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Background: The aim of this review is to summarize the effects of krill oil (KO) or fish oil (FO) on eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) incorporation in plasma phospholipids or membrane of red blood cells (RBCs) as shown in human and animal studies. Furthermore, we discuss the findings in relation to the possible different health effects, focusing on lipids, inflammatory markers, cardiovascular disease risk, and biological functions of these two sources of long-chain n-3 polyunsaturated fatty acids (PUFAs). Methods: A literature search was conducted in PubMed in January 2015. In total, 113 articles were identified, but based on selection criteria, 14 original papers were included in the review. Results: Studies on bioavailability of EPA and DHA from KO and FO in humans and animals are limited and the interpretation is difficult, as different amounts of EPA and DHA have been used, duration of intervention differs, and different study groups have been included. Two human studies - one postprandial study and one intervention study - used the same amount of EPA and DHA from KO or FO, and they both showed that the bioavailability of EPA and DHA from KO seems to be higher than that from FO. Limited effects of KO and FO on lipids and inflammatory markers in human and animal studies were reported. Gene expression data from animal studies showed that FO upregulated the cholesterol synthesis pathway, which was the opposite of the effect mediated by KO. KO also regulated far more metabolic pathways than FO, which may indicate different biological effects of KO and FO. Conclusion: There seems to be a difference in bioavailability of EPA and DHA after intake of KO and FO, but more studies are needed before a firm conclusion can be made. It is also necessary to document the beneficial health effects of KO with more human studies and to elucidate if these effects differ from those after regular fish and FO intake.
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http://dx.doi.org/10.2147/VHRM.S85165
Comparison of bioavailability of krill oil versus
sh oil and health effect
Stine M Ulven1
Kirsten B Holven2
1Department of Health, Nutrition
and Management, Faculty of Health
Sciences, Oslo and Akershus
University College of Applied
Sciences, 2Department of Nutrition,
Institute for Basic Medical Sciences,
University of Oslo, Oslo, Norway
Correspondence: Stine M Ulven
Department of Health, Nutrition and
Management, Faculty of Health Sciences,
Oslo and Akershus University College of
Applied Sciences, PO Box 4, Street Olavs
plass, 0130 Oslo, Norway
Tel +47 6723 6348
Email stinemarie.ulven@hioa.no
Background: The aim of this review is to summarize the effects of krill oil (KO) or fish oil
(FO) on eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) incorporation in plasma
phospholipids or membrane of red blood cells (RBCs) as shown in human and animal studies.
Furthermore, we discuss the findings in relation to the possible different health effects, focusing
on lipids, inflammatory markers, cardiovascular disease risk, and biological functions of these
two sources of long-chain n-3 polyunsaturated fatty acids (PUFAs).
Methods: A literature search was conducted in PubMed in January 2015. In total, 113 articles
were identified, but based on selection criteria, 14 original papers were included in the
review.
Results: Studies on bioavailability of EPA and DHA from KO and FO in humans and animals
are limited and the interpretation is difficult, as different amounts of EPA and DHA have been
used, duration of intervention differs, and different study groups have been included. Two human
studies – one postprandial study and one intervention study – used the same amount of EPA and
DHA from KO or FO, and they both showed that the bioavailability of EPA and DHA from KO
seems to be higher than that from FO. Limited effects of KO and FO on lipids and inflammatory
markers in human and animal studies were reported. Gene expression data from animal studies
showed that FO upregulated the cholesterol synthesis pathway, which was the opposite of the
effect mediated by KO. KO also regulated far more metabolic pathways than FO, which may
indicate different biological effects of KO and FO.
Conclusion: There seems to be a difference in bioavailability of EPA and DHA after intake of
KO and FO, but more studies are needed before a firm conclusion can be made. It is also neces-
sary to document the beneficial health effects of KO with more human studies and to elucidate
if these effects differ from those after regular fish and FO intake.
Keywords: human studies, animal studies, gene expression, cardiovascular disease, long-chain
polyunsaturated fatty acids, inflammation, lipid metabolism
Introduction
Fish consumption reduces the risk of developing cardiovascular disease (CVD) and
CVD mortality.1,2 Intervention trials with fish and fish oil (FO) have shown reduced
total mortality and CVD risk.3–6 Fatty fish and FO are rich in long-chain n-3 polyun-
saturated fatty acids (PUFAs), namely, eicosapentaenoic acid (EPA, 20:5 n-3) and
docosahexaenoic acid (DHA, 22:6 n-3). One of the beneficial health effects of long-
chain n-3 PUFAs may be mediated by reduction in plasma triglycerides (TGs).7 The
effect of long-chain n-3 PUFAs on inflammation is uncertain.8,9
The American Heart Association dietary guidelines for long-chain n-3 PUFAs and
fish intake for primary prevention of coronary diseases are two servings of fatty fish
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Ulven and Holven
per week.9 This recommendation will provide an amount of
250–500 mg EPA + DHA per day.10 A food-based approach
for achieving adequate intake of long-chain n-3 PUFAs is
recommended.11 However, for individuals who do not like
fish or for other reasons choose not to include fish in their
diet, nutritional supplements may be a good alternative for
supply of long-chain n-3 PUFAs.
Because fish is a restricted resource, there is a grow-
ing interest in exploiting alternative sources of long-chain
n-3 PUFAs. Krill oil (KO) is extracted from Antarctic krill
(Euphausia superba), which is a rich source of long-chain
n-3 PUFAs. Krill is by far the most dominant member of the
Antarctic zooplankton community in terms of biomass and,
thus, attractive for commercial harvest. Persistent organic pol-
lutants (POPs) accumulate in marine ecosystems and in the
lipid reserve of organisms, and these are efficiently removed
from FO through processing and purification.12 Limited data
exist if the content of POPs in FO and KO are comparable.
In a recent study,13 a comparison between the toxicological
profiles of KO and FO products showed that the two KO
products included in the study were ranked as containing
intermediate levels of POP contaminants when compared
overall to the FO products analyzed in the study.
Both FO and KO contain a high proportion of EPA and
DHA, but in contrast to FO, KO contains a major part of
these fatty acids in the form of phospholipids (PLs) (mainly
phosphatidylcholine).14 In fish, the fatty acids are mainly
stored as TGs, whereas in krills, 30%–65% of the fatty acids
are incorporated into PLs.14 Whether fatty acid esterification
in TGs or PLs has impact on the efficiency of absorption of
the fatty acids into the blood and on serum lipid levels are
issues for discussion. Because PLs comprise the structure of
cell membranes, long-chain n-3 PUFAs in the form of PLs
might facilitate the passage of fatty acids through the intes-
tinal wall and increase the bioavailability of these fatty acids
in KO, compared to when they are consumed from FO. The
overall fatty acid composition in KO resembles that of FO,
but the EPA content is higher.14 This makes the ratio between
EPA and DHA different between KO and FO. FO often has a
ratio of approximately 1:1, while KO has a ratio of 2:1.15 The
functional similarity of EPA and DHA lies in their ability to
alter cell membrane PL fatty acid composition, disrupt lipid
rafts and signal transduction, and regulate gene expression,
either directly by activating transcription factors such as
peroxisome proliferator-activated receptors or by activating
membrane-bound receptors such as the G protein-coupled
receptor GPR120.16 The functional difference between EPA
and DHA is in the synthesis of eicosanoids (prostaglandins,
thromboxanes, and leukotrienes), whereby they compete
with arachidonic acid (AA, 20:4, n-6) as a substrate for
cyclooxygenase and lipoxygenase, which gives rise to dif-
ferent biological responses.17 Additionally, EPA gives rise to
E-series resolvins and DHA gives rise to D-series resolvins
and protectins, which are anti-inflammatory mediators, which
may also explain the different biological responses of EPA
and DHA.17
In addition to long-chain n-3 PUFAs, KO also contains
the antioxidant astaxanthin, which may have a possible health
effect.18 Whether these differences in EPA and DHA levels
and astaxanthin can mediate the different biological functions
of FO and KO remains unclear.
The aim of this review is to summarize the effects of
long-chain n-3 PUFAs after intake of KO or FO on EPA and
DHA incorporation in plasma PLs or membrane of red blood
cells (RBCs) in humans and animals. Furthermore, we aim
to discuss the findings in relation to the possible different
health effects, focusing on lipids, inflammatory markers,
CVD risk, and biological function of these two sources of
long-chain n-3 PUFAs.
Methods for selection of studies
from the literature
A literature search was conducted in PubMed in January 2015
using the following terms: “[krill oil and absorption], [krill
oil and bioavailability], [krill oil and health effects], [krill oil
and omega-3], and [krill oil and n-3].” In total, 113 articles
were identified, but after removing duplicates and studies not
including KO in human or animal experiments, 45 papers
were screened by reading abstracts. In total, 31 studies were
excluded based on the following criteria: not an original paper
(n=13), not using FO and KO in the same study (n=14), and
health effects other than lipid levels, inflammation, and endo-
cannabinoid levels (n=4). In total, 14 original papers were
included in the review. Among these, seven were clinical
trials and seven were animal studies. The search was limited
to English literature and the search was conducted to obtain
any literature published before January 2015. One of the
researchers performed the literature search and both of the
researchers independently extracted the data.
Results
Human studies
Seven human randomized trials – five double-blind19–23 and
two open-label15,24 ones – investigating the effects of KO
compared with FO were identified (Table 1). Three of the
studies19,21,24 included healthy subjects (between 20 years
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PUFA bioavailability and health effects of krill oil versus sh oil
and 50 years), two studies20,22 included healthy overweight
or obese subjects (35–64 years), and two studies15,23 included
healthy subjects with normal or slightly elevated lipid levels
and patients with hyperlipidemia (mean age: 40–50 years).
All but one study (only male in the study by Schuchardt
et al21) included both male and female subjects.
Two of the studies provided similar amounts of FO and
KO, but different amounts of EPA and DHA.22,23 Three of the
studies compared similar amounts of EPA and DHA in FO
and KO,19–21 and two studies gave both different amounts of
oil and EPA and DHA.15,24 In two of the studies, the effect
of different forms (triglyceride, ethyl ester and phospholipid
forms) of EPA and DHA was compared.21,24 One study21 was a
postprandial study lasting up to 72 hours after intake, whereas
the intervention period in the remaining studies ranged from
4 weeks to 12 weeks.
Bioavailability
Five of the seven studies reported effects of these oils on
bioavailability and/or plasma fatty acid composition of EPA
and DHA.15,19,21,22,24 Ramprasath et al19 administered similar
amounts of EPA and DHA (600 mg EPA and DHA) as KO
or FO to 24 healthy subjects in a 4-week crossover trial.
They showed that consumption of both KO and FO increased
plasma EPA and DHA levels, plasma levels of total n-3 fatty
acids, level of RBC EPA, and the sum of EPA and DHA
concentrations in RBCs (omega-3 index) compared with
control. Intake of KO significantly increased plasma EPA
levels, the level of total n-3 PUFAs, the level of RBC EPA,
and the omega-3 index to a greater degree compared with
FO. The change in omega-3 index after consumption of KO
was two-fold higher than that with FO. Maki et al22 adminis-
tered the same amount of KO and FO, but different amounts
of EPA and DHA, in a 4-week randomized controlled trial
with 76 overweight and obese men and women. The subjects
were given 2 g/d of KO (216 mg/d EPA and 90 mg/d DHA),
menhaden oil (MO) (212 mg/d EPA and 178 mg/d DHA), or
olive oil (OO). The increase in plasma EPA and DHA con-
centrations were similar for the KO and MO groups and both
were significantly different compared to the control group
given OO. Ulven et al15 administered different doses of KO
and FO and different amounts of EPA and DHA in a 7-week
randomized trial with 113 subjects with normal or slightly
elevated total blood cholesterol and/or TG levels. The subjects
were given 3 g/d of KO (EPA + DHA =543 mg) or 1.8 g/d of
FO (EPA + DHA =864 mg). A third group did not receive any
supplementation. They found a significant increase in plasma
EPA, DHA, and DPA (docosapentaenoic acid) levels in the
subjects supplemented with both KO and FO compared with
the controls, but there were no significant differences in the
changes in any of the n-3 PUFAs between the FO and the KO
groups despite the difference in n-3 dose. All these results
support the hypothesis that EPA and DHA from KO have a
better bioavailability compared to those from FO.
In contrast, Laidlaw et al24 administered different amounts
of oil, as well as EPA and DHA from four different n-3
supplements, in a 28-day crossover trial with 35 healthy
subjects. The four supplements and doses were reesterified
TG (rTG) FO (EPA, 650 mg; DHA, 450 mg), ethyl ester (EE)
FO (EPA, 756 mg; DHA, 228 mg), PL KO (EPA, 150 mg;
DHA, 90 mg), and TG salmon oil (SO) (EPA, 180 mg; DHA,
220 mg). The increase in whole-blood n-3 fatty acids after
rTG supplementation was statistically significantly greater
than for the other products; moreover, the whole-blood DHA
increase, EPA + DHA increase, and EPA increase was greater
than the increase of the PL and TG products. When compar-
ing the PL KO and the TG SO groups, which had similar daily
intake of EPA (150 mg and 180 mg, respectively), the mean
whole-blood EPA percentage increase was almost identical
in the two groups, suggesting that the structural form of EPA
does not seem to play a role on the bioavailability.
Schuchardt et al21 compared the bioavailability of iden-
tical doses of EPA + DHA (1,680 mg) from KO to that of
other chemical forms of EPA and DHA in a double-blinded
crossover postprandial study lasting up to 72 hours after
intake. They gave 12 healthy male subjects a single dose of
FO capsules consisting either of rTG or of EE or KO capsules
consisting of EPA + DHA mainly as PLs. They found that
the EPA, DHA, EPA + DHA, and total n-3 fatty acid levels
in plasma PLs were higher after the KO treatment compared
to the levels after rTG and EE treatment; however, this was
not statistically significant, even though a trend was observed
for difference in EPA bioavailability between rTG and KO.
This may suggest that the bioavailability of EPA and DHA in
plasma PLs is higher from KO compared to that from FO.
Plasma lipids
Among the seven studies, four studies reported the effect
on plasma TGs and lipoproteins.15,19,22,23 In the study by
Ramprasath et al,19 the total cholesterol and low-density
lipoprotein (LDL) cholesterol concentrations in the plasma
were increased after intake of both KO and FO compared
with control, whereas serum TG and high-density lipoprotein
(HDL) cholesterol concentrations did not change with any
of the treatments. The response on lipoproteins did not differ
between the groups in the studies by Maki et al22 and Ulven
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Ulven and Holven
Table 1 Human studies with krill oil and sh oil
Study Study design Intervention Amount of n-3 PUFA Duration Individuals Age Fatty acid composition Lipids Inammation and
oxidative stress
Other health effects
Laidlaw
et al (2014)24
Open-label,
randomized,
crossover study
Four groups:
1) concentrated rTG FO,
2) EE FO, 3) PL KO, and
4) TG SO.
Group 1: EPA, 650 mg; DHA,
450 mg. Group 2: EPA, 756 mg;
DHA, 228 mg. Group 3: EPA,
150 mg; DHA, 90 mg.
Group 4: EPA, 180 mg; DHA,
220 mg
28-day period,
followed by a
4-week washout
period
35 healthy subjects
(male and female)
35±14 years Higher increase in omega-3
fatty acids after rTG
supplementation compared
with the PL and TG
products. The PL group
intake of EPA was similar
to that of the TG group,
and the whole-blood EPA
increase was almost identical.
Intake of rTG was most
benecial in reducing
Omega-3 Serum
Equivalence Score and
the Omega-3 Red Blood
Cell Equivalence Score
as surrogate markers for
cardiovascular risk.
Ramprasath
et al (2013)19
Double-blinded,
randomized,
placebo-controlled
crossover trial
Three treatment groups:
1) KO, 2) FO, and
3) placebo control, CO.
Three treatment groups
including KO or FO providing
600 mg of n-3 PUFAs
4 weeks’
treatment, with an
8-week washout
period
24 healthy volunteers with
BMI of 23.8±3 kg/m2
28.2±5.4 years Both KO and FO increased
plasma EPA and DHA levels,
plasma levels of total n-3
PUFAs, and RBC EPA level
compared with CO.
KO increased plasma EPA
levels, the level of total
n-3 PUFA, RBC EPA level
and omega-3 index more
compared to FO.
Total and LDL-C
concentrations were
increased following KO
and FO supplementation
compared with control.
No change in serum TG
and HDL-C concentrations
with any of the treatments.
Ulven
et al (2011)15
Open single-center,
randomized,
parallel-group
designed study
KO: 3.0 g/d (n=41),
FO: 1.8 g/d (n=40) vs
no dietary intervention
(n=41).
KO: 543 mg EPA + DHA; FO:
864 mg EPA + DHA vs no
dietary intervention
7 weeks 113 subjects with normal
or slightly elevated total
blood cholesterol and/or
TG levels
KO: 38.7±11.1 years;
FO: 40.3±14.8 years;
control:
40.5±12.1 years
A signicant increase in
plasma EPA, DHA, and
DPA in KO and FO groups
compared with the controls.
No differences between FO
and KO groups.
No differences in serum
lipids between the study
groups.
No differences in markers
of oxidative stress and
inammation between the
study groups
Banni
et al (2011)20
Randomized,
double-blind,
controlled, parallel
clinical trial
2 g/d dose of KO
(n=21), MO (n=23), or
OO (n=19).
KO: 309 mg/d of EPA/DHA
2:1; MO: 390 mg/d of EPA/
DHA 1:1
4 weeks 63 subjects: healthy
overweight or obese men
and women, with waist
circumference of $102 cm
(men) or $88 cm (women)
35–64 years of age Intake of KO signicantly
decreased 2-AG in obese,
but not in overweight,
subjects. No effect of MO
or OO treatments on
2-AG. There was no effect
of KO, MO, or OO on
arachidonoylethanolamine
(AEA)
Schuchardt
et al (2011)21
Randomized,
double-blind
crossover trial
Three EPA + DHA
formulations: 1) FO
rTGs, 2) FO EEs, and
3) KO (mainly PLs).
Total EPA + DHA intake:
1,680 mg for all three groups.
Groups 1 and 2: EPA intake
1,080 mg and DHA intake
672 mg. Group 3: EPA intake
1,050 mg and DHA intake
630 mg
Postprandial study:
measurements
recorded 2 h, 4 h,
6 h, 8 h, 24 h,
48 h, and 72 h after
capsule ingestion
12 healthy young men
between 20 years and
50 years and with BMI
between 20 kg/m2 and
28 kg/m2
31±5 years The EPA, DHA, EPA + DHA,
and total n-3 PUFA levels in
plasma PLs were higher after
KO treatment, compared
to rTG and EE. The DHA,
EPA + DHA, and total n-3
PUFA uptake from the rTG
FO formulation was higher
compared to the same from
EE FO, and the EPA uptake
was higher after EE FO
treatment than after rTG FO
treatment.
Maki
et al (2009)22
Randomized,
double-blind
parallel-arm trial
Three groups: 1) 2 g/d
of KO, 2) 2 g/d MO, and
3) 2 g/d control OO.
Four 500 mg capsules
per day.
KO: 216 mg/d EPA and
90 mg/d DHA; MO: 212 mg/d
EPA and 178 mg/d DHA
4 weeks 76 healthy overweight and
obese men and women,
35–64 years of age, with
waist circumference of
$102 cm (men) or $88 cm
(women)
KO: 49.4±1.7 years;
MO: 49.6±1.4 years;
and placebo:
47.4±1.6 years
The increase in plasma EPA
and DHA was similar for
the KO and MO groups,
and both were signicantly
different compared to the
control group.
No differences in
lipoprotein lipids between
groups.
No differences in hsCRP
and F2-isoprostanes between
groups
No difference in glucose
homeostasis markers
between groups. Systolic
blood pressure declined
signicantly more in the
MO group than in the
control group.
(Continued)
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PUFA bioavailability and health effects of krill oil versus sh oil
Table 1 Human studies with krill oil and sh oil
Study Study design Intervention Amount of n-3 PUFA Duration Individuals Age Fatty acid composition Lipids Inammation and
oxidative stress
Other health effects
Laidlaw
et al (2014)24
Open-label,
randomized,
crossover study
Four groups:
1) concentrated rTG FO,
2) EE FO, 3) PL KO, and
4) TG SO.
Group 1: EPA, 650 mg; DHA,
450 mg. Group 2: EPA, 756 mg;
DHA, 228 mg. Group 3: EPA,
150 mg; DHA, 90 mg.
Group 4: EPA, 180 mg; DHA,
220 mg
28-day period,
followed by a
4-week washout
period
35 healthy subjects
(male and female)
35±14 years Higher increase in omega-3
fatty acids after rTG
supplementation compared
with the PL and TG
products. The PL group
intake of EPA was similar
to that of the TG group,
and the whole-blood EPA
increase was almost identical.
Intake of rTG was most
benecial in reducing
Omega-3 Serum
Equivalence Score and
the Omega-3 Red Blood
Cell Equivalence Score
as surrogate markers for
cardiovascular risk.
Ramprasath
et al (2013)19
Double-blinded,
randomized,
placebo-controlled
crossover trial
Three treatment groups:
1) KO, 2) FO, and
3) placebo control, CO.
Three treatment groups
including KO or FO providing
600 mg of n-3 PUFAs
4 weeks’
treatment, with an
8-week washout
period
24 healthy volunteers with
BMI of 23.8±3 kg/m2
28.2±5.4 years Both KO and FO increased
plasma EPA and DHA levels,
plasma levels of total n-3
PUFAs, and RBC EPA level
compared with CO.
KO increased plasma EPA
levels, the level of total
n-3 PUFA, RBC EPA level
and omega-3 index more
compared to FO.
Total and LDL-C
concentrations were
increased following KO
and FO supplementation
compared with control.
No change in serum TG
and HDL-C concentrations
with any of the treatments.
Ulven
et al (2011)15
Open single-center,
randomized,
parallel-group
designed study
KO: 3.0 g/d (n=41),
FO: 1.8 g/d (n=40) vs
no dietary intervention
(n=41).
KO: 543 mg EPA + DHA; FO:
864 mg EPA + DHA vs no
dietary intervention
7 weeks 113 subjects with normal
or slightly elevated total
blood cholesterol and/or
TG levels
KO: 38.7±11.1 years;
FO: 40.3±14.8 years;
control:
40.5±12.1 years
A signicant increase in
plasma EPA, DHA, and
DPA in KO and FO groups
compared with the controls.
No differences between FO
and KO groups.
No differences in serum
lipids between the study
groups.
No differences in markers
of oxidative stress and
inammation between the
study groups
Banni
et al (2011)20
Randomized,
double-blind,
controlled, parallel
clinical trial
2 g/d dose of KO
(n=21), MO (n=23), or
OO (n=19).
KO: 309 mg/d of EPA/DHA
2:1; MO: 390 mg/d of EPA/
DHA 1:1
4 weeks 63 subjects: healthy
overweight or obese men
and women, with waist
circumference of $102 cm
(men) or $88 cm (women)
35–64 years of age Intake of KO signicantly
decreased 2-AG in obese,
but not in overweight,
subjects. No effect of MO
or OO treatments on
2-AG. There was no effect
of KO, MO, or OO on
arachidonoylethanolamine
(AEA)
Schuchardt
et al (2011)21
Randomized,
double-blind
crossover trial
Three EPA + DHA
formulations: 1) FO
rTGs, 2) FO EEs, and
3) KO (mainly PLs).
Total EPA + DHA intake:
1,680 mg for all three groups.
Groups 1 and 2: EPA intake
1,080 mg and DHA intake
672 mg. Group 3: EPA intake
1,050 mg and DHA intake
630 mg
Postprandial study:
measurements
recorded 2 h, 4 h,
6 h, 8 h, 24 h,
48 h, and 72 h after
capsule ingestion
12 healthy young men
between 20 years and
50 years and with BMI
between 20 kg/m2 and
28 kg/m2
31±5 years The EPA, DHA, EPA + DHA,
and total n-3 PUFA levels in
plasma PLs were higher after
KO treatment, compared
to rTG and EE. The DHA,
EPA + DHA, and total n-3
PUFA uptake from the rTG
FO formulation was higher
compared to the same from
EE FO, and the EPA uptake
was higher after EE FO
treatment than after rTG FO
treatment.
Maki
et al (2009)22
Randomized,
double-blind
parallel-arm trial
Three groups: 1) 2 g/d
of KO, 2) 2 g/d MO, and
3) 2 g/d control OO.
Four 500 mg capsules
per day.
KO: 216 mg/d EPA and
90 mg/d DHA; MO: 212 mg/d
EPA and 178 mg/d DHA
4 weeks 76 healthy overweight and
obese men and women,
35–64 years of age, with
waist circumference of
$102 cm (men) or $88 cm
(women)
KO: 49.4±1.7 years;
MO: 49.6±1.4 years;
and placebo:
47.4±1.6 years
The increase in plasma EPA
and DHA was similar for
the KO and MO groups,
and both were signicantly
different compared to the
control group.
No differences in
lipoprotein lipids between
groups.
No differences in hsCRP
and F2-isoprostanes between
groups
No difference in glucose
homeostasis markers
between groups. Systolic
blood pressure declined
signicantly more in the
MO group than in the
control group.
(Continued)
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Ulven and Holven
Table 1 (Continued)Table 1 (Continued)
Study Study design Intervention Amount of n-3 PUFA Duration Individuals Age Fatty acid composition Lipids Inammation and
oxidative stress
Other health effects
Bunea
et al (2004)23
Double-blind,
randomized trial
Four groups: Group A:
KO (2–3 g daily);
Group B: KO (1–1.5 g
daily); Group C: FO
(3 g daily); Group
D: placebo (3 g/d,
microcrystalline
cellulose).
Group A: KO 2 g/d
(BMI ,30 kg/m2), 3 g/d
(BMI .30 kg/m2).
Group B: KO 1 g/d
(BMI ,30 kg/m2), 1.5 g/d
(BMI .30 kg/m2). Group C:
FO 3 g/d (180 mg EPA +120 mg
DHA/g of oil). Group D:
placebo 3 g/d (microcrystalline
cellulose).
12 weeks 120 patients with
hyperlipidemia and with
blood cholesterol levels
between 194 mg/dL and
348 mg/dL (18–85 years)
51±9.46 years KO and FO reduced
total cholesterol. Placebo
increased total cholesterol.
Similar effects were
observed for LDL-C.
KO and FO signicantly
increased HDL-C, whereas
the level of HDL-C was
unchanged in the placebo
group. KO taken as 1 g/d,
2 g/d, and 3 g/d reduced
TG. A nonsignicant
reduction of TG after a
daily dose of 1.5 g/d KO,
FO, and placebo.
Blood glucose levels
were reduced by KO
and FO, whereas placebo
treatment resulted in a
nonsignicant increase of
blood glucose
Abbreviations: 2-AG, 2-arachidonoylglycerol; BMI, body mass index; d, days; DHA, docosahexaenoic acid; EE, ethyl ester; EPA, eicosapentaenoic acid; F2-isoprostanes,
8-iso-prostaglandin F2a (8-iso-PGF2a); FO, sh oil; HDL-C, high-density lipoprotein cholesterol; hsCRP, high-sensitivity C-reactive protein; h, hours; KO, krill oil; LDL-C,
low-density lipoprotein cholesterol; MO, menhaden oil; OO, olive oil; PL, phospholipid; PUFA, polyunsaturated fatty acid; RBC, red blood cell; rTG, reesteried triglyceride;
SO, salmon oil; TG, triglyceride; CO, corn oil; DPA, docosapentaenoic acid.
et al.15 However, a significant increase in LDL cholesterol
was observed within the FO group, and a significant increase
in the HDL cholesterol/TG ratio was observed within the KO
group in the study by Ulven et al.15
Bunea et al23 investigated the effect of intake of KO and
FO for 3 months on blood lipids in a randomized controlled
study of 120 patients with hyperlipidemia. There were four
groups; two KO groups (2–3 g/d, and 1–1.5 g/d; dependent
on body mass index), an FO group (3 g FO [180 mg EPA and
120 mg DHA/g oil]), and a control group given placebo. Both
total and LDL cholesterol were reduced in all groups receiv-
ing KO and FO (within-group differences); however, the KO
groups had a greater decrease than patients receiving FO. In
contrast, subjects in the placebo group showed increased mean
total cholesterol and LDL cholesterol levels. HDL cholesterol
increased in all patients receiving KO or FO, whereas the level
of HDL cholesterol was unchanged in the placebo group. KO
taken in doses of 2 g/d and 3 g/d reduced the blood TGs level
significantly, whereas a daily dose of 1.0 g and 1.5 g KO, FO,
and placebo resulted in a nonsignificant reduction of blood
TGs level (all within-group changes). Both FO and KO per-
formed significantly better than placebo in the regulation of
TG, total cholesterol, and HDL cholesterol levels.
Other cardiovascular risk markers
Five out of seven studies investigated the effect on other
cardiovascular risk markers.15,20,22–24 Laidlaw et al24 also
investigated the effect of the supplements on the OmegaScore,
Omega-3 Serum Equivalence Score, and the Omega-3 RBC
Equivalence Score as surrogate markers for cardiovascular
risk. They found that the rTG FO supplement was the most
successful in reducing risk according to these parameters,
with the EE FO supplement being quite similar, and the PL
KO and TG SO supplements being less successful. However,
this is not surprising as the difference in scores is calculated
by the difference in plasma EPA and DHA levels.
Maki et al22 investigated the effect of KO and FO
responses on glucose homeostasis, high-sensitivity
C-reactive protein, F2-isoprostanes, weight, and diastolic
blood pressure and demonstrated that these parameters
did not differ among the groups. The systolic blood pres-
sure declined modestly in both the KO and MO groups,
while increasing in the control group; however, only the
difference between the MO and the control group was
significant. Ulven et al15 observed no statistically signifi-
cant differences in the serum markers of oxidative stress
and inflammation between the study groups. Bunea et al23
showed that both KO and FO reduced blood glucose levels,
whereas placebo treatment resulted in a nonsignificant
increase (all within-group changes). The between-group
comparison showed that intake of 1 g and 1.5 g KO was
significantly more effective than 3 g FO in reducing glu-
cose levels, whereas 2 g and 3 g KO led to significantly
greater reduction of glucose compared to 3 g FO. Both FO
and KO performed significantly better than placebo in the
regulation of glucose levels.
Plasma endocannabinoids have been suggested to be
involved in the regulation of the homeostasis of body com-
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PUFA bioavailability and health effects of krill oil versus sh oil
Table 1 (Continued)Table 1 (Continued)
Study Study design Intervention Amount of n-3 PUFA Duration Individuals Age Fatty acid composition Lipids Inammation and
oxidative stress
Other health effects
Bunea
et al (2004)23
Double-blind,
randomized trial
Four groups: Group A:
KO (2–3 g daily);
Group B: KO (1–1.5 g
daily); Group C: FO
(3 g daily); Group
D: placebo (3 g/d,
microcrystalline
cellulose).
Group A: KO 2 g/d
(BMI ,30 kg/m2), 3 g/d
(BMI .30 kg/m2).
Group B: KO 1 g/d
(BMI ,30 kg/m2), 1.5 g/d
(BMI .30 kg/m2). Group C:
FO 3 g/d (180 mg EPA +120 mg
DHA/g of oil). Group D:
placebo 3 g/d (microcrystalline
cellulose).
12 weeks 120 patients with
hyperlipidemia and with
blood cholesterol levels
between 194 mg/dL and
348 mg/dL (18–85 years)
51±9.46 years KO and FO reduced
total cholesterol. Placebo
increased total cholesterol.
Similar effects were
observed for LDL-C.
KO and FO signicantly
increased HDL-C, whereas
the level of HDL-C was
unchanged in the placebo
group. KO taken as 1 g/d,
2 g/d, and 3 g/d reduced
TG. A nonsignicant
reduction of TG after a
daily dose of 1.5 g/d KO,
FO, and placebo.
Blood glucose levels
were reduced by KO
and FO, whereas placebo
treatment resulted in a
nonsignicant increase of
blood glucose
Abbreviations: 2-AG, 2-arachidonoylglycerol; BMI, body mass index; d, days; DHA, docosahexaenoic acid; EE, ethyl ester; EPA, eicosapentaenoic acid; F2-isoprostanes,
8-iso-prostaglandin F2a (8-iso-PGF2a); FO, sh oil; HDL-C, high-density lipoprotein cholesterol; hsCRP, high-sensitivity C-reactive protein; h, hours; KO, krill oil; LDL-C,
low-density lipoprotein cholesterol; MO, menhaden oil; OO, olive oil; PL, phospholipid; PUFA, polyunsaturated fatty acid; RBC, red blood cell; rTG, reesteried triglyceride;
SO, salmon oil; TG, triglyceride; CO, corn oil; DPA, docosapentaenoic acid.
position by regulating food intake and energy expenditure.
In a randomized controlled trial, Banni et al20 investigated
whether an intake of 2 g/d of KO (309 mg/d of EPA/DHA),
MO (390 mg/d of EPA/DHA), or OO for 4 weeks could
modify plasma endocannabinoids in overweight and obese
subjects. Intake of KO, but not MO or OO, significantly
decreased 2-arachidonoylglycerol in obese subjects, but not
in overweight subjects. There was no effect of KO, MO, or
OO on arachidonoylethanolamine in either obese or over-
weight subjects; thus, KO seemed more efficient than FO in
reducing plasma endocannabinoid levels.
Animal studies
Seven papers investigating the effect of KO compared with
FO in animal models were identified (Table 2). The main
purpose of these studies was to study the effects of KO and
FO on inflammation and/or lipid metabolism25–29 and on
arthritis.30 One study31 investigated the effect of different
sources of n-3 fatty acids on digestibility, tissue deposition,
eicosanoid metabolism, and oxidative stability.
Bioavailability
Among the seven papers, four studies reported data on bio-
availability and digestibility of EPA and DHA from KO and
FO.26,27,29,31 In one of the studies, the same amounts of FO or
KO, but different amounts and structural forms of EPA and
DHA (TG versus PL), were used in the experiments,29 while
in two studies, different amounts of FO and KO, but similar
doses of EPA and DHA were used in the experiments.26,27
Tou et al31 examined the effects of different sources of n-3
PUFAs.
Tillander et al29 used a high-fat diet model and fed the
mice with similar doses of KO and FO for 6 weeks. The
content of EPA and DHA was lower in KO compared to that
in FO, but both groups showed significantly increased plasma
and liver PLs of EPA and DHA compared to controls. No
difference in increase of EPA and DHA was seen between
the FO and the KO groups, which indicates that KO may
have a higher bioavailability compared to FO.
Vigerust et al26 used a high-fat-diet transgenic mouse
model expressing human tumor necrosis factor (TNF) and fed
the mice with similar doses of EPA and DHA from KO and
FO for 6 weeks. In the plasma, EPA and DHA significantly
increased in both groups compared to controls. The increase
in plasma EPA and DHA between the two groups did not
differ, suggesting that the bioavailability is not dependent
on the structural form of EPA and DHA. Batetta et al27 fed
Zucker rats with similar doses of EPA and DHA for 4 weeks,
and they reported that plasma EPA and DHA were higher in
the FO and KO groups compared to the levels in the corn oil,
(CO) group. In the study by Tou et al,31 Sprague Dawley rats
were fed a high-fat diet consisting of different marine oils, all
containing different amounts of EPA and DHA, for 8 weeks.
They measured the digestibility using the formula [(fatty
acid intake – fecal fatty acids)/(fatty acid intake)] ×100 and
showed no significant difference in EPA digestibility among
rats fed the different marine oils. The DHA digestibility was
higher in SO- than KO-fed rats. There were no significant
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Ulven and Holven
Table 2 Animal studies with krill oil and sh oil
Study Animal
model
Amount of n-3 PUFA Duration Experimental diet Plasma lipids and plasma
fatty acid composition
(EPA and DHA)
Lipids and composition
of fatty acids in liver
(EPA and DHA)
Other lipid effects Inammation and
oxidative stress
Other effects
Tillander
et al (2014)29
Male
C57BL/6J
mice
Control: EPA 0.03 E%, DHA
0.05 E%; FO group: EPA 8.97
E%, DHA 6.40 E%; KO: EPA
5.23 E%, DHA 2.28 E%
6 weeks Mice were fed ad libitum
either a high-fat diet (HF)
containing 24% (w/w) fat
(21.3% lard and 2.3% soy oil)
(n=9), HF diet supplemented
with FO (15.7% lard, 2.3% soy
oil, and 5.8% FO) (n=6), or
HF diet supplemented with
KO (15.7% lard, 2.3% soy oil,
and 5.7% KO) (n=6).
FO signicantly reduced total
C, CEs, free C, TGs, and PLs
compared to control. KO
signicantly reduced NEFA
compared to control. No
signicant differences between
FO and KO. FO and KO
signicantly increased EPA and
DHA compared to control. No
signicant differences between
KO and FO.
FO and KO signicantly
increased total C compared
to control. FO signicantly
increased PLs compared
to control. No signicant
difference between KO and
FO. FO and KO signicantly
increased EPA and DHA in
PLs compared to control. No
signicant differences between
FO and KO.
FO signicantly reduced VLDL-C,
HDL-C, and VLDL-TG compared to
control. VLDL-C reduction by FO
was signicantly different from that
by KO.
FO mainly increased the expression
of genes involved in fatty acid
metabolism. KO specically
decreased the expression of genes
involved in isoprenoid/cholesterol
metabolism and lipid synthesis.
Vigerust
et al (2013)26
Male
transgenic
mice
expressing
human TNFα
Control: EPA 0.03 wt%, DHA
0.05 wt%. FO: EPA 5.23 wt%
and DHA 2.82 wt%. KO: EPA
5.39 wt% and DHA 2.36 wt%
6 weeks Mice were fed ad libitum
either a high-fat diet (HF)
containing 23.6% (w/w) fat
(21.3% lard and 2.3% soy oil)
(n=10), HF diet supplemented
with FO (18.5% lard, 2.3% soy
oil, and 2.9% FO) (n=8), or HF
diet supplemented with KO
(15.6% lard, 2.3% soy oil, and
5.8% KO) (n=8).
KO signicantly reduced TGs
compared to control. KO
and FO signicantly reduced
total C, CE, free C, HDL-C,
and non-HDL-C compared to
control. FO signicantly reduced
LDL-C compared to control. No
signicant difference between FO
and KO. KO and FO signicantly
increased plasma EPA and
DHA compared to control.
No signicant differences
between FO and KO.
KO and FO signicantly
increased EPA and DHA
compared to control. Signicant
lower DHA increase mediated
by KO compared to that by FO.
KO signicantly increased the
production of acylcarnitine classes
compared to control. The increase
was signicantly different from that
caused by FO.
FO signicantly increased
the hepatic content of the
proinammatory cytokine
IL17 compared to control.
No differences of other
cytokines between groups.
KO increased peroxisomal and
mitochondrial oxidation of fatty
acids. KO signicantly increased
ACOX1 activity. KO and FO
increased CPTII activity and
downregulated expression of genes
involved in fatty acid synthesis, and
cholesterol import and synthesis. KO
signicantly decreased the expression
of Ldlr more than FO.
Ferramosca
et al (2012)25
Male Wistar
rats
Control: 0 g EPA and 0 g
DHA/100 g diet. FO: 0.20 g
EPA and 0.29 g DHA/100 g
diet. KO: 0.30 g EPA and
0.17 g DHA/100 g diet
1–6 weeks Rats were fed ad libitum a
standard diet, supplemented
with 2.5% olive oil (control),
2.5% FO, or 2.5% KO.
KO and FO signicantly
decreased TG and C compared
to control. KO had a more
pronounced effect.
KO and FO signicantly
reduced TG and C compared
to control. KO had a more
pronounced effect.
The activity, the protein level, and
the expression of the transport
protein for citrate across the
mitochondrial inner membrane were
reduced by KO and FO, which was
more pronounced in KO group.
ACC and FAS activity was reduced
by KO and FO, being the highest in
KO group.
Tou
et al (2011)31
Female
Sprague
Dawley rats
CO and FxO: EPA and DHA
not detected. KO: 13.2 mg
EPA/g diet and 4.6 mg DHA/g
diet. MO: 5.5 mg EPA/g diet
and 2.0 mg DHA/g diet.
SO: 10.0 mg EPA/g diet and
1.9 mg DHA/g diet. TO:
2.6 mg EPA/g diet and 2.9 mg
DHA/g diet
8 weeks Rats were fed AIN-93G
diet, which consisted of
replacing 7% lipids with 12%
lipid by weight. The dietary
oils consisted of one of the
following: 1) CO (n=10),
2) FxO (n=10), 3) KO (n=10),
4) MO (n=10), 5) SO (n=10),
6) TO (n=10).
EPA signicantly highest after
intake of SO. KO, MO, and SO
signicantly increased EPA-TG
compared to FxO. KO and FxO
signicantly increased EPA-PL
compared to MO, SO, and
TO. SO and TO signicantly
increased DHA compared to
CO. KO, MO, SO, and TO
signicantly increased DHA-TG
and DHA-PL compared to CO.
MO, SO, and TO signicantly
increased DHA-TG compared
to KO.
In gonadal adipose tissue, EPA
signicantly highest after intake
of KO. DHA signicantly highest
after intake of KO, MO, and TO
compared to FxO intake. DHA
signicantly highest after intake
of MO and TO compared to SO
intake. In retroperitoneal adipose
tissue, EPA signicantly highest after
intake of KO. DHA signicantly
highest after intake of KO and MO
compared to SO intake.
No signicant differences in
urinary 13,14-dihydro-15-
keto PGE2 or 11-dehydro
TXB2 among groups. No
differences in RBC TBARS
among groups. Serum TBARS
and liver TAC signicantly
highest after intake of MO
compared to KO, SO, and
TO intake. No signicant
differences in gene expression
of Zn/Cu SOD, Mn SOD,
CAT, or GSH-Px among
groups.
No signicant differences in
EPA digestibility among rats fed
marine oils. DHA digestibility was
signicantly higher after intake of
SO compared to KO-fed rats. No
differences in DHA digestibility in
rats fed MO or TO compared to
SO- or KO-fed rats.
Burri
et al (2011)28
Male CBA/J
mice
Control: EPA and DHA
0 g/100 g diet. KO: 0.19 g
EPA/100 g diet and 0.11 g
DHA/100 g diet. FO:
0.17 g EPA/100 g diet and
0.11 g DHA/100 g diet
12 weeks Mice were fed AIN-93M
diet containing 4% lipid from
soybean oil, or soybean oil
substituted with 1.1% FO or
1.5% KO. Total n-3 PUFA
amount: 0.31% (FO) and
0.29% (KO).
No signicant changes in plasma
TG, total C, free fatty acids, PL,
glucose, and insulin within or
between any of the groups.
KO downregulated the expression
of genes involved in glucose, fatty
acid, and cholesterol synthesis. FO
modulated fewer pathways than KO.
FO did not modulate key metabolic
pathways regulated by KO. FO
upregulated the cholesterol synthesis
pathway.
(Continued)
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PUFA bioavailability and health effects of krill oil versus sh oil
Table 2 Animal studies with krill oil and sh oil
Study Animal
model
Amount of n-3 PUFA Duration Experimental diet Plasma lipids and plasma
fatty acid composition
(EPA and DHA)
Lipids and composition
of fatty acids in liver
(EPA and DHA)
Other lipid effects Inammation and
oxidative stress
Other effects
Tillander
et al (2014)29
Male
C57BL/6J
mice
Control: EPA 0.03 E%, DHA
0.05 E%; FO group: EPA 8.97
E%, DHA 6.40 E%; KO: EPA
5.23 E%, DHA 2.28 E%
6 weeks Mice were fed ad libitum
either a high-fat diet (HF)
containing 24% (w/w) fat
(21.3% lard and 2.3% soy oil)
(n=9), HF diet supplemented
with FO (15.7% lard, 2.3% soy
oil, and 5.8% FO) (n=6), or
HF diet supplemented with
KO (15.7% lard, 2.3% soy oil,
and 5.7% KO) (n=6).
FO signicantly reduced total
C, CEs, free C, TGs, and PLs
compared to control. KO
signicantly reduced NEFA
compared to control. No
signicant differences between
FO and KO. FO and KO
signicantly increased EPA and
DHA compared to control. No
signicant differences between
KO and FO.
FO and KO signicantly
increased total C compared
to control. FO signicantly
increased PLs compared
to control. No signicant
difference between KO and
FO. FO and KO signicantly
increased EPA and DHA in
PLs compared to control. No
signicant differences between
FO and KO.
FO signicantly reduced VLDL-C,
HDL-C, and VLDL-TG compared to
control. VLDL-C reduction by FO
was signicantly different from that
by KO.
FO mainly increased the expression
of genes involved in fatty acid
metabolism. KO specically
decreased the expression of genes
involved in isoprenoid/cholesterol
metabolism and lipid synthesis.
Vigerust
et al (2013)26
Male
transgenic
mice
expressing
human TNFα
Control: EPA 0.03 wt%, DHA
0.05 wt%. FO: EPA 5.23 wt%
and DHA 2.82 wt%. KO: EPA
5.39 wt% and DHA 2.36 wt%
6 weeks Mice were fed ad libitum
either a high-fat diet (HF)
containing 23.6% (w/w) fat
(21.3% lard and 2.3% soy oil)
(n=10), HF diet supplemented
with FO (18.5% lard, 2.3% soy
oil, and 2.9% FO) (n=8), or HF
diet supplemented with KO
(15.6% lard, 2.3% soy oil, and
5.8% KO) (n=8).
KO signicantly reduced TGs
compared to control. KO
and FO signicantly reduced
total C, CE, free C, HDL-C,
and non-HDL-C compared to
control. FO signicantly reduced
LDL-C compared to control. No
signicant difference between FO
and KO. KO and FO signicantly
increased plasma EPA and
DHA compared to control.
No signicant differences
between FO and KO.
KO and FO signicantly
increased EPA and DHA
compared to control. Signicant
lower DHA increase mediated
by KO compared to that by FO.
KO signicantly increased the
production of acylcarnitine classes
compared to control. The increase
was signicantly different from that
caused by FO.
FO signicantly increased
the hepatic content of the
proinammatory cytokine
IL17 compared to control.
No differences of other
cytokines between groups.
KO increased peroxisomal and
mitochondrial oxidation of fatty
acids. KO signicantly increased
ACOX1 activity. KO and FO
increased CPTII activity and
downregulated expression of genes
involved in fatty acid synthesis, and
cholesterol import and synthesis. KO
signicantly decreased the expression
of Ldlr more than FO.
Ferramosca
et al (2012)25
Male Wistar
rats
Control: 0 g EPA and 0 g
DHA/100 g diet. FO: 0.20 g
EPA and 0.29 g DHA/100 g
diet. KO: 0.30 g EPA and
0.17 g DHA/100 g diet
1–6 weeks Rats were fed ad libitum a
standard diet, supplemented
with 2.5% olive oil (control),
2.5% FO, or 2.5% KO.
KO and FO signicantly
decreased TG and C compared
to control. KO had a more
pronounced effect.
KO and FO signicantly
reduced TG and C compared
to control. KO had a more
pronounced effect.
The activity, the protein level, and
the expression of the transport
protein for citrate across the
mitochondrial inner membrane were
reduced by KO and FO, which was
more pronounced in KO group.
ACC and FAS activity was reduced
by KO and FO, being the highest in
KO group.
Tou
et al (2011)31
Female
Sprague
Dawley rats
CO and FxO: EPA and DHA
not detected. KO: 13.2 mg
EPA/g diet and 4.6 mg DHA/g
diet. MO: 5.5 mg EPA/g diet
and 2.0 mg DHA/g diet.
SO: 10.0 mg EPA/g diet and
1.9 mg DHA/g diet. TO:
2.6 mg EPA/g diet and 2.9 mg
DHA/g diet
8 weeks Rats were fed AIN-93G
diet, which consisted of
replacing 7% lipids with 12%
lipid by weight. The dietary
oils consisted of one of the
following: 1) CO (n=10),
2) FxO (n=10), 3) KO (n=10),
4) MO (n=10), 5) SO (n=10),
6) TO (n=10).
EPA signicantly highest after
intake of SO. KO, MO, and SO
signicantly increased EPA-TG
compared to FxO. KO and FxO
signicantly increased EPA-PL
compared to MO, SO, and
TO. SO and TO signicantly
increased DHA compared to
CO. KO, MO, SO, and TO
signicantly increased DHA-TG
and DHA-PL compared to CO.
MO, SO, and TO signicantly
increased DHA-TG compared
to KO.
In gonadal adipose tissue, EPA
signicantly highest after intake
of KO. DHA signicantly highest
after intake of KO, MO, and TO
compared to FxO intake. DHA
signicantly highest after intake
of MO and TO compared to SO
intake. In retroperitoneal adipose
tissue, EPA signicantly highest after
intake of KO. DHA signicantly
highest after intake of KO and MO
compared to SO intake.
No signicant differences in
urinary 13,14-dihydro-15-
keto PGE2 or 11-dehydro
TXB2 among groups. No
differences in RBC TBARS
among groups. Serum TBARS
and liver TAC signicantly
highest after intake of MO
compared to KO, SO, and
TO intake. No signicant
differences in gene expression
of Zn/Cu SOD, Mn SOD,
CAT, or GSH-Px among
groups.
No signicant differences in
EPA digestibility among rats fed
marine oils. DHA digestibility was
signicantly higher after intake of
SO compared to KO-fed rats. No
differences in DHA digestibility in
rats fed MO or TO compared to
SO- or KO-fed rats.
Burri
et al (2011)28
Male CBA/J
mice
Control: EPA and DHA
0 g/100 g diet. KO: 0.19 g
EPA/100 g diet and 0.11 g
DHA/100 g diet. FO:
0.17 g EPA/100 g diet and
0.11 g DHA/100 g diet
12 weeks Mice were fed AIN-93M
diet containing 4% lipid from
soybean oil, or soybean oil
substituted with 1.1% FO or
1.5% KO. Total n-3 PUFA
amount: 0.31% (FO) and
0.29% (KO).
No signicant changes in plasma
TG, total C, free fatty acids, PL,
glucose, and insulin within or
between any of the groups.
KO downregulated the expression
of genes involved in glucose, fatty
acid, and cholesterol synthesis. FO
modulated fewer pathways than KO.
FO did not modulate key metabolic
pathways regulated by KO. FO
upregulated the cholesterol synthesis
pathway.
(Continued)
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Ulven and Holven
Table 2 (Continued)
Study Animal
model
Amount of n-3 PUFA Duration Experimental diet Plasma lipids and plasma
fatty acid composition
(EPA and DHA)
Lipids and composition
of fatty acids in liver
(EPA and DHA)
Other lipid effects Inammation and
oxidative stress
Other effects
Ierna
et al (2010)30
Male DBA/1
mice,
induced with
arthritis
following
25 days of
feeding
CO: EPA and DHA 0 g/100 g
diet. KO: 0.30 g EPA/100 g
diet and 0.14 g DHA/100 g
diet. FO: 0.29 g EPA/100 g
diet and 0.18 g DHA/100 g
diet.
68 days Mice were fed AIN-93G diet
with substitution of soybean
oil with a blend of oils. The
three diets (control and diet
supplemented with FO or KO)
were similar for total fatty
acids, and FO and KO were
balanced for EPA and DHA.
KO increased clinical arthritis
more slowly compared
to control. Hind paw
thickness and histopathology
associated with arthritis were
signicantly reduced by KO
compared to control. FO
signicantly increased serum
IL1α and IL13 compared to
control.
A signicantly higher weight gain by
KO compared to control.
Batetta
et al (2009)27
Male Zucker
rats
CO: EPA and DHA 0 g/100 g
diet. KO: 0.30 g EPA/100 g
diet and 0.14 g DHA/100 g
diet. FO: 0.29 g EPA/100 g
diet and 0.18 g DHA/100 g
diet
4 weeks Rats were fed AIN-93G diet
with substitution of soybean
oil with a blend of oils. The
three diets (control, and diet
supplemented with FO or KO)
were similar for total fatty
acids, and FO and KO were
balanced for EPA and DHA.
KO and FO signicantly reduced
LDL-C compared to control.
FO and KO signicantly increased
TG compared to control.
No difference in HDL-C. FO and
KO signicantly increased EPA
and DHA compared to CO.
FO and KO signicantly
reduced TG compared to
control. KO signicantly
reduced TG to a greater extent
compared to FO. FO and KO
signicantly increased EPA and
DHA compared to control.
EPA was signicantly higher
in PL after FO and KO intake
compared to control. DHA PL
was signicantly increased by
KO compared to control.
Heart TG was signicantly reduced
by KO compared to control. FO and
KO signicantly increased EPA and
DHA in VAT and SAT TG and PL
compared to control. In heart, KO
and FO signicantly increased EPA
and DHA in TG and PL compared
to control.
No differences in
proinammatory and anti-
inammatory cytokines in
any groups. In macrophages
incubated with LPSs, TNFα
secretion was signicantly
lower after intake of FO and
KO compared to control.
No difference between FO
and KO. In VAT, lower level
of AEA induced by KO and
FO compared to control.
2-AG level lowered by KO.
In liver and heart, AEA
lowered by KO and FO,
more pronounced effect by
KO. 2-AG increased by KO.
In VAT, MAGL activity was
decreased by FO and KO compared
to control. In heart, MAGL activity
signicantly decreased by KO
compared to control.
Abbreviations: 2-AG, 2-arachidonoylglycerol; ACC, acetyl Co-A carboxylase; ACOX1, peroxisomal acyl-CoA oxidase; AEA, N-arachidonoylethanolamine; C, cholesterol;
CAT, catalase; CE, cholesterol ester; CoA, coenzyme A; CO, corn oil; CPTII, carnitine palmitoyltransferase II; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid;
FAS, fatty acid synthetase; FxO, axseed oil; FO, sh oil; HDL, high-density lipoprotein; GSH-Px, glutathione peroxidase; IL, interleukin; ;IL-1a, interleukin-1alpha, KO, krill
oil; LDL-C, low-density lipoprotein cholesterol; LDLR, LDL receptor; LPS, lipopolysaccharide; MAGL, monoacylglycerol lipase; MO, menhaden oil; NEFA, nonesteried fatty
acid; OO, olive oil; PGE2, prostaglandin E2; PL, phospholipid; PUFA, polyunsaturated fatty acid; RBC, red blood cell; SO, salmon oil; SOD, superoxide dismutase; TAC, total
antioxidant capacity; TBARS, thiobarbituric acid-reactive substances; TG, triglyceride; TNFα, tumor necrosis factor alpha; TO, tuna oil; TXB2, thromboxane B2; VAT, visceral
adipose tissue; VLDL, very-low-density lipoprotein; AIN, American Institute of Nutrition rodent diet, SAT, subcutaneous adipose tissue.
differences in DHA digestibility in rats fed MO or tuna oil
(TO) compared to SO- or KO-fed rats.
Plasma lipids
Among the seven studies, five studies reported the effects
on plasma lipids.25–29
In two of the studies,25,29 the authors used the same amount
of FO or KO, containing different amounts and EPA and
DHA, in the experiments. Tillander et al29 found no differ-
ences in plasma lipids between the FO and the KO groups
after 6 weeks. However, within the FO group, total plasma
cholesterol, cholesterol ester, free cholesterol, TGs, and PLs
were significantly reduced compared to the same in controls.
In contrast, Wistar rats fed the same amount of FO and KO
for 1–6 weeks showed significantly decreased plasma TG
and total cholesterol compared to controls, but these effects
seemed to be more pronounced after KO intake compared
to FO intake.25 The reason for this discrepancy may be that
Tillander et al29 used mice on a high-fat diet and not lean
rats, and moreover, the amount of oil differed between the
two studies.
In three of the studies, similar amounts of EPA and DHA
from KO and FO were used in the experiments, and the dose
of EPA and DHA was similar between the experiments.26–28
Vigerust et al26 did not observe any significant difference
between the effects of KO and FO on plasma lipids, but KO
significantly reduced plasma TG compared to controls, sug-
gesting that KO is more effective than FO in lowering plasma
TG. However, LDL cholesterol was significantly reduced
in the FO group compared to controls, thus suggesting that
FO is more effective than KO in lowering plasma LDL
cholesterol. Total plasma cholesterol, free cholesterol, and
HDL cholesterol were however significantly reduced in both
groups compared to controls, but no differences between KO
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521
PUFA bioavailability and health effects of krill oil versus sh oil
Table 2 (Continued)
Study Animal
model
Amount of n-3 PUFA Duration Experimental diet Plasma lipids and plasma
fatty acid composition
(EPA and DHA)
Lipids and composition
of fatty acids in liver
(EPA and DHA)
Other lipid effects Inammation and
oxidative stress
Other effects
Ierna
et al (2010)30
Male DBA/1
mice,
induced with
arthritis
following
25 days of
feeding
CO: EPA and DHA 0 g/100 g
diet. KO: 0.30 g EPA/100 g
diet and 0.14 g DHA/100 g
diet. FO: 0.29 g EPA/100 g
diet and 0.18 g DHA/100 g
diet.
68 days Mice were fed AIN-93G diet
with substitution of soybean
oil with a blend of oils. The
three diets (control and diet
supplemented with FO or KO)
were similar for total fatty
acids, and FO and KO were
balanced for EPA and DHA.
KO increased clinical arthritis
more slowly compared
to control. Hind paw
thickness and histopathology
associated with arthritis were
signicantly reduced by KO
compared to control. FO
signicantly increased serum
IL1α and IL13 compared to
control.
A signicantly higher weight gain by
KO compared to control.
Batetta
et al (2009)27
Male Zucker
rats
CO: EPA and DHA 0 g/100 g
diet. KO: 0.30 g EPA/100 g
diet and 0.14 g DHA/100 g
diet. FO: 0.29 g EPA/100 g
diet and 0.18 g DHA/100 g
diet
4 weeks Rats were fed AIN-93G diet
with substitution of soybean
oil with a blend of oils. The
three diets (control, and diet
supplemented with FO or KO)
were similar for total fatty
acids, and FO and KO were
balanced for EPA and DHA.
KO and FO signicantly reduced
LDL-C compared to control.
FO and KO signicantly increased
TG compared to control.
No difference in HDL-C. FO and
KO signicantly increased EPA
and DHA compared to CO.
FO and KO signicantly
reduced TG compared to
control. KO signicantly
reduced TG to a greater extent
compared to FO. FO and KO
signicantly increased EPA and
DHA compared to control.
EPA was signicantly higher
in PL after FO and KO intake
compared to control. DHA PL
was signicantly increased by
KO compared to control.
Heart TG was signicantly reduced
by KO compared to control. FO and
KO signicantly increased EPA and
DHA in VAT and SAT TG and PL
compared to control. In heart, KO
and FO signicantly increased EPA
and DHA in TG and PL compared
to control.
No differences in
proinammatory and anti-
inammatory cytokines in
any groups. In macrophages
incubated with LPSs, TNFα
secretion was signicantly
lower after intake of FO and
KO compared to control.
No difference between FO
and KO. In VAT, lower level
of AEA induced by KO and
FO compared to control.
2-AG level lowered by KO.
In liver and heart, AEA
lowered by KO and FO,
more pronounced effect by
KO. 2-AG increased by KO.
In VAT, MAGL activity was
decreased by FO and KO compared
to control. In heart, MAGL activity
signicantly decreased by KO
compared to control.
Abbreviations: 2-AG, 2-arachidonoylglycerol; ACC, acetyl Co-A carboxylase; ACOX1, peroxisomal acyl-CoA oxidase; AEA, N-arachidonoylethanolamine; C, cholesterol;
CAT, catalase; CE, cholesterol ester; CoA, coenzyme A; CO, corn oil; CPTII, carnitine palmitoyltransferase II; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid;
FAS, fatty acid synthetase; FxO, axseed oil; FO, sh oil; HDL, high-density lipoprotein; GSH-Px, glutathione peroxidase; IL, interleukin; ;IL-1a, interleukin-1alpha, KO, krill
oil; LDL-C, low-density lipoprotein cholesterol; LDLR, LDL receptor; LPS, lipopolysaccharide; MAGL, monoacylglycerol lipase; MO, menhaden oil; NEFA, nonesteried fatty
acid; OO, olive oil; PGE2, prostaglandin E2; PL, phospholipid; PUFA, polyunsaturated fatty acid; RBC, red blood cell; SO, salmon oil; SOD, superoxide dismutase; TAC, total
antioxidant capacity; TBARS, thiobarbituric acid-reactive substances; TG, triglyceride; TNFα, tumor necrosis factor alpha; TO, tuna oil; TXB2, thromboxane B2; VAT, visceral
adipose tissue; VLDL, very-low-density lipoprotein; AIN, American Institute of Nutrition rodent diet, SAT, subcutaneous adipose tissue.
and FO were observed. These data are in line with the results
of Batetta et al,27 who showed that KO and FO significantly
reduced LDL cholesterol compared to control. In contrast,
Burri et al,28 who fed mice for 12 weeks with similar amounts
of EPA and DHA, did not see any changes in plasma lipids
in any of the groups. These conflicting results may be due to
the longer period of supplementation and probably because
the mice were lean and not fed a high fat diet, as was done
by Batetta et al27 and Vigerust et al,26 respectively.
Inammation
Vigerust et al26 did not observe any substantial difference
in levels of proinflammatory cytokines between treat-
ment groups. Batetta et al27 compared the effects of KO
and FO on ectopic fat and inflammation in obese rats.
Lipopolysaccharides significantly increased the release of
TNFα from all three groups; however, the increase was higher
in the control compared to FO- and KO-treated groups, with
no difference between these two groups. In these obese rats,
KO also seemed to have a more pronounced inhibitory effect
on the endocannabinoid system compared to FO, which is
in accordance with the results of the human study by Banni
et al.20
Ierna et al30 used an arthritis-induced mouse model to
show that clinical arthritis score and hind paw swelling were
significantly reduced in the KO group compared to controls.
Mice fed the KO also had lower infiltration of inflammatory
cells into the joint and synovial layer hyperplasia when com-
pared to control. Thus, in this mouse model, KO seems to be
more efficient compared to FO, in the treatment of arthritis.
KO did not modulate the levels of serum cytokines, whereas
consumption of FO increased the level of interleukin (IL)-1a
and IL-13.30 Tou et al31 observed no significant effects on
the Series-2 prostaglandins, thromboxane B metabolites,
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Ulven and Holven
and markers of oxidative stress when rats were fed different
marine oils.
Biological effects
In four studies, the aim was to understand biological effects
of KO and FO by studying gene expression levels and protein
activity in the liver.25,26,28,29 Ferramosca et al25 fed the same
amount of FO and KO to rats and both oils significantly
reduced the hepatic activity and expression of the mitochon-
drial tricarboxylate carrier. They also observed that FO and
KO significantly reduced the activity of enzymes catalyzing
de novo lipogenesis compared to the activity in controls.
Tillander et al29 used quantitative polymerase chain reaction
(PCR) to study changes in hepatic gene expression after KO
and FO supplementation. FO mainly increased the expres-
sion of genes involved in fatty acid metabolism, while KO
specifically decreased the expression of genes involved in
isoprenoid/cholesterol and lipid synthesis.
Vigerust et al26 showed that KO significantly increased
the mitochondrial and peroxisomal fatty acid β-oxidation,
as well as the overall carnitine turnover in the liver, which
can explain the TG-lowering effect of KO seen in this study.
Thus, it seems that KO has a greater potential to promote
lipid catabolism. By the use of quantitative PCR, Vigerust
et al26 showed that both KO and FO downregulated specific
hepatic target genes involved in de novo lipogenesis and
genes involved in cholesterol import and synthesis compared
to the control-treated groups.
Burri et al28 also fed mice with different amounts of FO and
KO to maintain the content of EPA and DHA similar in the two
groups to evaluate the efficacy of KO and FO administration
on gene expression profiling in liver. Long-chain n-3 PUFAs
derived from KO downregulated the activity of pathways
involved in hepatic glucose production as well as in lipid
and cholesterol synthesis. The data also suggested that KO
increases the activity of the mitochondrial respiratory chain.
Long-chain n-3 PUFAs derived from FO modulated fewer
pathways, even if the content of EPA and DHA was the same
as KO, and did not modulate key metabolic pathways regulated
by KO. FO also upregulated the cholesterol synthesis pathway,
which was the opposite of the effect mediated by KO.
Discussion
Studies on the bioavailability of EPA and DHA from KO and
FO in humans and animals are limited and their interpreta-
tion is difficult, as different amounts of EPA and DHA have
been used, duration of intervention differs among the studies,
and different study groups have been included. Two human
studies that are included in this review – one postprandial
study and one intervention study – used the same amount
of EPA and DHA from KO or FO, and they both show that
the bioavailability of EPA and DHA from KO seems to be
higher than from that from FO.19,21 This strengthens the
hypothesis that there is a difference between the bioavail-
ability of PUFAs from KO and FO. In contrast, Laidlaw
et al24 showed that similar amounts of EPA from PL KO and
TG SO resulted in the same increase in whole-blood EPA,
suggesting that there is no difference in bioavailability of
DHA from FO and KO. The problem in comparing these
studies is that one study analyzed whole-blood fatty acids,
while the two other studies used plasma PLs and plasma
RBCs. In future studies, the same amount of EPA and
DHA from KO and FO should be compared in plasma PLs,
RBCs, and whole blood. If possible, adipose tissue biopsies
should also be taken to study whether the fatty acids from
KO and FO are differently incorporated into adipose tissue,
as shown in the animal study by Tou et al.31 In animals, one
study29 also indicates that KO may have a higher bioavail-
ability compared to FO; however, another study indicates
that bioavailability is not dependent on the structural form
of EPA and DHA.26
The doses of KO and FO, type of study subjects, and
duration of the studies showed very limited effects on lipids
and inflammatory markers in human studies. Most of the
studies did not see any effects between the groups. In one
study,19 total cholesterol and LDL cholesterol increased fol-
lowing intake of KO and FO compared to controls, while
Bunea et al23 showed reduction in concentration of total
cholesterol and LDL cholesterol by KO and FO, as well
as reduction in TG by KO. KO (at most doses) was more
efficient than FO in reducing glucose and LDL cholesterol,
whereas high-dose KO was more efficient in reducing plasma
TG than FO.23
In the future, better-designed clinical studies are war-
ranted to gain insight into the beneficial health effects of
KO compared to FO. The animal studies show that there is
a very small difference between KO and FO when it comes
to health effects. KO seems to be more efficient in reducing
the concentration of plasma TG, liver TG, and endocan-
nabinoids, compared to FO, in animal studies. No adverse
effects were reported.
Because KO and FO differ in their structural form, this
may influence the incorporation of EPA and DHA into cells,
resulting in different biological effects. KO also contains the
antioxidant astaxanthin that protects the unsaturated bonds
in the fatty acid from oxidative damage, which may influ-
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PUFA bioavailability and health effects of krill oil versus sh oil
ence the biological effects of KO. The possible biological
difference between FO and KO was studied in animal mod-
els using gene expression analysis.25,26,28,29 EPA and DHA
possibly regulate the activity of transcription factors by
acting as ligands for the peroxisome-proliferator-activated
receptor alpha (PPARα) or influence the activity of sterol
regulator element-binding protein 1-c (SREBP1c).32,33
Consequently, these fatty acids have the ability to control
transcription factor activity, which in turn regulates gene
expression. Many of the beneficial health effects of EPA and
DHA may be linked to their role of regulating expression
of genes encoding proteins involved in transport, uptake,
and storage of lipids, as well as enzymes involved in meta-
bolic pathways and processes. The results from the studies
included here show that FO upregulated the cholesterol
synthesis pathway, which was opposite of the effect medi-
ated by KO. KO also regulated more metabolic pathways
than FO because glucose, fatty acid, and lipid metabolism
pathways were affected by KO in some studies, and the same
biological response was not seen with FO. This difference
in biological effect may be caused by the different structure
of PLs in KO and TG in FO.
In humans, it is also possible to perform biological studies
using peripheral blood mononuclear cells (PBMCs), which
are readily available, and FO has previously been shown to
be able to modulate gene expression in these cells in human
trials.34 PBMC gene expression analysis in human dietary
intervention studies with FO and KO can be a powerful tool
to understand the underlying molecular mechanisms of the
effect mediated by these oils on lipid metabolism and inflam-
mation in humans.
Conclusion
Studies suggest that there may be a difference in the bioavail-
ability of EPA and DHA after intake of KO and FO. However,
more human studies designed to compare the effect of KO
and FO are needed to conclude if the bioavailability of EPA
and DHA differs between KO and FO. Furthermore, it is also
necessary to document beneficial health effects of KO with
high-quality human studies and to investigate whether these
effects differ compared to the effects observed after regular
fish and FO intake.
Acknowledgments
This work was supported by the Oslo and Akershus
University College of Applied Sciences, University of Oslo,
and the Throne Holst Foundation for Nutrition Research,
Norway.
Disclosure
The authors report no conflicts of interest in this work.
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... Phospholipids improve tissue uptake and facilitate efficient brain delivery [6]. The potent antioxidant and anti-inflammatory compound astaxanthin is a natural component of krill oil [7]. In a MPTP-induced Parkinson Disease (PD) mouse model, astaxanthin protected dopaminergic neurons in the nigrostriatal circuit in young mice, but not in older animals [8]. ...
... In a MPTP-induced Parkinson Disease (PD) mouse model, astaxanthin protected dopaminergic neurons in the nigrostriatal circuit in young mice, but not in older animals [8]. Krill oil is also a dietary source of the essential nutrient choline [7] which is a component of the phospholipid phosphatidylcholine (PC) and a precursor of the neurotransmitter acetylcholine [9]. Thus, due to the combination of several compounds with neuroprotective properties (choline, EPA/DHA and astaxanthin) [10,11], exquisite bioavailability, krill oil may be a nutraceutical of choice to boost brain health [9]. ...
Article
There is accumulating evidence that interfering with the basic aging mechanisms can enhance healthy longevity. The interventional/therapeutic strategies targeting multiple aging hallmarks could be more effective than targeting one hallmark. While health-promoting qualities of marine oils have been extensively studied, the underlying molecular mechanisms are not fully understood. Lipid extracts from Antarctic krill are rich in long-chain omega-3 fatty acids choline, and astaxanthin. Here, we used C. elegans and human cells to investigate whether krill oil promotes healthy aging. In a C. elegans model of Parkinson´s disease, we show that krill oil protects dopaminergic neurons from aging-related degeneration, decreases alpha-synuclein aggregation, and improves dopamine-dependent behavior and cognition. Krill oil rewires distinct gene expression programs that contribute to attenuating several aging hallmarks, including oxidative stress, proteotoxic stress, senescence, genomic instability, and mitochondrial dysfunction. Mechanistically, krill oil increases neuronal resilience through temporal transcriptome rewiring to promote anti-oxidative stress and anti-inflammation via healthspan regulating transcription factors such as SNK-1. Moreover, krill oil promotes dopaminergic neuron survival through regulation of synaptic transmission and neuronal functions via PBO-2 and RIM-1. Collectively, krill oil rewires global gene expression programs and promotes healthy aging via abrogating multiple aging hallmarks, suggesting directions for further pre-clinical and clinical explorations.
... This has been previously reported, for example, for n-3 PUFAs bound in PLs in krill oil (high bioavailability), as compared with natural fish oil where EPA and DHA are bound in TAGs. 28,29 Recent clinical trials have reported a rapid incorporation of EPA and DHA from oral nutrition supplements into colonic tissue of colorectal cancer Symbol * denotes a significant difference between control and the respective treatment group (P < 0.05). Symbol # denotes a significant difference between the respective NaBt-and DHA/NaBt-treated groups (P < 0.05). ...
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Docosahexaenoic acid (DHA) and sodium butyrate (NaBt) exhibit a number of interactive effects on colon cancer cell growth, differentiation, or apoptosis; however, the molecular mechanisms responsible for these interactions and their impact on cellular lipidome are still not fully clear. Here, we show that both dietary agents together induce dynamic alterations of lipid metabolism, specific cellular lipid classes, and fatty acid composition. In HT-29 cell line, a model of differentiating colon carcinoma cells, NaBt supported incorporation of free DHA into non-polar lipids and their accumulation in cytoplasmic lipid droplets. DHA itself was not incorporated into sphingolipids; however, it significantly altered representation of individual ceramide (Cer) classes, in particular in combination with NaBt (DHA/NaBt). We observed altered expression of enzymes involved in Cer metabolism in cells treated with NaBt or DHA/NaBt, and exogenous Cer 16:0 was found to promote induction of apoptosis in differentiating HT-29 cells. NaBt, together with DHA, increased n-3 fatty acid synthesis and attenuated metabolism of monounsaturated fatty acids. Finally, DHA and/or NaBt altered expression of proteins involved in synthesis of fatty acids, including elongase 5, stearoyl CoA desaturase 1, or fatty acid synthase, with NaBt increasing expression of caveolin-1 and CD36 transporter, which may further promote DHA incorporation and its impact on cellular lipidome. In conclusion, our results indicate that interactions of DHA and NaBt exert complex changes in cellular lipidome, which may contribute to the alterations of colon cancer cell differentiation/apoptotic responses. The present data extend our knowledge about the nature of interactive effects of dietary fatty acids. K E Y W O R D S
... In addition, it is rich in vitamin A, E, and carotenoid astaxanthin, which makes it more stable and resistant to oxidation, compared to fish oil in terms of biological effects [5,6]. Krill oil is also associated with the regulation of lipid metabolism, inflammation, and oxidative stress [7]. Given this perspective, considering the nutritional quality of krill oil and its benefits, it is questioned whether it has any influence on adiposity. ...
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An excess of body fat is one of the biggest public health concerns in the world, due to its relationship with the emergence of other health problems. Evidence suggests that supplementation with long-chain polyunsaturated fatty acids (omega-3) promotes increased lipolysis and the reduction of body mass. Likewise, this clinical trial aimed to evaluate the effects of supplementation with krill oil on waist circumference and sagittal abdominal diameter in overweight women. This pilot, balanced, double-blind, and placebo-controlled study was carried out with 26 women between 20 and 59 years old, with a body mass index >25 kg/m2. The participants were divided into the control (CG) (n = 15, 3 g/daily of mineral oil) and krill oil (GK) (n = 16, 3 g/daily of krill oil) groups, and received the supplementation for eight weeks. Food intake variables were obtained using a 24 h food recall. Anthropometric measurements (body mass, body mass index, waist circumference, and sagittal abdominal diameter) and handgrip strength were obtained. After the intervention, no changes were found for the anthropometric and handgrip strength variables (p > 0.05). Regarding food intake, differences were found for carbohydrate (p = 0.040) and polyunsaturated (p = 0.006) fatty acids, with a reduction in the control group and an increase in krill oil. In conclusion, supplementation with krill oil did not reduce the waist circumference and sagittal abdominal diameter. Therefore, more long-term studies with a larger sample size are necessary to evaluate the possible benefits of krill oil supplementation in overweight women.
... The oral administration also ameliorates NAFLD and dyslipidemia with lower liver damage and adiposity indices, together with a reduction in the blood levels of triglycerides and total/LDL cholesterols and downregulation of hepatic genes involving lipid synthesis (e.g., SREBP1c, FAS, and PPARα) [40][41][42]. Furthermore, many animal studies on the dietary effects of KO supplemented in HFD have shown similar beneficial effects on hepatic steatosis and dyslipidemia as well as improvements in insulin resistance (reviewed in [24,[27][28][29][30][31][32][33][34][35][36]). Thus, these results demonstrated convincing inhibitory effects of KO on the progress of obesity and the metabolic syndromes. ...
Article
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Obesity increases the risks of metabolic syndromes including nonalcoholic fatty liver disease (NAFLD), diabetic dyslipidemia, and chronic kidney disease. Dietary krill oil (KO) has shown antioxidant and anti-inflammatory properties, thereby being a therapeutic potential for obesity-induced metabolic syndromes. Thus, the effects of KO on lipid metabolic alteration were examined in a high-fat diet (HFD)-fed mice model. The HFD model (n = 10 per group) received an oral gavage with distilled water as a control, metformin at 250 mg/kg, and KO at 400, 200, and 100 mg/kg for 12 weeks. The HFD-induced weight gain and fat deposition were significantly reduced in the KO treatments compared with the control. Blood levels were lower in parameters for NAFLD (e.g., alanine aminotransferase, and triglyceride), type 2 diabetes (e.g., glucose and insulin), and renal dysfunction (e.g., blood urea nitrogen and creatinine) by the KO treatments. The KO inhibited lipid synthesis through the modification of gene expressions in the liver and adipose tissues and adipokine-mediated pathways. Furthermore, KO showed hepatic antioxidant activities and glucose lowering effects. Histopathological analyses revealed that the KO ameliorated the hepatic steatosis, pancreatic endocrine/exocrine alteration, adipose tissue hypertrophy, and renal steatosis. These analyses suggest that KO may be promising for inhibiting obesity and metabolic syndromes.
... The raw materials that can be used in supplements in Japan are a triglyceride (TG) form (DHA/TG, EPA/TG) and a phospholipid (PL) form (DHA/PL, EPA/PL). DHA/PL and EPA/PL are known to be more bioavailable than DHA/TG and EPA/TG (11). However, commercially available fish oil, the main source of DHA/TG and EPA/TG, is more cost effective than krill oil, the main source of DHA/PL and EPA/PL (12). ...
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Background Health benefits of n-3 (Omega-3) polyunsaturated fatty acids are well studied. A self-emulsifying drug delivery system (SEDDS) is expected to improve n-3 polyunsaturated fatty acids absorption. Objective The present study investigated how a single ingestion of a new SEDDS containing triglyceride form of docosahexaenoic acid (DHA/TG) would affect the plasma DHA level in healthy participants. Methods Fifteen healthy participants (Age 20–65 years old, BMI, 18.5–25 kg/m2) were enrolled in this randomized, double-blind, crossover study. Participants in a fasting state consumed a single dose of 920 mg DHA and 80 mg eicosapentaenoic acid (EPA) in SEDDS soft capsules (SEDDS capsule) or non-emulsifying soft capsules (control capsule). Blood was sampled at 0, 1.5, 3, 5, 7, and 9 h after dosing. The primary outcome was the baseline-adjusted incremental area under the curve (AUC) for plasma DHA levels (iAUC_DHA). Results The iAUC_DHA were significantly higher for the SEDDS capsule (147.9 ± 15.8 µg · h/mL) than for the control capsule (106.4 ± 18.1 µg · h/mL) (P = 0.018, SEDDS/control ratio, 1.4). Although plasma EPA levels and iAUC values did not significantly differ between the SEDDS and control capsules. Cmax was significantly higher with the SEDDS capsule for both DHA (P = 0.019) and EPA (P = 0.012) than with the control capsule. Conclusion These results suggest that SEDDS improves the absorbability of DHA/TG in healthy participants. This indicates that SEDDS capsules would be beneficial for efficient ingestion of DHA. This trial was registered at the University Hospital Medical Information Network Clinical Trials Registry as UMIN000044188 (https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000050425).
... In human studies, KO has proven beneficial for a few diseases, including osteoarthritis, arthritis, knee joint pain and hyperlipidemia [44], all of which are closely associated with inflammation and oxidative stress. To date, KO has not been investigated for its effects on clinical DM and complications. ...
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Diabetic cardiomyopathy (DCM) is a common complication of diabetes mellitus (DM), resulting in high mortality. Myocardial fibrosis, cardiomyocyte apoptosis and inflammatory cell infiltration are hallmarks of DCM, leading to cardiac dysfunction. To date, few effective approaches have been developed for the intervention of DCM. In the present study, we investigate the effect of krill oil (KO) on the prevention of DCM using a mouse model of DM induced by streptozotocin and a high-fat diet. The diabetic mice developed pathological features, including cardiac fibrosis, apoptosis and inflammatory cell infiltration, the effects of which were remarkably prevented by KO. Mechanistically, KO reversed the DM-induced cardiac expression of profibrotic and proinflammatory genes and attenuated DM-enhanced cardiac oxidative stress. Notably, KO exhibited a potent inhibitory effect on NLR family pyrin domain containing 3 (NLRP3) inflammasome that plays an important role in DCM. Further investigation showed that KO significantly upregulated the expression of Sirtuin 3 (SIRT3) and peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), which are negative regulators of NLRP3. The present study reports for the first time the preventive effect of KO on the pathological injuries of DCM, providing SIRT3, PGC-1α and NLRP3 as molecular targets of KO. This work suggests that KO supplementation may be a viable approach in clinical prevention of DCM.
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Euphausia superba (Antarctic krill) serine protease (ESP) was investigated to gain insights into the activity-structural relationship, folding behavior, and regulation of the catalytic function. We purified ESP from the krill muscle and characterized biochemical distinctions via enzyme kinetics. Studies of inhibition kinetics and unfolding in the presence of a serine residue modifier, such as phenylmethanesulfonyl fluoride, were conducted. Structural characterizations were measured by spectrofluorimetry, including 1-anilinonaphthalene-8-sulfonate dye labeling for hydrophobic residues. The computational simulations such as docking and molecular dynamics were finally conducted to detect key residues and folding behaviors in a nano-second range. The kinetic parameters of ESP were measured as KmBANH = 0.97 ± 0.15 mM and kcat/KmBANH = 4.59 s⁻¹/mM. The time-interval kinetics measurements indicated that ESP inactivation was transformed from a monophase to a biphase process to form a thermodynamically stable state. Spectrofluorimetry measurements showed that serine is directly connected to the regional folding of ESP. Several osmolytes such as proline and glycine only partially protected the inactive form of ESP by serine modification. Computational molecular dynamics and docking simulations showed that three serine residues (Ser183, Ser188, and Ser207) and Cys184, Val206, and Gly209 are key residues of catalytic functions. Our study revealed the functional roles of serine residues as key residues of catalytic function at the active site and of the structural conformation as key folding factors, where ESP displays a flexible property of active site pocket compared to the overall structure. Communicated by Ramaswamy H. Sarma
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Bile acids (BAs) metabolism plays an important role in alcohol liver disease (ALD) through the gut microflora-bile acids-liver axis. Antarctic Krill Oil (AKO) has protective effects on the liver, while whether AKO can protect against liver injury caused by alcohol is unclear. This study investigated the effects of AKO on BAs metabolism and intestinal microbiota in a rat model of alcohol-induced liver disease. Sprague-Dawley (SD) rats were randomly divided into five groups: control group, model group, low-dose AKO-treatment group (100 mg/kg/d), high-dose AKO-treatment group (200 mg/kg/d), and AKO control group (200 mg/kg/d). Administration of alcohol (8 to 10 mL/kg/ d) for 16 weeks induced liver injury in rats. We found that AKO supplementation significantly protected the liver against alcohol-induced injury, evidenced by allayed hepatic histopathological changes, and inhibited the alcohol-induced elevation of serum biochemical indices. Furthermore, AKO could regulate BAs metabolism by activating the intestinal-hepatic FXR-FGF15-FGFR4 signaling axis with subsequently decreased cholesterol 7α-hydroxylase (CYP7A1) and sterol 12α-hydroxylase (CYP8B1) levels, reduced hepatic BAs production, decreased serum BAs level and increased fecal excretion of BAs. Additionally, 16S rDNA sequencing revealed that the gut microbiome richness and composition were altered in alcohol-treated rats in comparison to the control and AKO-administrated rats. Spearman's correlation analysis showed that differential gut bacterial genera correlated with the levels of BAs profiles in the serum, liver, and feces. These findings suggested that AKO dietary supplementation may protect against alcohol-induced liver injury through modulating BAs metabolism and altering the gut microbiome.
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Acute liver injury is a life-threatening syndrome that often results from the actions of viruses, drugs and toxins. Herein, the protective effect and potential mechanism of krill oil (KO), a novel natural product rich in long-chain n-3 polyunsaturated fatty acids bound to phospholipids and astaxanthin, on lipopolysaccharide (LPS)-evoked acute liver injury in mice were investigated. Male C57BL/6J mice were administered intragastrically with 400 mg kg-1 KO or fish oil (FO) once per day for 28 consecutive days prior to LPS exposure (10 mg kg-1, intraperitoneally injected). The results revealed that KO pretreatment significantly ameliorated LPS-evoked hepatic dysfunction indicated by reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities and attenuated hepatic histopathological damage. KO pretreatment also mitigated LPS-induced hepatic oxidative stress, as evidenced by decreased malondialdehyde (MDA) contents, elevated glutathione (GSH) levels, and elevated catalase (CAT) and superoxide dismutase (SOD) activities. Additionally, LPS-evoked overproduction of pro-inflammatory mediators in serum and the liver was inhibited by KO pretreatment. Furthermore, KO pretreatment suppressed LPS-induced activation of the hepatic toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB)/NOD-like receptor family pyrin domain containing 3 (NLRP3) signaling pathway. Interestingly, the hepatoprotective effect of KO was superior to that of FO. Collectively, the current findings suggest that KO protects against LPS-evoked acute liver injury via inhibition of oxidative stress and inflammation.
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Intake of marine n-3 fatty acids has been shown to have beneficial effects on cardiovascular disease. Gene expression analyses in peripheral blood mononuclear cells (PBMCs) are used to understand the underlying mechanisms of action of marine n-3 fatty acids. The aim of this review was to summarize the effects mediated by marine n-3 fatty acids on gene expression in PBMCs. A systematic literature search was conducted in PubMed in May 2014 and 14 papers were included. Targeted gene expression studies were reported in 9 papers and focused on genes involved in lipid metabolism and inflammation. Whole genome transcriptome analyses were conducted in 5 papers, and processes and pathways related to atherosclerotic plaque formation such as inflammation, oxidative stress response, cell cycle, cell adhesion, and apoptosis were modulated after fish oil supplementation. PBMC gene expression profiling has a potential to clarify further the molecular effects of fish oil consumption on human health.
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Fish oil dietary supplements and complementary medicines are pitched to play a role of increasing strategic importance in meeting daily requirements of essential nutrients, such as long-chain (≥C20, LC) omega-3 polyunsaturated fatty acids and vitamin D. Recently a new product category, derived from Antarctic krill, has been launched on the omega-3 nutriceutical market. Antarctic krill oil is marketed as demonstrating a greater ease of absorption due to higher phospholipid content, as being sourced through sustainable fisheries and being free of toxins and pollutants; however, limited data is available on the latter component. Persistent Organic Pollutants (POP) encompass a range of toxic, man-made contaminants that accumulate preferentially in marine ecosystems and in the lipid reserves of organisms. Extraction and concentration of fish oils therefore represents an inherent nutritional-toxicological conflict. This study aimed to provide the first quantitative comparison of the nutritional (EPA and DHA) versus the toxicological profiles of Antarctic krill oil products, relative to various fish oil categories available on the Australian market. Krill oil products were found to adhere closely to EPA and DHA manufacturer specifications and overall were ranked as containing intermediate levels of POP contaminants when compared to the other products analysed. Monitoring of the pollutant content of fish and krill oil products will become increasingly important with expanding regulatory specifications for chemical thresholds.
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Omega-3 fatty acids confer beneficial health effects, but North Americans are lacking in their dietary omega-3-rich intake. Supplementation is an alternative to consumption of fish; however, not all omega-3 products are created equal. The trial objective was to compare the increases in blood levels of omega-3 fatty acids after consumption of four different omega-3 supplements, and to assess potential changes in cardiovascular disease risk following supplementation. This was an open-label, randomized, cross-over study involving thirty-five healthy subjects. Supplements and daily doses (as recommended on product labels) were: Concentrated Triglyceride (rTG) fish oil: EPA of 650 mg, DHA of 450 mg Ethyl Ester (EE) fish oil: EPA of 756 mg, DHA of 228 mg Phospholipid (PL) krill oil: EPA of 150 mg, DHA of 90 mg Triglyceride (TG) salmon oil: EPA of 180 mg, DHA of 220 mg. Subjects were randomly assigned to consume one of four products, in random order, for a 28-day period, followed by a 4-week washout period. Subsequent testing of the remaining three products, followed by 4-week washout periods, continued until each subject had consumed each of the products. Blood samples before and after supplementation were quantified for fatty acid analysis using gas chromatography, and statistically analysed using ANOVA for repeated measures. At the prescribed dosage, the statistical ranking of the four products in terms of increase in whole blood omega-3 fatty acid levels was concentrated rTG fish oil > EE fish oil > triglyceride TG salmon oil > PL krill oil. Whole blood EPA percentage increase in subjects consuming concentrated rTG fish oil was more than four times that of krill and salmon oil. Risk reduction in several elements of cardiovascular disease was achieved to a greater extent by the concentrated rTG fish oil than by any other supplement. Krill oil and (unconcentrated) triglyceride oil were relatively unsuccessful in this aspect of the study. For the general population, the form and dose of omega-3 supplements may be immaterial. However, given these results, the form and dose may be important for those interested in reducing their risk of cardiovascular disease. Trial registration ClinicalTrials.gov: NCT01960660.
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Marine derived oils are rich in long-chain polyunsaturated omega-3 fatty acids, in particular eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which have long been associated with health promoting effects such as reduced plasma lipid levels and anti-inflammatory effects. Krill oil (KO) is a novel marine oil on the market and is also rich in EPA and DHA, but the fatty acids are incorporated mainly into phospholipids (PLs) rather than triacylglycerols (TAG). This study compares the effects of fish oil (FO) and KO on gene regulation that influences plasma and liver lipids in a high fat diet mouse model. Male C57BL/6J mice were fed either a high-fat diet (HF) containing 24% (wt/wt) fat (21.3% lard and 2.3% soy oil), or the HF diet supplemented with FO (15.7% lard, 2.3% soy oil and 5.8% FO) or KO (15.6% lard, 2.3% soy oil and 5.7% KO) for 6 weeks. Total levels of cholesterol, TAG, PLs, and fatty acid composition were measured in plasma and liver. Gene regulation was investigated using quantitative PCR in liver and intestinal epithelium. Plasma cholesterol (esterified and unesterified), TAG and PLs were significantly decreased with FO. Analysis of the plasma lipoprotein particles indicated that the lipid lowering effect by FO is at least in part due to decreased very low density lipoprotein (VLDL) content in plasma with subsequent liver lipid accumulation. KO lowered plasma non-esterified fatty acids (NEFA) with a minor effect on fatty acid accumulation in the liver. In spite of a lower omega-3 fatty acid content in the KO supplemented diet, plasma and liver PLs omega-3 levels were similar in the two groups, indicating a higher bioavailability of omega-3 fatty acids from KO. KO more efficiently decreased arachidonic acid and its elongation/desaturation products in plasma and liver. FO mainly increased the expression of several genes involved in fatty acid metabolism, while KO specifically decreased the expression of genes involved in the early steps of isoprenoid/cholesterol and lipid synthesis. The data show that both FO and KO promote lowering of plasma lipids and regulate lipid homeostasis, but with different efficiency and partially via different mechanisms.
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Due to structural differences, bioavailability of krill oil, a phospholipid based oil, could be higher than fish oil, a triglyceride-based oil, conferring properties that render it more effective than fish oil in increasing omega-3 index and thereby, reducing cardiovascular disease (CVD) risk. The objective was to assess the effects of krill oil compared with fish oil or a placebo control on plasma and red blood cell (RBC) fatty acid profile in healthy volunteers.Participants and methods: Twenty four healthy volunteers were recruited for a double blinded, randomized, placebo-controlled, crossover trial. The study consisted of three treatment phases including krill or fish oil each providing 600 mg of n-3 polyunsaturated fatty acids (PUFA) or placebo control, corn oil in capsule form. Each treatment lasted 4 wk and was separated by 8 wk washout phases. Krill oil consumption increased plasma (p = 0.0043) and RBC (p = 0.0011) n-3 PUFA concentrations, including EPA and DHA, and reduced n-6:n-3 PUFA ratios (plasma: p = 0.0043, RBC: p = 0.0143) compared with fish oil consumption. Sum of EPA and DHA concentrations in RBC, the omega-3 index, was increased following krill oil supplementation compared with fish oil (p = 0.0143) and control (p < 0.0001). Serum triglycerides and HDL cholesterol concentrations did not change with any of the treatments. However, total and LDL cholesterol concentrations were increased following krill (TC: p = 0.0067, LDL: p = 0.0143) and fish oil supplementation (TC: p = 0.0028, LDL: p = 0.0143) compared with control. Consumption of krill oil was well tolerated with no adverse events. Results indicate that krill oil could be more effective than fish oil in increasing n-3 PUFA, reducing n-6:n-3 PUFA ratio, and improving the omega-3 index.Trial registration: clinicaltrials.gov# NCT01323036.
Article
Inflammation is a condition which contributes to a range of human diseases. It involves a multitude of cell types, chemical mediators, and interactions. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are omega-3 (n-3) fatty acids found in oily fish and fish oil supplements. These fatty acids are able to partly inhibit a number of aspects of inflammation including leukocyte chemotaxis, adhesion molecule expression and leukocyte-endothelial adhesive interactions, production of eicosanoids like prostaglandins and leukotrienes from the n-6 fatty acid arachidonic acid, production of inflammatory cytokines, and T-helper 1 lymphocyte reactivity. In addition, EPA gives rise to eicosanoids that often have lower biological potency than those produced from arachidonic acid and EPA and DHA give rise to anti-inflammatory and inflammation resolving mediators called resolvins, protectins and maresins. Mechanisms underlying the anti-inflammatory actions of marine n-3 fatty acids include altered cell membrane phospholipid fatty acid composition, disruption of lipid rafts, inhibition of activation of the pro-inflammatory transcription factor nuclear factor kappa B so reducing expression of inflammatory genes, activation of the anti-inflammatory transcription factor peroxisome proliferator activated receptor γ and binding to the G protein coupled receptor GPR120. These mechanisms are interlinked, although the full extent of this is not yet elucidated. Animal experiments demonstrate benefit from marine n-3 fatty acids in models of rheumatoid arthritis (RA), inflammatory bowel disease (IBD) and asthma. Clinical trials of fish oil in RA demonstrate benefit, but clinical trials of fish oil in IBD and asthma are inconsistent with no overall clear evidence of efficacy. This article is part of a Special Issue entitled "Oxygenated metabolism of PUFA: analysis and biological relevance."
Article
Background Several epidemiological and experimental studies suggest that n-3 polyunsaturated fatty acids (PUFA) can exert favourable effects on atherothrombotic cardiovascular disease, including arrhythmias. We investigated whether n-3 PUFA could improve morbidity and mortality in a large population of patients with symptomatic heart failure of any cause. Methods We undertook a randomised, double-blind, placebo-controlled trial in 326 cardiology and 31 internal medicine centres in Italy. We enrolled patients with chronic heart failure of New York Heart Association class II–IV, irrespective of cause and left ventricular ejection fraction, and randomly assigned them to n-3 PUFA 1 g daily (n=3494) or placebo (n=3481) by a concealed, computerised telephone randomisation system. Patients were followed up for a median of 3·9 years (IQR 3·0–4·5). Primary endpoints were time to death, and time to death or admission to hospital for cardiovascular reasons. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00336336. Findings We analysed all randomised patients. 955 (27%) patients died from any cause in the n-3 PUFA group and 1014 (29%) in the placebo group (adjusted hazard ratio [HR] 0·91 [95·5% CI 0·833–0·998], p=0·041). 1981 (57%) patients in the n-3 PUFA group and 2053 (59%) in the placebo group died or were admitted to hospital for cardiovascular reasons (adjusted HR 0·92 [99% CI 0·849–0·999], p=0·009). In absolute terms, 56 patients needed to be treated for a median duration of 3·9 years to avoid one death or 44 to avoid one event like death or admission to hospital for cardiovascular reasons. In both groups, gastrointestinal disorders were the most frequent adverse reaction (96 [3%] n-3 PUFA group vs 92 [3%] placebo group). Interpretation A simple and safe treatment with n-3 PUFA can provide a small beneficial advantage in terms of mortality and admission to hospital for cardiovascular reasons in patients with heart failure in a context of usual care. Funding Società Prodotti Antibiotici (SPA; Italy), Pfizer, Sigma Tau, and AstraZeneca.