Recent Advances in Nutritional Sciences
Mechanisms by which Dietary Fatty
Acids Modulate Plasma Lipids1
Maria Luz Fernandez2and Kristy L. West*
Department of Nutritional Sciences, University of Connecticut,
Storrs, CT 06269 and *Custom Learning Designs, Inc., 375
Concord Avenue, Belmont, MA 02478
on plasma LDL cholesterol (LDL-C) concentrations and
therefore on the risk for coronary heart disease. Numerous
studies have been conducted in animal models to elucidate
the mechanisms by which different types of fatty acids
modulate plasma cholesterol concentrations. In addition,
multiple clinical trials and epidemiological data have dem-
onstrated the effects of fatty acids in determining the con-
centrations of circulating LDL. SFAs and trans fatty acids
have a detrimental effect on plasma lipids, whereas PUFAs
of the (n-6) family and monounsaturated fatty acids de-
crease plasma LDL-C concentrations. Among the SFAs,
stearic acid (18:0) appears to have a neutral effect on LDL-
C, while lauric (12:0), myristic (14:0), and palmitic (16:0)
acids are considered to be hypercholesterolemic. SFAs
increase plasma LDL-C by increasing the formation of LDL
in the plasma compartment and by decreasing LDL turn-
over. Although unsaturated fatty acids increase cholesterol
synthesis, they also increase hepatic LDL receptor number
and LDL turnover in vivo. Fatty acids are also ligands of
important regulatory elements, which can play a role in
determining plasma cholesterol. This article presents a
summary of the major effects of various types of fatty acids
on plasma lipid concentrations and the mechanisms in-
volved. J. Nutr. 135: 2075–2078, 2005.
Dietary fatty acids have a considerable effect
dietary fat saturation
Dietary fat saturation plays a considerable role in modulat-
ing plasma cholesterol concentrations and determining the
risk for coronary heart disease (CHD).3In fact, SFAs are
recognized as the single dietary factor that has the greatest
negative effect on LDL cholesterol (LDL-C) concentrations
(1). In contrast, monounsaturated fatty acids (MUFAs) and
PUFAs of the (n-6) family have been shown to decrease
plasma cholesterol concentrations in clinical studies (2,3) and
in various animal models (4–6). According to Hu et al. (7),
replacing 5% of the energy of SFAs by unsaturated fatty acids
results in a 43% decrease in CHD. Recently trans fatty acids
(TFAs) have emerged as the most detrimental type of fat
relative to increased risk for CHD, since some studies demon-
strated that in addition to increasing plasma LDL-C, TFAs
also decrease plasma HDL cholesterol (HDL-C) and may
increase lipoprotein (a) (8). PUFAs of the (n-3) family have
multiple beneficial effects on CHD risk (9). The present
review discusses only the effects of (n-3) PUFAs in modulating
VLDL metabolism and reducing plasma triglycerides (TGs).
The concentration of LDL in blood is determined by the
production of this lipoprotein via VLDL through the delipi-
dation cascade and the efficiency of its removal from circula-
tion by LDL receptor or nor-receptor mechanisms (6). In
addition, the secretion of VLDL is influenced by the availabil-
ity of apolipoprotein (apo) B in the liver and the activities of
regulatory enzymes involved in the assembly and transport of
VLDL, including microsomal transfer protein and acyl-coen-
zyme A (CoA):cholesterol acyltransferase (ACAT). More-
over, the effects of fatty acids in regulating gene expression
(10) may also contribute to the mechanisms that determine
plasma LDL-C. Fatty acids regulate at least 4 families of
transcription factors: the peroxisome proliferator activated re-
ceptors (PPARs), liver X receptors (LXRs), hepatic nuclear
factor-4 (HNF-4), and sterol regulatory element binding pro-
teins (SREBPs) (10). A brief review of the postulated effects of
fatty acids in regulating plasma cholesterol follows.
Fat saturation and cholesterol synthesis. Modulation of
cholesterol synthesis is not a major mechanism by which
PUFAs lower plasma LDL cholesterol (11). This has been
confirmed using deuterium incorporation into newly synthe-
sized cholesterol as a sensitive method, with results that closely
resemble those obtained from traditional methods such as
sterol balance (12). Both methods revealed that although
cholesterol synthesis increases with high PUFA intake
(11,12), the lowering of plasma LDL-C observed with PUFAs
is likely due to other mechanisms, including redistribution of
cholesterol between plasma and tissue pools (11) and upregu-
lation of the LDL receptor (13). In contrast, the observed
increases in plasma cholesterol concentrations due to SFAs do
not appear to be related to a rise in cholesterol synthesis (12).
However, when intake of TFAs was compared to palmitic acid,
an increase in both cholesterol synthesis and plasma LDL-C
concentrations was observed (14), suggesting that cholesterol
synthesis contributed to the higher concentration of circulat-
ing LDL observed with TFA intake.
Fat saturation and LDL receptors. Many studies have
shown that dietary fatty acids regulate plasma LDL-C levels by
affecting LDL receptor activity, protein, and mRNA abun-
Mustad et al. (18) demonstrated that dietary SFA (palmitic
acid) markedly decreased LDL receptor protein levels in pigs
1Manuscript received 3 June 2005.
2To whom correspondence should be addressed.
3Abbreviations used: ACAT, acyl-coenzyme A:cholesterol acyltransferase;
apo, apolipoprotein; Bmax, maximal binding; CHD, coronary heart disease; CoA,
coenzyme A; CYP7, cholesterol 7?-hydroxylase; FCR, fractional catabolic rate;
HDL-C, HDL cholesterol; HNF-4, hepatic nuclear factor 4; LDL-C, LDL choles-
terol; LPL, lipoprotein lipase; LXR, liver X receptor; MUFA, monounsaturated fatty
acid; PPAR, peroxisome proliferator activated receptor; PPRE, peroxisome pro-
liferator response element; SREBP, sterol regulatory element binding protein;
TFA, trans fatty acid; TG, triglyceride; TGRL, triglyceride-rich lipoprotein.
0022-3166/05 $8.00 © 2005 American Society for Nutritional Sciences.
by guest on June 2, 2013
fed a diet containing 0.25% cholesterol, compared to pigs fed
a diet with cholesterol only or to controls fed a low-fat,
cholesterol-free diet. In contrast, pigs fed a diet high in PUFA
(linoleic acid) had increased LDL receptor levels compared to
pigs fed a diet with cholesterol only or a low-fat, cholesterol-
free diet (18). These distinct effects of dietary fatty acids were
accompanied by parallel changes in LDL receptor mRNA
levels. These data provide strong evidence for an independent
and positive effect of PUFAs on the regulation of LDL recep-
tor expression. It is important to note that these differential
effects of dietary fatty acids were observed only in pigs fed
the lowest level of dietary cholesterol, suggesting that high
cholesterol intake has a dominant and repressive effect on
LDL receptor mRNA levels that cannot be alleviated by fatty
Cholesterol-raising SFAs (12:0, 14:0, 16:0) decrease LDL
receptor activity, protein, and mRNA abundance, while un-
saturated fatty acids increase these variables. Dietary modifi-
cation of hepatocyte membrane fluidity may be one way in
which diets high in PUFAs affect LDL receptor activity dif-
ferently than diets enriched in SFAs. Support for this sugges-
tion comes from in vitro studies (19) and studies in rats (20),
which showed significant alterations in LDL binding to the
LDL receptor as a result of changes in membrane fluidity. It
has also been suggested that dietary fatty acids can directly
influence the number of receptors available for uptake of
circulating LDL by specifically affecting LDL receptor synthe-
sis. In vitro binding studies demonstrated that alterations in
LDL uptake associated with dietary fatty acid composition can
be attributed to changes in LDL maximal binding (Bmax), an
indicator of receptor number (13).
In support of the in vitro studies, PUFAs decreased LDL
apo B pool size by 50% and increased LDL fractional catabolic
rate (FCR) 2-fold when compared to SFA intake in guinea
pigs (16). The differences in plasma LDL-C concentrations, as
influenced by the chain length of the saturated fatty acid, were
also correlated to both receptor expression (Bmax) and LDL
FCR (17). Guinea pigs fed the long-chain SFA had lower
plasma LDL-C concentrations, which correlated with the fast-
est LDL FCR when compared to guinea pigs fed diets high in
lauric or myristic acids (16). Similarly, in hamsters lauric,
myristic, and pamitic acids increased plasma LDL-C concen-
trations compared to a diet high in stearic acid by decreasing
LDL apo B/E receptor activity and increasing LDL production
In vitro studies with different cell types (22) and studies
with hamsters (23,24) showed that fatty acids can affect the
storage of cholesterol esters and influence sterol distribution. It
has been suggested that dietary fatty acids and cholesterol
regulate hepatic LDL receptor activity via cholesteryl ester and
free cholesterol regulatory pools. These cholesterol regulatory
pools are affected by ACAT, the rate-limiting enzyme of
cholesterol esterification. SFAs suppress this enzyme, which
may result in a greater proportion of cholesterol remaining in
the regulatory pool. An increase in hepatic cholesteryl ester is
negatively correlated with LDL receptor activity in hamsters
(23). However, data from many animal studies are not consis-
tent with this hypothesis. For example, in African green mon-
keys, an increase in ACAT activity is correlated with increases
in plasma LDL cholesterol and increased deposition of cho-
lesterol in the aorta (25).
Fatty acids and molecular regulation. The PPAR-medi-
ated regulation of several genes involved in lipoprotein me-
tabolism leads to the following effects: 1) increased hydrolysis
of TG-rich lipoproteins, 2) stimulation of cellular fatty acid
uptake and conversion to acyl-CoA derivatives, 3) stimulation
of ?-oxidation, and 4) reductions in fatty acid and TG syn-
thesis and VLDL production. Together, these effects help
explain the hypolipidemic effect of certain types of fatty acids.
PPAR? interacts with both saturated and unsaturated fatty
acids, although SFAs have a lower affinity (26). Transcrip-
tional regulation is mediated through peroxisome proliferator
response elements (PPREs) in the promoter regions of target
genes Target genes in the liver include apoA-I, apoA-II,
apoC-III, and lipoprotein lipase (LPL) (27). The coordinated
changes in the expression of these genes contribute to hepatic
lipid homeostasis by regulating, either directly or indirectly,
lipid flux into and out of the liver.
The TG- and cholesterol-lowering action of certain fatty
acids is attributable to an enhanced catabolism of TG-rich
lipoproteins (TGRLs) and inhibition of hepatic VLDL secre-
tion (27). Effects of fatty acids on TG and cholesterol metab-
olism are partly mediated by changes in the expression of LPL
and apoC-III. LPL hydrolyzes the TG component of chylomi-
cron and VLDL particles, which enables the removal of the
remaining lipoprotein remnants from circulation by the liver.
In hepatocytes and preadipocytes, fatty acids stimulate the
transcription of the LPL gene by binding to a PPRE in the LPL
promoter (28). In addition, most human studies report that
dietary (n-3) PUFAs decrease the residence time of VLDL in
serum (9). However, dietary PUFAs have little or no effect on
LPL or hepatic lipase activity in postheparin serum in humans
(29). LPL may be more reactive toward VLDL with PUFA
TGs as substrate, leading to more rapid lipolysis of TGRLs
with dietary PUFAs (30). In addition, dietary (n-3) PUFAs
accelerate chylomicrons clearance in rats (31) and enhance
the conversion of VLDL apoB to LDL apoB in pigs (32).
Overall, the marked decrease in plasma LDL concentrations in
animals fed (n-3) PUFAs could be due to reductions in the
rate of LDL entry into the plasma, resulting from increased
VLDL catabolism (30).
Due to its action in blocking LPL activity, apoC-III levels
are positively correlated with plasma TG concentrations (33).
Metabolic studies suggest that high levels of apoC-III impair
the clearance of TGRLs due to interference with apoE-medi-
ated uptake of these particles by cellular receptors (34). The
reduction in apoC-III levels in response to fatty acid intake is
thought to enhance the LPL-mediated effects on lipoprotein
metabolism, leading to increased catabolism of VLDL parti-
cles. Consequentially, the dual action of fatty acids on the
expression of the LPL and apoC-III genes provides a potential
model by which fatty acids reduce plasma TG concentrations.
HNF-4 is a key regulator of genes involved in glucose,
cholesterol, and fatty acid metabolism (35). The promoters of
apoA-I, apoA-II, apoA-IV, apoB, apoC-II, and apoC-III all
contain binding sites for HNF-4 (35). Increased levels of HDL
are correlated with a decreased risk for coronary artery disease.
The protective effects of HDL on atherosclerosis are correlated
with levels of specific HDL particles. Fatty acids exert a neg-
ative effect on apoA-I transcription (36) via a sequence lo-
cated in the proximal promoter region of the human apoA-I
gene. However, this negative effect is counteracted by a pos-
itive regulatory site that responds to PPAR. This regulatory
site is localized in the apoA-I promoter A site and binds to
other nuclear receptors, such as the retinoid X receptor (37).
The subtle interaction between these two opposing mecha-
nisms determines the overall effect of fatty acids on apoA-I
The liver X receptor (LXR) may act as a sterol sensor that
functions to help an organism cope with high free cholesterol
levels in the blood (38). Tobin et al. (39) demonstrated that
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in the liver, LXR? expression is induced by PUFAs. This effect
occurs as a result of a direct (40) induction of LXR? gene
transcription. Due to the established ability of fatty acids to
serve as ligands for the PPARs, it is possible that PPARs are
involved in mediating the effect of fatty acids on LXR?
LXR regulates intracellular cholesterol levels by inducing
the expression of cholesterol 7?-hydroxylase (CYP7), the ini-
tial and rate-limiting enzyme in the conversion of cholesterol
to bile acids. Fatty acids not only enhance PPAR activity; they
also induce LXR? protein, mRNA, and gene transcription.
Through induction of LXR? via PUFAs, the LXR?-regulatory
pathway facilitates the elimination of excess cholesterol by
stimulating CYP7, thereby resulting in the conversion of cho-
lesterol to bile acids. Conversion of cholesterol into bile acids
is an irreversible and terminal process of cholesterol catabo-
lism. In addition to the increase in CYP7 activity, unsaturated
fatty acid synthesis is prevented through the suppression of
SREBP-1c expression via the antagonistic effect of PUFAs
(41). This could be an indirect mechanism by which PUFAs
increase LDL receptor expression by the elimination of cho-
lesterol from the liver via increased bile acid synthesis. A
summary of the possible mechanisms by which (n-6) PUFAs
may lower plasma cholesterol is depicted in Figure 1.
The major role of SREBPs in both lipogenesis and choles-
terol metabolism is well established (41). The SREBP-1a iso-
form is a regulator of genes encoding proteins involved in both
lipogenesis and cholesterol biosynthesis (42). The SREBP-1c
isoform in the liver is a key regulator of the liver’s response to
insulin and is a major determinant of lipogenic gene transcrip-
tion (42). PUFA-rich diets repress the transcription of lipo-
genic genes by suppressing SREBP-1 gene transcription or by
reducing the maturation of SREBP-1 protein, thereby reducing
the levels of MUFAs, TGs, and cholesterol esters in plasma
and liver. In the liver, PUFAs inhibit the expression of
SREBP-1c to a greater extent compared with dietary SFAs or
MUFAs (43). Moreover, (n-3) PUFAs appear to be more potent
than (n-6) PUFAs in suppressing SREBP-1 expression (43).
A study by Vasandani et al. (30) showed that dietary (n-3)
PUFAs markedly decreased triglyceride and cholesterol ester
levels in the liver and the concentration of apoB-containing
lipoproteins in the plasma of LDL-receptor–deficient mice.
These results suggest an important mechanism by which di-
etary (n-3) PUFAs lower plasma TGs. The potential mecha-
nisms of action by (n-3) PUFAs include the following: 1)
suppression of SREBP-1 expression and processing, leading to
decreased lipogenesis and decreased VLDL secretion; 2) en-
hanced hepatic clearance of lipoproteins through increased
LPL expression and decreases in apoC-III levels; and 3) in-
creased reverse cholesterol transport (Fig. 2).
In conclusion, fatty acids substantially affect plasma LDL-C
concentrations and therefore the risk for CHD. Although
SFAs have a negative effect on LDL-C levels, unsaturated fat
decreases plasma cholesterol. Possible mechanisms by which
(n-6) PUFAs decrease plasma cholesterol include upregulation
of the LDL receptor and increased CYP7 activity, whereas
(n-3) PUFAs decrease plasma TGs by decreasing lipogenesis
and VLDL secretion, increasing LPL activity, and increasing
reverse cholesterol transport. By reducing plasma cholesterol
and TG levels, both (n-6) and (n-3) PUFAs reduce cardio-
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