Why do omega-3 fatty acids lower serum triglycerides?
William S. Harrisa,b and Deepti Bulchandanib
Purpose of review
Fish oils rich in n-3 fatty acids (n-3 FA) reduce serum
triglyceride levels. This well known effect has been shown to
be caused by decreased very low-density lipoprotein
triglyceride secretion rates in kinetic studies in humans.
Animal studies have explored the biochemical mechanisms
underlying this effect. Triglyceride synthesis could be
reduced by n-3 fatty acids in three general ways: reduced
substrate (i.e. fatty acids) availability, which could be
secondary to increase in b-oxidation, decreased free fatty
acids delivery to the liver, decreased hepatic fatty acids
synthesis; increased phospholipid synthesis; or decreased
activity of triglyceride-synthesizing enzymes (diacylgylcerol
acyltranferase or phosphatidic acid phosphohydrolase).
Recent findings
Rarely were experimental conditions used in rat studies
physiologically relevant to the human situation in which
1.2% energy as n-3 fatty acids lowers serum triglyceride
levels. Nevertheless, the most consistent effect of n-3 fatty
acids feeding in rats is to decrease lipogenesis. Increased
b-oxidation was frequently, but not consistently, reported with
similar numbers of studies reporting increased mitochondrial
compared with peroxisomal oxidation. Inhibition of
triglyceride-synthesizing enzymes was only occasionally
noted.
Summary
As the vast majority of studies fed unphysiologically high
doses of n-3 fatty acids, these findings in rats must be
considered tentative, and the mechanism by which n-3 fatty
acids reduce triglyceride levels in humans remains
speculative.
Keywords
beta-oxidation, fish oils, lipogenesis, rats, triglycerides
Curr Opin Lipidol 17:387393. 2006 Lippincott Williams & Wilkins.
a
Mid America Heart Institute, Saint Lukes Health System and bUniversity of
MissouriKansas City School of Medicine, Kansas City, Missouri, USA
Correspondence to William S. Harris, South Dakota Health Research Foundation,
Nutrition and Metabolic Diseases, 1400 W. 22nd Street, Sioux Falls, SD 57105,
USA
E-mail: Bill.Harris@usd.edu
Current Opinion in Lipidology 2006, 17:387393
Abbreviations
DGAT diacylgylcerol acyltranferase
DHA docosahexaenoic
EPA eicosapentaenoic
FA fatty acids
NEFA nonesterified fatty acids
2006 Lippincott Williams & Wilkins
0957-9672
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Introduction
Fish oils rich in omega-3 fatty acids (n-3 FA) have well
known and long-appreciated triglyceride-lowering prop-
erties [1]. Intakes of 34 g of eicosapentaenoic (EPA) and
docosahexaenoic (DHA) acids reduce serum triglycerides
by 2050%, depending on baseline values [2]. The
mechanisms by which they accomplish this have been
explored in kinetic studies in humans and animals, in
perfused liver and primary hepatocytes from n-3 FA-fed
animals, and in cell lines incubated with n-3 FA. Virtually
universal agreement exists that n-3 FA reduce hepatic
secretion of triglyceride-rich lipoproteins in humans, but
the molecular mechanisms responsible for this effect
(which occurs with intakes of only about 1.2% of energy
from EPA DHA) are not clear. The purpose of this
paper is to critically review the literature relating to the
hepatic mechanism of action of n-3 FA as studied in the
rat model (as it is by far the most common), and to assess
the extent to which the findings from these studies may
explain the effects seen in humans.
Effects of n-3 fatty acids on triglyceride-rich
lipoprotein kinetics in humans
There have been six studies [38] of the effects of n-3 FA
on triglyceride metabolism in humans. All six studies
found a reduced production (i.e. plasma appearance) rate
of very low-density lipoprotein (VLDL) with n-3 FA
consumption. Two also found increased clearance rates.
The study that is perhaps the most informative (based on
having the largest sample size, a relevant n-3 FA dose and
patient population, the longest duration and the use of
compartmental modeling) was that of Chan et al. [8]. In
this study, n-3 FA (Omacor, Reliant Pharmacueticals,
Liberty Corner, NJ) reduced production rates by 32%
but VLDL particle clearance rates were not altered.
Bordin et al. [7] provided similar amounts of n-3 FA
and reported essentially the same percentage reduction
in VLDL apoB production rates. These studies firmly
establish that at least part of the mechanism by which n-3
FA reduce serum triglyceride concentrations in humans
by inhibiting hepatic VLDL secretion rates. [We will not
address here the potential enhancement by n-3 FA of
serum triglyceride clearance mechanisms (i.e. lipoprotein
lipase) which may also play a role in reducing serum
triglyceride concentrations [911].] The consistency of
the kinetic studies allows for a more focused framing of
the question: what is (are) the molecular mechanism(s) by
which n-3 FA reduce VLDL-triglyceride secretion from
the liver? As n-3 FA feeding has not been linked with
hepatic steatosis (quite the contrary), a primary effect on
387
 388 Hyperlipidaemia and cardiovascular disease

apo-B degradation seems unlikely (despite cell culture
data suggesting it as a possibility [12,13]), leaving a
primary effect of reduced triglyceride synthesis as the
most likely candidate.
Potential mechanisms: review of
biochemical pathways
VLDL triglyceride synthesis could be reduced by n3 FA
by three general mechanisms:
(1) reduced substrate (i.e. FA) availability which could
be secondary to: (a) an increase in beta-oxidation,
whether microsomal or peroxisomal, (b) a decrease in
delivery of non-esterified FA (NEFA) to the liver, or
(c) a decrease in lipogenesis (i.e. FA synthesis);
(2) decreased activity of triglyceride-synthesizing
enzymes, such as diacylgylcerol acyltranferase
(DGAT) or phosphatidic acid phosphohydrolase
(PAP); or
(3) increased phospholipid synthesis [which could drain
diacylglycerol (DAG) away from DGAT].
Fatty acid regulation of gene transcription
The hepatic enzymes that control FA and triglyceride
metabolism are obviously under transcriptional control,
regulated by transcription factors which are nuclear recep-
tors that activate/deactivate entire enzymatic pathways.
How FA, especially n-3 FA, interact with these transcrip-
tion factors has recently been reviewed by Jump and
colleagues [14,15]. At least four families of transcription
factors may be involved: peroxisome proliferator-activated
receptor alpha (PPARa), liver X receptors, hepatic nuclear
factor-4a and sterol regulatory element-binding protein-1c.
These FA can also generate a bewildering array of
bioactive eicosanoids via cyclo-oxygenase, lipoxygenase
and mono-oxygenases [16], and are known to influence
protein kinase C activity [17]. The fact that both eicosa-
noids and protein kinase C can also modulate transcription
factor activity underscores the extreme complexity of
metabolic regulation. Indirect effects on gene regulation
may result from alterations in lipid raft composition by
n-3 FA [18]. Such mechanisms influence the activity of
G-linked proteins [19] and other membrane-bound recep-
tors [20]. A fuller discussion of these more fundamental
regulatory mechanisms is, however, beyond the scope of
this paper.
Methods
The goal of this paper is to review animal studies in which
the effects of n-3 FA on triglyceride metabolism were
explored, and to determine the extent to which consensus
has been reached on any particular mechanism of action.
We will evaluate whether commonly employed study
designs are able, even in theory, to provide satisfactory
answers to the question at hand.
Studies included
As the vast majority of animal studies that have addressed
this particular question have used rats, we focused only
on this species in the hope of eliminating at least one
source of variation. For inclusion, the studies had to
involve the following characteristics, which we deemed
to be the most physiologically relevant. First, rats had to
be fed with n-3 FA (whether fish oil or EPA or DHA
individually). This eliminated studies in which hepato-
cytes from rats on standard chow were incubated with n-3
FA in vitro. Second, triglyceride metabolism in isolated
hepatocytes had to be probed using non-3 FA as sub-
strates (e.g. palmitate, oleate, linoleate or glycerol). This
restriction was added because the question of the extent
to which EPA or DHA themselves were oxidized or
incorporated into triglycerides or phospholipid was, we
felt, of little practical relevance given their low levels
in the diet. What is relevant is how small amounts of
these FA alter normal FA/triglyceride metabolism. We
searched Medline 1966present for omega-3 fatty acids
(or fish oil or EPA or DHA), rats and triglycerides. From
these studies (and others referenced in them), and after
applying the inclusion criteria described above, we
arrived at the set of studies summarized here (Table 1).
Results
We located 35 publications including 42 experiments that
met our inclusion criteria (Table 2) [2155] . Before
summarizing the results of this literature survey, an
examination of the diversity of study designs from which

Table 1 Summary of the effects of omega-3 fatty acids on VLDL kinetics in humans

Triglyceride
(mg/dl) FCR Production rate
Duration (varying units) (varying units)
Author Patients n n-3 FA (weeks) Fraction traced Base %D %D %D
Nestel [3] Norm/HTG 6 19 g; 4.3% 19 VLDL-apo B 277 70 40 66
Sanders [4] HTG 5 4.7 g; 1.7% 4.5 VLDL-TG 1146 51 22 45
Harris [5] Norm/HTG 3/6 13 g; 5% 1017 VLDL-TG 442 66 8 40
Fisher [6] HTG/T2DM 5 10.4 g; 3.8% 10 VLDL-apo B 591 66 47 57
Bordin [7] Normals 10 3 g; 1.1% 3 VLDL-apo B 98 22 14 29
Chan [8] Obese HTG 24 3.4 g; 1.2% 6 VLDL-apo B 177 25 4 32
FA, fatty acids; TG, triglyceride; HTG, hypertriglyceridemic patients; VLDL, very low-density lipoproteins; FCR, fractional catabolic rate.

Reported to be statistically significant.

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 Omega-3 fatty acids lower serum triglycerides Harris and Bulchandani 389

Table 2 Summary of studies examining the hypotriglyceridemic mechanism of action in rats

Effect on

b-Ox

Author N Dose n-3 FA Duration Control MO PO Lipogenesis DGAT PAP sNEFA

Aarsland [21] 9 1.1% EPA 5 days Palmitate " " NT NT NT NT

Yamazaki [22] 12 9% EPA DHA 14 days Safflower # " NT NT NT NT
Rustan [23] 12 6.5% EPA DHA 3 weeks Sunflower NT " NT # $ #
Waterman [24] 10 20% EPA DHA 10 days Corn NT NT $ NT NT
Marsh [25] 12 3.2% EPA DHA 11 days Chow NT NT $ # NT
Halmiski [26] 30 6.2% EPA DHA 1 month Safflower $ " NT $ # NT
Gronn [27] 6 2.7% EPA DHA 14 days Olive " " NT NT NT NT
Benhizia [28] 14 7.6% EPA DHA 15 days Corn NT # NT NT NT
Willumsen [29] 12 3.6% EPA 8h Palm " " $ NT $ $
12 3.6% DHA # " $ NT # $
Ikeda [30] 12 1.8% EPA 2 weeks Oleate " NT # $ # NT
12 2% DHA $ NT # $ # NT
Ribeiro [31] 6 2% EPA DHA 3 weeks Corn " NT # NT NT
Niot [32] 10 0.3% EPA DHA 7 weeks Safflower palm rape # $ NT NT NT NT
Yeo [33] 16 4.8% EPA 3 weeks Sunflower NT NT # NT NT
Otto [34] 12 1.8% EPA DHA 6 weeks Lard NT NT NT NT $
Ukropec [35] 36 8.3% EPA DHA 3 weeks Saturates " " NT NT NT #
Willumsen [36] 6 2.7% EPA 15 days Palmitate " " # " $ #
Geelen [37] 24 3.6% EPA DHA 14 days Corn NT # # NT NT
Wong [38] 10 9% EPA DHA 2 weeks Safflower $ " # NT NT NT
Osmundsen [39] 12 2% EPA 10 days Palmitate " # NT NT NT NT
12 2% DHA $ " NT NT NT NT
Halvorsen [40] 12 12% EPA DHA 3 weeks Monounsaturates " " NT NT NT #
Brown [41] 10 9.2% EPA DHA 14 days Low fat NT # NT NT NT
Brown [42] 4 12% EPA DHA 14 days Olive " NT # NT NT
Jen [43] 18 6.6% EPA DHA 16 weeks Corn NT # NT NT NT
Al-Shurbaji [44] 12 8.5% EPA DHA 3 weeks Sunflower NT NT $ # NT
Sebokova [45] 6 6% EPA DHA 14 days Tallow NT # NT NT NT
Neschen [46] 20 18% EPA DHA 21 days Safflower " " NT NT NT NT
Iritani [47] 8 1.53% EPA 5 days Linoleate NT # NT NT NT
8 0.5% DPA DHA NT #
Madsen [48] 8 2% EPA 37 days Low-fat diet " $ NT # NT NT
8 2% DHA " " NT $ NT NT
Kanazawa [49] 10 1.4% DHA EPA 6 weeks Corn $ NT NT $ NT
Willumsen [50] 10 1.8% EPA 10 days Palmitate " $ NT " $ NT
10 1.8% DHA " " NT $ $ NT
Froyland [51] 12 1.8% EPA 3 months Corn " $ NT NT NT NT
12 1.8% DHA " " NT NT NT NT
Topping [52] 10 3.2% EPA DHA 10 days Safflower NT # NT NT NT
Otto [53] 12 6% EPA DHA 6 weeks Corn NT NT $ NT #
Clarke [54] 8 6% EPA DHA 3h Safflower NT # NT NT NT
Williams [55] 12 1.1% DHA 3 days Linolenate NT $ NT NT NT

Doses are presented as a percentage of total energy. It was calculated for each study assuming that the percentage of energy that these FA
contributed to the diet was 2 the weight percentage of these FA in the diet. EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; b-Ox, beta
oxidation; DGAT, diacylglycerol acyl transferase; PAP, phosphatidic acid phosphohydrolase; sNEFA, serum non-esterified fatty acids; NT, not tested;
#, decreased; ", increased; $, no effect.

they were derived is instructive and will serve to con-
textualize the findings. Few investigators used study
designs that would be considered physiologically relevant
to humans. In 11 studies, treatment lasted less than
2 weeks, with one study examining the effects of EPA
only 3 h after dosing. About half of the studies used
intakes of n-3 FA of more than 3% energy (which is
itself about twice the effective dose in humans). Only five
used 1.5% energy or less, whereas 16 fed 6% energy or
more and one provided 20% energy as n-3 FA. Only one
study [36] explored all of the potential mechanisms in
the same experimental setting. Not included in Table 2
are three studies in which hepatic levels of apo-B were
reported to be reduced by n-3 FA feeding [31,41,42].
This effect is commonly observed in studies with cul-
tured cell lines (as noted above), but whether this is a
primary effect of n-3 FA in vivo or simply a response to a
decrease in triglyceride availability is unknown.
Not cataloged in Table 2 are a variety of other, potentially
relevant variations in experimental conditions encoun-
tered in these studies that could produce disparate
results. These include differences in: the substrates used
to test effects on FA oxidation (oleate [41], palmitate
[21,36,44], lauroyl-CoA [22] or linoleate [27]), strains of
rats (Zucker obese [32,43], Wistar [35,51], Sprague
Dawley [26,49]), physiological states (fed [43] compared
with fasted [39]) or the use of insulin to stimulate

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 390 Hyperlipidaemia and cardiovascular disease

lipogenesis [52]), background dietary composition DHA. Given the extreme dissimilarity between these
(essential FA-free [55], types of fiber [56], sucrose study designs and most of the others, we can reasonably
[45]), cofactors and experimental conditions used in conclude that virtually every time that n-3 FA are fed to
enzyme assays [25,39,], the enzymes deemed represen- rats, lipogenesis is inhibited.
tative of specific mechanistic pathways (malic enzyme
[30], tricarboxylic acid cycle [47], acetyl-CoA carboxylase The next most consistently described effect of n-3 FA
[29]) and the methods used to infer effects of n-3 FA on feeding was an increase in FA b-oxidation. Out of 47
enzymes when enzymatic activities were not directly experiments, 33 found it to be increased, with about half
measured (e.g. using the phospholipid/triglyceride ratio reporting increased peroxisomal oxidation and the other
as a surrogate of DGAT activity [33]). half mitochondrial. Notably, however, about one-third of
the time, no change in b-oxidation was found. Impor-
As noted above, this review included only rats not tantly, one of the latter studies [49] utilized arguably the
rabbits, hamsters, green monkeys, salmon or mice, in most relevant study design of all 1.4% EPA DHA fed
which similar experiments have been conducted. No for 6 weeks compared with a corn oil control. Another
studies in perfused livers have been included here study that failed to detect a change in b-oxidation was
(e.g. [57]), nor studies using cultured cell lines. In the that of Niot et al. [32]. In this trial, 0.3% energy as
latter, significantly different conclusions may be drawn EPA DHA was provided for 7 weeks compared with
regarding the mechanism of action of n-3 FA. For a mixed-fat control diet. Here, peroxisomal FA oxidation
example, studies in HepG2 cells typically do not report was unaffected and mitochondrial was actually reduced.
a decrease in lipogenesis [58], the most consistent effect This dose (the human equivalent of about 1 g/d) would,
noted in rats (see below). Whats more, it has been however, be unlikely to lower serum triglyceride in
reported [59] that the effects of n-3 FA on hepatic humans (and its effects on rat serum triglyceride were
triglyceride metabolism can differ significantly within not reported, although liver triglyceride was reduced). It
the same experiment when using rat primary hepato- should also be noted that while PPAR-a-stimulated
cytes, human primary hepatocytes and cultured cell lines. peroxisomal FA oxidation can be substantial in rats, it
may not play a significant role in humans [60]. Indeed, n-3
Findings of literature review FA still lower serum triglyceride levels in PPAR-a knock-
The results from these studies have been condensed and out mice [61]. Hence, finding enhanced peroxisomal
summarized in Table 3. Given the caveats outlined FA oxidation with n-3 FA feeding in rats may not only
above, it might be surprising that any consensus would be irrelevant for humans, but may also occur without
emerge from this exercise. One effect, however, was PPAR-a activation.
quite consistently observed: n-3 FA feeding decreases
hepatic lipogensis FA synthesis. This was explored 16 Effects on triglyceride-synthetic enzymes were mixed. In
times and found to be reduced 13 times. The three six studies in which PAP was measured, half found it to
exceptions included one study [55] in which DHA was be depressed and half did not. The situation is somewhat
fed for 3 days compared with a linolenic acid control, and clearer for DGAT. Its activity was measured in 17 set-
another study [29] in which lipogenesis was not decreased tings, but it was reduced in only six. Hence, the weight of
when measured 8 h after a single dose of either EPA or the evidence does not support an inhibition of these
enzymes as the mechanism by which n-3 FA lower
triglyceride production.
Table 3 Summary of the findings reported in Table 2 regarding
potential mechanisms by which n-3 FA reduce triglyceride
synthesis in rats
Finally, a reduction in serum NEFA could potentially
reduce hepatic triglyceride synthesis. This was examined
EPA
DHA EPA DHA Total eight times and, in five, serum NEFA was indeed low-
ered. Evidence exists that n-3 FA inhibit hormone-sen-
Mechanism Yes No Yes No Yes No Yes No sitive lipase (in rat retroperitoneal but not subcutaneous
" b-oxidation 14 7 11 4 8 3 33 14 fat [62]); hence, a decrease in NEFA could be a primary
" Mitochondrial 4 5 8 0 3 3 15 8 effect. On the other hand, the very act of lowering serum
" Peroxisomal 8 2 3 4 5 0 16 6 triglyceride levels might be expected to result in less
" Not specified 2 0 0 0 0 0 2 0
# Serum NEFA 4 1 1 1 0 1 5 3 NEFA derived from the action of lipoprotein lipase on
# Lipogenesis 8 0 3 1 2 2 13 3 VLDL-triglyceride. Whats more, an increase in hepatic
# DGAT 4 5 2 3 0 3 6 11 FA extraction could also lower serum NEFA levels, but
# PAP 3 2 1 3 2 1 6 6
such an effect would more likely be a secondary, not a
EPA, eicosapentaenoic acid; DHA, docosahexaenoic acid; DGAT, primary, effect of n-3 FA feeding, as reduced triglyceride
diacylglycerol acyl transferase; PAP, phosphatidic acid phosphohydro-
lase; serum NEFA, serum nonesterified fatty acids; #, decreased; synthesis would not logically follow increased hepatic
", increased. NEFA extraction. The extent to which the supply of

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 Omega-3 fatty acids lower serum triglycerides Harris and Bulchandani 391

Figure 1 Potential mechanisms by which N-3 fatty acids influence hepatic triglyceride metabolism

Feeding n-3 FA has been reported to inhibit () lipogenesis and the activities of diacylglycerol acyl transferase (DGAT), phosphatidic acid (PA) and
hormone-sensitive lipase, and to stimulate () b-oxidation, phospholipid synthesis and apo-B degradation. The end result is a reduced rate of secretion
of very low-density lipoprotein (VLDL) triglyceride. DAG, diacylglycerol; TG, triglyceride; PAP, phoshphohydrolase; FA, fatty acids; NEFA, nonesterified
fatty acids.

NEFA to the liver plays a role in the triglyceride-lowering
effect of n-3 FA will require further study (Fig. 1).
Conclusion
Doses of 34 g of n-3 FA (about 1.2% of energy) clearly
reduce triglyceride levels in humans by decreasing trigly-
ceride secretion from the liver. As experimental designs
have often failed to replicate the human situation, how-
ever, the molecular mechanisms by which this occurs
remain uncertain. In particular, unphysiologically high
doses of n-3 FA have been very commonly utilized and
supplementation periods have been as short as a single
dose. The clearest signal we currently have from the rat
studies reviewed here is that n-3 FA decrease hepatic
lipogenesis. Their effects on stimulating b-oxidation
may also be relevant, but the inconsistency in this finding
and the relative lack of peroxisomal oxidation in humans
compared with rodents call this particular pathway into
question. Therefore, it is the opinion of the authors that the
mechanism of action of n-3 FA in human hepatic trigly-
ceride metabolism remains an unanswered question.
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:
 of special interest
 of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (pp. 459462).
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