omega-3 FAs compared to control on liver fat, but not for
ALT or AST. The pooled data suggest that Omega-3 FAs
supplementation may decrease liver fat; however, the op-
timal dose is currently not known.
Inflammation
Rangel-Huerta et al. (2012) reviewed 26 RCTs interested on
supplementing Omega-3 FAs over 10 years; 10 of them
implemented on healthy and others for chronic diseases
participants. The gathered studies used placebo or control
groups. RCTs with prospective, parallel or crossover de-
signs were all considered. In the studies of healthy
participants selected in this review, Omega-3 supplemen-
tation generally had no effect on inflammatory biomarkers,
which may be due to low level in serum. Among CVDs
patients, the evidence of clinical efficacy was not strong
enough to make final recommendations for a specific dose
or duration of supplementation, but the level of CRP and IL-
6 was affected significantly after 12 weeks of supplement
intake. The other factors did not affect by supplementation
like TNF-a. In acute disease like severe acute pancreatitis,
the combined Omega-3 FAs with antibiotic had sig-
nificantly lower inflammatory marker CRP than patients
who took antibiotic only after 5 days of intervention.
Based on the above selected review studies, Table 1
summarizes the conclusions of the reviews on the asso-
ciation of Omega-3 FAs and diseases which ranged from

Table 1 Influence of Omega-3 FAs in health conditions based on review studies

Authors Type of study Condition of interest Effect of Omega-3 FAs
Improve Not improve

Rizos et al. (2012) Review CVD H

Chowdhury et al. (2012) Review Cerebrovascular disease H
Delgado-Lista et al. (2012) Review High risk CVD H
Marik and Varon (2009) Review CVD H
Hooper et al. (2006) Review CVD H
Wu et al. (2012) Review Type-2 DM H
Gerber (2012) Review Cancer H
MacLean et al. (2006) Review Cancer H
Hooper et al. (2006) Review Cancer H
Lin and Su (2007) Review Depressive disorder H
Parker et al. (2012) Review Liver disease H
Rangel-Huerta et al. (2012) Review Inflammation H

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 Author's personal copy
Role of fish oil in human health
chronic to severe conditions. The selection of the past
diseases depended on the literatures linked them directly or
indirectly to inflammatory status. In fact, there are many
diseases have linked to inflammation, but the selected cases
are the major in causing disabilities and death worldwide.
Table 1 shows the controversial effect of Omega-3 FAs
through RCTs or cohorts of dietary consumption or
supplementation.
Role of Omega-3 FAs on inflammation
Inflammation is an ordered sequelae of events engineered
to maintain tissue and organ homeostasis. The timely re-
lease of mediators and expression of receptors are essential
to complete the program and restore tissues and integrum.
Inflammation is characterized by redness, swelling, heat,
pain and numerous physiological changes, including in-
creased blood flow and permeability across blood
capillaries (Romano 2008). There are two types of in-
flammation, the first is acute inflammation which lasts for
short time and characterized by edema and migration of
leukocytes, and the second one is the chronic inflammation
which lasts for long time and characterized by the presence
of lymphocytes and macrophages and the proliferation of
blood vessels and connective tissue (Seki et al. 2009). A
preclinical animal experiment reported that erythrocyte
DHA was inversely correlated, and arachidonic acid AA
and the AA/DHA and AA/EPA ratios were positively
correlated with plasma IL-6, TNFa, and CRP levels
(McNamara et al. 2010). In Table 2, gathered studies of
RCTs and other methodologies showed the effects of
Omega-3 FAs on inflammation among healthy and dis-
eased population for many aged groups.
Relation of metabolic syndrome and obesity
with inflammation
Metabolic syndrome is identified as a condition of in-
creased risk for cardiovascular disease (CVD) and type 2
DM in both sexes. Subjects with metabolic syndrome have
three times risk of suffering a heart attack or stroke, twice
of dying from such an event, and fivefold greater risk of
developing type 2 DM when compared to people without
the metabolic syndrome (Stern et al. 2004). Overweight
and obesity progress to metabolic syndrome through
pathophysiological mechanisms at the moment which are
largely unclear. It has been hypothesized that the state of
chronic low-grade inflammation associated with excess
adipose tissue may explain the development of the obesity-
related pathologies, such as type 2 DM and CVD
(Medzhitov 2008). Furthermore, it plays an important role
in the development of insulin resistance that triggers the
associated comorbidities of metabolic syndrome, such as
atherosclerosis, dyslipidemia, hypertension, prothrombotic
state, and hyperglycemia (Boura-Halfon and Zick 2009).
The link between obesity and inflammation has been
derived from the finding that pro-inflammatory cytokines
are overexpressed in obesity (Hotamisligil et al. 1993).
Adipose tissue is a heterogeneous mix of adipocytes, stro-
mal preadipocytes, immune cells, and endothelium, and it
can respond rapidly and dynamically to alterations in nu-
trient excess through adipocyte hypertrophy and
hyperplasia (Halberg et al. 2008). With obesity and pro-
gressive adipocyte enlargement, the blood supply to
adipocytes may be reduced with consequent hypoxia (Cinti
et al. 2005). Hypoxia has been proposed to be an inciting
etiology of necrosis and macrophage infiltration into adi-
pose tissue that leads to overproduction of proinflammatory
factors like inflammatory chemokines. This results in a lo-
calized inflammation in adipose tissue that propagates an
overall systemic inflammation associated with the devel-
opment of obesity-related comorbidities (Trayhurn and
Wood 2004). Among inflammatory chemokines, three were
produced by macrophages: tumor necrosis factor-alpha
(TNF-a), interleukin-6 (IL-6), and adiponectin (Karaster-
giou and Mohamed-Ali 2010).
The factor of concern in this review is IL-6. The primary
source of circulating IL-6 is macrophages that have infil-
trated WAT; IL-6 has an important role in the regulation of
whole-body energy homeostasis and inflammation. Both
in vitro and in vivo studies have confirmed that IL-6 is
capable of suppressing lipoprotein lipase activity. IL-6
receptor is also expressed in several regions of the brain,
such as the hypothalamus, in which it controls appetite and
energy intake (Stenlof et al. 2003). Figure 1 explained by
Emanuela et al. (2012) describes the mechanism linking
abdominal obesity with metabolic syndrome via inflam-
matory process.
Interrelationship between CRP and IL-6
The level of C reactive protein is synthesized and secreted
primarily in human hepatocytes and is regulated mainly by
(IL-6) and (IL-1) (Zhang et al. 2009). The induction of IL-6
and IL-1b could be inhibited by the farnesoid X receptor
(FXR; NR1H4). FXR is a member of the nuclear hormone
receptor superfamily that functions as a ligand-activated
transcription factor and is highly expressed in the liver,
intestine, kidney and adrenal glands (Forman et al. 1995).
FXR regulates many genes involved in bile acid synthesis,
lipid and lipoprotein metabolism (Rader 2007). FXR can be
activated by physiological concentrations of bile acids
(Makishima et al. 1999), or by potent synthetic FXR li-
gands including GW4064, 6a-ethyl-chenodeoxycholic acid
123

Table 2 Effect of Omega-3 FAs in inflammation
Authors/country
Apparently healthy
Itariu et al. (2012) Austria
Kiecolt-Glaser et al. (2012) USA
Makhoul et al. (2011) Alaskan Eskimos 330 Obese adults, in a cross-sectional study.
Skulas-Ray et al. (2011)
Pot et al. (2009) Netherlands
Bouwens et al. (2009) Netherlands
Micallef et al. (2009) Australia
Cardiovascular diseases
Yusof et al. (2013) UK
Zhao et al. (2009) China
123
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M. S. Ellulu et al.
Study information Outcome
55 adults at Open-label RCT; severely obese PUFAs decreased the gene expression of the
non-diabetic patients underwent elective most analyzed inflammatory genes in
bariatric surgery. 27 selected to have 3.36 gm. subcutaneous adipose tissue (P \ 0.05) and
Daily of PUFAs for 8 weeks before the increased production of anti-inflammatory
surgery and 28 selected to be control with eicosanoids in visceral subcutaneous adipose
equivalent butterfat intake tissue (P \ 0.05)
138 healthy middle-aged and older adults who Serum interleukin-6 decreased by 10 % and
were sedentary and overweight, three-arm 12 % in low and high dose Omega-3 groups,
randomized, placebo-controlled, double-blind respectively, compared to a 36 % increase in
4-month trial compared responses to (1) 2.5 the placebo group. Low- and high-dose
gm/day Omega-3, or (2) 1.25 gm/day Omega- Omega-3 groups showed modest 0.2 % and -
3, or (3) placebo capsules that mirrored the 2.3 % changes in serum tumor necrosis factor
proportions of fatty acids in the typical alpha, compared to a 12 % increase in the
American diet control group
High RBC (EPA/DHA) associated with
Evaluation of level of EPA/DHA in RBCs in attenuated dyslipidemia and low-grade
relation with diabetes biomarkers such as systemic inflammation among overweight and
C-reactive protein, triglyceride, glucose, obese persons. Recommended for Omega-3
insulin, and others FAs intakes which help in the reduction of
obesity-related disease risk
23 men and 3 postmenopausal women with The higher dose (3.4 gm/day) of EPA ? DHA
moderate a placebo double-blind RCT, significantly lowered triglycerides, but neither
3-period crossover trial hypertriglyceridemia dose improved endothelial function nor
(150–500 mg/dl) compared the effects of 0.85 inflammatory status over 8 weeks in healthy
nutritional dose (0.85gm/day equivalent to 3.4 adults with moderate hypertriglyceridemia
gm Pharmaceutical dose) of EPA ? DHA
77 middle aged (50–70 years) at double-blinded 1.5 gm/day of PUFAs did not affect serum
placebo RCT. 39 selected for 3.5 gm of fish oil inflammatory biomarkers (IL-1a, IL-1b, IL-2,
(1.5 gm/day total PUFAs) for 12 weeks and 38 IL-4, IL-5, IL-6, IL-8, IL-10, IL-13, TNF-a,
for placebo group Interferon-y and others
111 healthy aged (C65 years) allocated in 3 A high EPA ? DHA intake changed the
groups in placebo RCT for 26 weeks (36: 1.8 expression of 1,040 genes, whereas HOSF
gm/day EPA/DHA; 37: 0.4 gm/day EPA/ intake changed the expression of only 298
DHA; 38: 4.0 gm high–oleic acid sunflower genes. EPA ? DHA intake resulted in a
oil HOSF/day) all supplemented as capsules. decreased expression of genes involved in
The study tested gene expression of inflammatory- and atherogenic-related
inflammatory markers pathways, such as nuclear transcription factor
kB signaling, eicosanoid synthesis, scavenger
receptor activity, adipogenesis, and hypoxia
signaling
124 free-living adults divided into tertiles of Plasma hs-CRP concentration was negatively
plasma hs-CRP (\1.0, 1.0–3.0 and C3.0 mg/l) correlated with total Omega-3 FAs
(P = 0.05), The highest hs-CRP tertile
(C3.0 mg/l) had significantly lower
concentrations of total Omega-3 FAs
(P = 0.05)
121 assigned into two groups: PUFAs group 47, The result at the end of the study revealed that no
and control group olive oil (2 gm/day) for differences were achieved in the inflammatory
21 days until the surgery markers including IL-6, CRP, lipid profile or
BP
76 patients of heart failure have assigned to two PUFA can decrease plasma levels of the pro-
groups: 38 as experimental group (2 gm/day: inflammatory cytokines IL-6, TNF-a and
EPA = 0.18 gm, and DHA = 0.12 gm), and ICAM-1 in patients with chronic heart failure
38 as placebo group through prospective, and can reduce plasma NT-proBNP
single-blind, randomized, placebo controlled. concentrations as biomarkers of risk
Duration of study: 3 months stratification in heart failure

Role of fish oil in human health
Table 2 continued
Authors/country
Tulk and Robinson (2009) Canada
Engler et al. (2005) USA
Other disease and health conditions
Kiecolt-Glaser et al. (2011) USA
Bowden et al. (2011) Netherlands
Freund-Levi et al. (2009) Sweden
Wang et al. (2008) China
Fig. 1 Mechanisms linking
abdominal obesity and
metabolic syndrome. TNF-a
tumor necrosis factor alpha;
IL-6 interleukin 6; NO nitric
oxide; ROS reactive oxygen
species; JNK c-jun N-terminal
kinase; IKK inhibitor of k
kinase; PKR protein kinase R.
(Emanuela et al. 2012)
(6ECDCA) and WAY-362450 (Evans et al. 2007). Acti-
vation of FXR has been shown to induce eNOS expression
in vascular endothelial cells and inhibit vascular smooth
Author's personal copy
Study information Outcome
8 patients of metabolic syndrome over 45 years. Increase in the Omega-3 PUFA content of a
Modification of Omega-6/Omega-3 ratio in a high-SFA OFTT does not acutely change
high-saturated fatty acid oral fat tolerance test. postprandial triglyceride or inflammatory
Duration: 3 trial days responses (IL-6, CRP) in men with metabolic
syndrome
20 hyperlipidemic children aged: (9–19 years) at DHA supplementation restores endothelial-
double-blinded placebo crossover RCT dependent flow-mediated dilation in
design. Used DHA: 1.2 gm/day for 6 weeks to hyperlipidemic children. Hence, the
evaluate change in Biomarker: CRP endothelium may be a therapeutic target for
DHA
68 medical students at parallel group, placebo- Students who received Omega-3 showed a 14 %
controlled, double-blind 12-week RCT to decrease in lipopolysaccharide (LPS)
determine whether Omega-3 decreases stimulated interleukin 6 (IL-6) production and
proinflammatory cytokine production and a 20 % reduction in anxiety symptoms,
depressive and anxiety symptoms in healthy without significant change in depressive
young adults. (2.5 gm/d, 2,085 mg EPA and symptoms
348 mg DHA)
33 end-stage renal disease (age C57 years); 18 CRP was decreased significantly
in experimental group (EPA:
0.96 gm ? DHA: 0.6 gm) and 15 in control
group. Double-blind, permuted-randomised
and placebo-controlled. Test CRP after
6 months
38 overage patients with Alzheimer disease (18: Treatment of AD patients with Omega-3 FA for
experimental group and 20 control). Study 6 months did not influence inflammatory
design: double-blinded-placebo RCT. biomarkers (CRP, IL-6 and TNF-a) in CSF or
Experimental group: EPA 0.15 gm. ? DHA plasma
0.43 gm/d; 6 months
40 adults with acute pancreatitis (20 Supplemented with Omega-3 FA diminishes the
experimental vs. 20 controls). Study design: hyperinflammatory response in severe acute
double-blinded-placebo RCT. Omega-3 FAs: pancreatitis by reducing the level of CRP
0.15–0.2 gm/kg/day fish oil (10 % significantly
Omegaven); 5 days
muscle cell inflammation by downregulation of inducible
nitric oxide synthase and cyclooxygenase-2 expression (Li
et al. 2008). Furthermore, agonist for the nuclear receptor,
123
 Author's personal copy
liver X receptor, also inhibited IL-6/IL-1b-induced CRP
expression in human hepatocytes. This was shown to be
mediated through inhibition of cytokine-induced NCoR
clearance from the CRP promoter (Blaschke et al. 2006).
Mechanisms for the anti-inflammatory effect of Omega-
3 FAs on cardiovascular health
Omega-3 FAs have the ability to respond to inflammation
in CVD and atherosclerosis through direct and indirect
mechanisms. A direct mechanism through which Omega-
3 FAs decrease inflammation includes its rapid effect on
the regulation of transcription factors (Tao et al. 2002),
and indirect modes of actions include the production of
three- and five series eicosanoids (Teran-Garcia et al.
2002) and inflammation-resolving lipid mediators (Serhan
et al. 2008) and suppression of acute phase reactants
(APRs) (Zhang et al. 2009). In addition, Omega-3 FAs
inhibit inflammation by reducing TNF-a, IL-6, CRP, etc,
and by increasing the three- and five-series eicosanoids,
lipoxins, resolvins and protectins that essentially derived
from Omega-3 FAs (Adkins and Kelley 2010). Figure 2
presents the pathway of Omega-3 FAs having anti-
inflammatory effect compared to Omega-6 FAs which
induce inflammation.
Fig. 2 The metabolism of n-3 and n-6 PUFA and the biosynthesis of
their respective eicosanoid and proresolving mediators. n-3 PUFAs
are generally less inflammatory than the n-6 PUFA. However, PGE2
derived from n-6 PUFA can have an antiinflammatory effect by
decreasing LTB4 production by the inhibition of 5-LOX and
123
M. S. Ellulu et al.
Hypothesized mechanisms of action of Omega-3 FAs
in improving IL-6
De Caterina and Libby (1996) and Khalfoun et al. (1997)
mentioned that EPA and DHA inhibited endotoxin-s-
timulated production of IL-6 induced by cultured human
endothelial cells. Also, Yaqoob and Calder (1995) and
Renier et al. (1993) found that feeding fish oil to mice has
decreased ex vivo production of TNF-a, IL-1b and IL-6 by
endotoxin-stimulated macrophages. In human, several
studies in healthy human volunteers involving supple-
mentation of the diet with fish oil have demonstrated
decreased production of TNF-a, IL-1b, IL-6 and various
growth factors by endotoxin-stimulated monocytes or
mononuclear cells (a mixture of lymphocytes and mono-
cytes) (Trebble et al. 2003; Caughey et al. 1996).
Conclusion
Omega-3 FAs are essential dietary requirements that are
used in preventing and treating many health conditions. In
previous review studies, Omega-3 FAs have used in CVDs,
diabetes, cancer, depression, inflammation and many other
conditions. The reviews of CVDs indicated controversial
decisions about the role of Omega-3 FAs, Chowdhury et al.
increasing production of LXA4 by stimulating 15-LOX. n-3 PUFA-
derived eicosanoids have different physiological potencies than n-6
PUFA-derived eicosanoids. HPETE hydroperoxyeicosatetraenoic
acid, LTA4 leukotriene A4, LXA4 lipoxin A4 (Adkins and Kelley
2010)
 Author's personal copy
Role of fish oil in human health
(2012); Delgado-Lista et al. (2012); Marik and Varon
(2009) have approved them as a protective and treating
factors, while Rizos et al. (2012); Wu et al. (2012); Hooper
et al. (2006) have not approved them as a beneficial factor
in case of CVDs and diabetes. In reviews of cancer, we
concluded three studies: Gerber (2012) have approved
Omega-3 FAs as a beneficial factor but MacLean et al.
(2006) and Hooper et al. (2006) did not approve. In other
studies regarding depression, liver diseases, and inflam-
mation, the review studies have approved the Omega-3
FAs as protective and treating factors.
The efficacy of Omega-3 FAs on inflammation have
been studied by number of RCTs, cohorts, and prospective
studies, and they involved healthy and diseased popula-
tions. Among healthy—or apparently healthy—population,
Itariu et al. (2012) from Austria and Kiecolt-Glaser et al.
(2012) from USA and others have indicated the positive
role of Omega-3 FAs in reducing the different markers of
inflammation even with the modest decrease. The modest
decrease of inflammatory markers among healthy popula-
tion is attributed to low level of inflammation. In diseased
populations such as CVDs, renal disease, acute pancreati-
tis, Omega-3 FAs majorly alleviate inflammation as
adjuvant treatment ‘‘not alone’’.
The activity of Omega-3 FAs in reducing the inflam-
mation among different populations has attracted
researchers worldwide to identify the molecular biosyn-
thesis of inflammatory markers and mechanism of action of
Omega-3 FAs. Emanuela et al. (2012) proved the role of
adipocyte in increasing the level of inflammatory markers
IL-6 and TNF-a, and reducing level of Adiponectin that
plays as precursors for initiating atherosclerosis, hyper-
tension, and insulin resistance leading to metabolic
syndrome. By increased level of IL-6, liver increases the
biosynthesis of CRP. Zhang et al. (2009) approved the
hepatocytes synthesis of CRP by IL-6 and IL-1 inductions.
The possible mechanism which explained the efficacy of
Omega-3 FAs in the pro-inflammatory markers IL-6 was
mentioned by De Caterina and Libby (1996) and Khalfoun
et al. (1997). Omega-3 FAs inhibited endotoxin-stimulated
production of IL-6 induced by cultured human endothelial
cells. Also, decreasing the production of TNF-a, IL-1b, IL-
6 and various growth factors by endotoxin-stimulated
monocytes or mononuclear cells (a mixture of lymphocytes
and monocytes) was established by Trebble et al. (2003)
and Caughey et al. (1996).
Finally, more investigations and studies are required to
identify the role of Omega-3 FAs in health benefits. Be-
cause of lacking evidences in the suitable doses and
duration of daily intakes in treating diseases, Omega-3 FAs
could not be recommended as a treatment, but they could
be used as a protective factors.
Conflict of interest The authors declare that they have no sig-
nificant competing professional or personal interests that might
influence the performance or presentation of the work described in
this manuscript.
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