ARTICLE IN PRESS
Prostaglandins, Leukotrienes and Essential Fatty Acids 72 (2005) 381–391
www.elsevier.com/locate/plefa
Review
Postprandial activation of hemostatic factors:
Role of dietary fatty acids
Asim K. Duttaroy
Department of Nutrition, Faculty of Medicine, University of Oslo, POB 1046 Blindern, N-0316 Oslo, Norway
Received 20 October 2004; accepted 30 March 2005
Abstract
Intake of dietary fat is an important determinant of the plasma concentration of triacylglycerol-rich lipoproteins, and the degree
of alimentary lipemia is reported to have effects on hemostatic status including platelet function. Although association between the
amount of dietary fat intake, lipemic response and certain cardiovascular disease (CVD) risk factors (VIIa and PAI-1) has been
reported, the significance of the fatty acid composition of ingested fat for the postprandial lipid concentrations and the hemostatic
factors is still unclear. Accumulating evidence suggests a relationship between dietary fatty acids and emerging hemostatic CVD risk
factors, although much of this evidence is incomplete or conflicting. In order to improve our knowledge in this area, sufficient
sample size in future studies are required to take into account of the genetic variation (gene polymorphisms for VII, PAI-1), sex,
physical activity, stage of life factors, and sufficient duration to account for adaptation for definitive conclusions.
r 2005 Elsevier Ltd. All rights reserved.
1. Introduction
The roles of dietary fat in the etiology of cardiovascular disease (CVD) have been extensively studied [1–3].
In view of these studies, dietary fat intakes currently
been recommended to help prevent CVD are based
mainly on the well-known effects of different dietary
fatty acids on plasma lipids. Both the postprandial and
fasting plasma lipids are thought to be associated with
CVD [2]. In fact, evidence continues to accrue for
disturbances in coagulation, fibrinolysis and platelet
behavior in hyperlipidemic states, which together might
constitute a prothrombotic state [4–10]. Both the
amount and composition of dietary fat may affect
the hemostatic system (Fig. 1). The magnitude of the
postprandial lipemic response appears to play a role in
the etiology and progression of CVD and a slow return
to the postabsorptive state may be specifically associated
with an increased risk of CVD [11,12]. There is
increasing evidence that an elevated concentration of
Tel.: +47 22 85 15 47; fax: +47 22 85 13 41.
E-mail address: a.k.duttaroy@medisin.uio.no.
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doi:10.1016/j.plefa.2005.03.003
triacylglycerol-rich lipoproteins in the postprandial state
may be responsible for atherogenesis by activating
hemostatic factors [13,14]. This issue has added importance because several hemostatic and fibrinolytic
factors are known CVD risk factors [15–18]. The
coagulation, fibrinolytic, and platelet activating systems
are complex and interact extensively with each other
[19,20] and therefore subtle changes in the balance
between these factors in hyperlipidemia can promote
CVD [21,22]. Many of the key reactions require
participation of biomembranes, suggesting that dietary
lipids, to the extent that they influence lipid composition
of the membranes and/or affect levels of plasma
lipoproteins, may have an important regulatory role in
the activation of the hemostatic system. Not surprisingly, considerable effort has been expended to determine if dietary fatty acids can influence CVD risk
through effects on the hemostatic process. It has become
increasingly clear that not all the effects of dietary fatty
acids on CVD risk can be explained by the effects of
fatty acids on traditional lipid/lipoprotein risk factors.
Therefore, a better understanding of the relationship
between diet and hemostasis is essential in order to
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Fig. 1. Interaction of dietary lipids with hemostatic factors: dietary
lipids can affect both the postprandial lipemic response as well as
activation of the hemostatic factors including platelet function. These
effects may depend on the amount and composition of dietary lipids.
develop therapeutic interventions that maximally reduce
CVD risk. Dietary lipids play important roles in the
development of CVD, as they regulate several processes
such as membrane fluidity, membrane receptor expression and function, eicosanoid synthesis, fasting and
postprandial plasma levels of lipids, and blood platelet
function by modifying cell membrane fatty acid
composition, and gene expression. However, the mechanisms involving transient activation of hemostatic
system during postprandial lipemia are not understood.
This review primarily addresses the roles of dietary fatty
acids on immediate transient perturbations in circulating lipoprotein and their relationships with the hemostatic factors, including platelet response after a meal.
2. Dietary fatty acids and their hyperlipidemic response
Dietary fat is composed principally of triacylglycerol,
which after digestion and absorption stimulates the
production of chylomicrons [2,13,23–29]. An intake of
40–50 g of fat in a meal results in significant lipemia in
healthy adults, with consecutive fat-containing meals
enhancing the lipemia [30]. Therefore, limiting fat intake
to approximately 30 g on each eating occasion may
minimize postprandial lipemia. The magnitude of the
postprandial lipemic response, however, is determined
by several factors such as amount and composition of
fat intake, fasting plasma triacylglycerol concentration,
age, lifestyle, and habitual dietary fat composition [31].
Impaired clearance of chylomicron remnants is associated with increased risk of atherosclerosis and CVD
[2,11,23–25,32–35]. A key factor in postprandial lipid
metabolism is the activity of the lipoprotein lipase,
which plays a role in the clearance of chylomicrons
derived from dietary fat [36]. The quantity, degree of
saturation, and chain length of fatty acids are suggested
to affect lipoprotein lipase activity [37]. The regulation
of triacylglycerol-rich lipoproteins hydrolysis by lipoprotein lipase is, however, not fully understood. It was
suggested that the adipose tissue is the site of a set of
mechanisms involved in the regulation of lipoprotein
lipase [13,38]. Cholesterol ester transfer protein (CETP)
also plays an important role in this regard as it
exchanges cholesteryl esters and triacylglycerol between
triacylglycerol-rich lipoproteins and HDL and LDL
particles[38–41]. CETP activity in the late postprandial
phase may determine to what extent impaired clearance
of plasma triacylglycerol-rich lipoproteins is atherogenic
[41]. An increase in CETP activity is suggested to
be associated with the degree of lipemia, as seen in
dyslipemic plasma. Fasting CETP activity has been
shown to be affected by dietary fatty acid composition
[42]. Postprandial studies indicated an increase in CETP
activity after intake of fatty meals, the increase being
higher after polyunsaturated fatty acid than after
monounsaturated fatty acid intakes [43].
Several proteins in the adipose tissue responsible for
lipid metabolism are regulated by nuclear hormone
receptors, peroxysome proliferator-activated receptors
(PPARs), liver X receptors (LXRs), retinol X receptor
(RXR), hepatic nuclear receptor a (HNFa, sterol
regulatory element binding protein 1c (SREBP1c) that
use lipids such as fatty acids, sterols, as their ligands
[44–47]. Phenotype analyses of knock-out or transgenic
mice pointed out the respective role of the orphan
nuclear receptors and their heterodimeric partner RXR.
These transciptional regulations have several targets: the
P450 cytochromes involved in the bile acid synthesis
Cyp7a1 and Cyp8b1; the intestinal bile acid binding
protein, CETP and phospholipid transfer protein, both
involved in the HDL catabolism; the ABC cholesterol
transporters, proteins for fatty acid transport, and
oxidation [48,49]. At present, important information is
lacking as to how postprandially derived fatty acids
affect expressions of genes through these nuclear
receptors that may influence the postprandial activation
of the hemostatic factors. Moreover, very little information is available on the roles of nuclear transcription
factors which may lead to an effective fatty acid
trapping by the adipose tissue that may prevent some
of the undesirable effects resulting from elevated plasma
non-esterified fatty acid concentrations. In the near
future, the identification and study of new target genes
in the adipose tissue by transcriptomic or proteomic
analyses will allow a better understanding of lipid
homeostasis in physiological as well as pathophysiological conditions.
In metabolic studies, variable effects of individual fatty
acids on plasma lipid and lipoprotein levels have been
observed [30,50]. Postprandial studies have also focused
on comparisons of the effect of a single fatty meal on the
lipemic responses of CVD patients and healthy individuals [51]. The results of postprandial studies have
often proved inconsistent, possibly due to differences in
experimental design, such as meal composition and the
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background diets, and type of volunteer. Specifically,
saturated fatty acids, with 12–16 carbon atoms tend to
increase plasma total and LDL cholesterol levels,
whereas stearic acid, 18:0, does not have a cholesterolraising effect, but may lower HDL cholesterol, and
increase Lp(a) concentration [52]. The prevalence of
stearic acid, 18:0, in the Western diet is likely to increase
with the introduction of synthetic fats designed to have
minimal effect on plasma cholesterol concentration; its
influence on hemostasis remains uncertain [32,53]. A
higher increase in triacylglylcerol-rich lipoproteins was
observed after consumption of the test fat containing
myristic acid, 14:0, than after those containing palmitic
acid, 16:0, or lauric acid, 12:0 [38], but the data are not
entirely consistent [5,54]. There is general agreement that
butter fat (which contains short-chain and medium-chain
saturated fatty acids), but not fats containing long-chain
saturated fatty acids, result in higher postprandial lipemic
responses than consumption of monounsaturated fatty
acids and polyunsaturated fatty acids [54,55]. Among the
cholesterol-raising saturated fatty acids, myristic acid,
14:0, appears to be more potent than lauric acid, 12:0, or
palmitic acid, 16:0, Stearic acid, 18:0) is unique amongst
the saturated fatty acids of similar chain length because it
is considered to have little or no effect on plasma
cholesterol concentration [56–58]. Oleic acid, 18:1n-9, is
an effective hypocholesterolaemic agent and, as one of
the key components in the increasingly advocated
Mediterranean-style diet, has been hailed as a potential
tool in the prevention of CVD [59,60]. Claims have been
made of both beneficial and detrimental alterations in
hemostasis when diets are supplemented with, or contain
large amounts of, oleic acid [33,60]. Trans fatty acids
appear to increase LDL cholesterol levels compared with
oleate [61]. Linoleic acid, 18:2n-6, has cholesterol-lowering effects [62], whereas n-3 long-chain polyunsaturated
fatty acids (LCPUFA) decrease the incidence of postprandial lipemia [36,63]. A background diet containing
excess of n-3 LCPUFA decreases postprandial lipemia by
stimulating lipoprotein lipase expression and decreasing
very low-density lipoprotein (VLDL) synthesis [36,64].
However, no such effects were observed in case of alpha
linolenic acid, 18:3n-3 [65]. Diet and/or drug treatments
that lower the level of triacylgylcerol-rich lipoproteins in
the fasted state also tend to have a beneficial effect on
postprandial lipoprotein levels. To date, however, firm
conclusions of how specific fatty acids influence postprandial response have not been reached [66–69].
3. Structure of triacylglycerols on postprandial lipemic
response
The positional distribution of fatty acids in triacylglycerols varies greatly among fats and oils of different
origin. The lipases in the digestive tract hydrolyze the
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fatty acids in the sn-1 and sn-3 positions, whereas
the long-chain fatty acids in the sn-2 position predominantly remain in this location and are absorbed as
2-monoacylglycerols [70]. Because the long-chain saturated fatty acids can form insoluble soaps with Ca2+
and Mg2+ in the gut, stearic acid, 18:0, and palmitic
acid, 16:0, are better absorbed if situated in the sn-2
position than if situated in the sn-1 and sn-3 positions
[71]. Furthermore, saturated fatty acids in the sn-2
position of dietary triaclylcglycerols have been shown to
slow down the clearance of chylomicrons in animals.
The 2-monoacylglycerols may remain on the chylomicron surface, causing changes in the physical properties
of the surface layer. Therefore, the positional distribution of saturated fatty acids may influence lipid
metabolism postprandially [25]. Because triacylglycerols
with saturated fatty acids in the sn-2 position may be
absorbed more efficiently and cleared from circulation
more slowly than triacylglycerols with saturated
fatty acids in the sn-1 and sn-3 positions, feeding
these dietary triacylglycerols may result in a more
pronounced postprandial lipemia. However, several
studies [13,29,66] found no significant differences in
plasma lipids after meals with triacylglycerols of
different positional distributions. The fatty acid composition of a diet has an effect on the fatty acid
composition of VLDL triacylglycerols and consequently
possibly also on the positional distribution of fatty acids
in VLDL triacylglycerols [28,71,72]. The relationship
between triacylglycerol molecular structures in dietary
fats, chylomicrons, and triacylglycerols provides new
means for understanding the effects of fatty acid
positional distribution on human lipid metabolism [70].
4. Postprandial lipemia and cardiovascular disease
Postprandial triglyceridemia may represent a procoagulant state involving disturbances of both blood
coagulation and fibrinolysis, in particular due to
elevation of the plasma levels of activated factor VII
(FVIIa) and plasminogen activator inhibitor (PAI-1)
[9,10,73,74]. Disturbances of the hemostatic system
therefore may, at least in part, account for by the link
between hypertriglyceridemia and coronary heart disease. Experimental results and clinical trial data suggest
that plasma accumulation of remnant lipoproteins is not
just an associated feature of an atherogenic lipoprotein
profile but triacylgylcerol-rich lipoproteins remnants
themselves contribute to the pathogenesis of atherosclerosis [22,75].
The Northwick Park Heart Study was a prospective
study in which FVII levels were found to be strongly
associated with coronary risk. This study showed
that elevated factor VII levels were related to fatal
myocardial infarctions but not to nonfatal myocardial
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infarctions [76]. The Atherosclerosis Risk in Communities Study, a prospective study of hemostatic factors
and the prevalence of coronary heart disease, showed no
association of coronary disease with FVII [77]. In this
study, only elevated levels of fibrinogen, FVIII, and von
Willebrand factor were identified as risk factors
associated with coronary heart disease, but their
measurement in healthy subjects did not seem to be
beneficial beyond more established risk factors. In the
Prospective Cardiovascular Munster study, FVIIc levels
were elevated in patients who had coronary events, but,
after multiple logistic regression analysis, FVIIc was not
identified as an independent risk factor for coronary
events [78]. The results of the Survival of Myocardial
Infarction Long-Term Evaluation study demonstrated
that a genetic propensity to high factor VII levels is not
associated with a risk for myocardial infarction.
Another prospective study, the Edinburgh Artery Study,
also failed to confirm FVII as an independent predictor
of coronary disease [79].
Factor VIIa is the first enzyme of the blood
coagulation system and serves a priming function for
triggering of the clotting cascade [80,81]. FVII circulates
mainly in an inactive, single-chain form. The two-chain
form, FVIIa, circulates at much lower concentration,
but is many times more active than the single-chain
form. The coagulant activity of factor FVII (FVIIc,
total activity of FVII in plasma) was identified as an
independent predictor of myocardial infarction in
initially healthy middle-aged men, and particularly of
fatal coronary events [82,83]. Both serum cholesterol
and triglyceride concentrations correlated positively
with the FVIIc level in this study. Addition of fat to
diet has been consistently shown to cause a rapid
conversion of the FVII zymogen into its active form
(FVIIa), whereas the concentration of total protein is
unaffected [9]. Postprandial activation of FVII is
dependent on lipolytic activity and it is mainly
supported by large triglyceride-rich lipoprotein of the
VLDL class [23,84–86]. Since FVIIa–tissue factor (TF)
complex is responsible for the initiation of the coagulation cascade, increased generation of FVIIa in the
postprandial state would increase the potential for
thrombin production in the event of plaque rupture
[87]. When the vascular lumen is damaged, TF is
exposed and then binds to the small amounts of
circulating factors FVIIa and FVII. This facilitates
conversion of FVII to FVIIa. FVIIa bound to TF in the
presence of calcium and phospholipids facilitates the
conversion of factor IX to factors IXa and X to factor
Xa (Fig. 2) [88,89]. Aberrant TF expression triggers
intravascular thrombosis in atherosclerosis, and other
diseases. The plasma levels of FVII are determined by
genetic and environmental factors [90,91]. Plasma FVII
levels increase with age and are higher in females and in
persons with hypertriglyceridemia [4,9,15,17,84,92–94].
Fig. 2. Factor VIIa and blood coagulation cascade. Activated factor
VIIa is generated by tissue factor (TF). Ultimately, prothrombinase
complex (FXa, Va, and platelets) which cleaves prothrombin to
thrombin. Thrombin then generates fibrin polymers by proteolytic
cleavage of fibrinogen, and also initiates platelet aggregation. FXa,
activated factor X, FX , factor X, FVa, activated Factor V, PC,
phosphatidylcholine, PS, phosphartidylserine.
The relationship between diet and FVII is conflicting
[8,19,35,53,86,95–99]. The high-fat meals led to variable
increase in FVIIc and FVIIa. The degree of postprandial
lipemia was correlated with the postprandial increase in
FVIIc. Roche and Gibney suggested that FVIIc rose
more rapidly with meals containing a high proportion of
oleic acid [100]. However, Larsen et al. [101] found no
differences in the postprandial response of plasma
triacylglycerol and FVIIc following five meals containing 70 g fat provided by rapeseed, olive, sunflower, palm
oils and butter. However, in that study the fat was
administered over two meals. Mennen et al. reported
increased FVIIa following 50 g fat test meals enriched
with approximately 20 g palmitate or stearate or
linoleate or linoleate and linolenate in elderly women
[67]. Sanders and his colleagues [24,102,103] reported
that that dietary oleate increased FVIIa to a greater
extent than stearate or medium-chain triacylglycerols.
However, we [66] did not find that 1,3 distearoyl-2oleolyl glycerol differed significantly from triolein with
regard to its effects on plasma triacylglycerol or FVIIa
at 3 h after a test meal in eight male subjects. Meals high
in triacylglycerol containing palmitic, oleic, elaidic,
linoleic and linolenic acids result in a postprandial
increase in FVIIa nd that a low-fat meal leads to a fall in
FVIIc. Randomized stearic acid-rich fats result in less
postprandial lipemia and a lower postprandial increase
in FVIIa, whereas unrandomized cocoa butter results in
similar postprandial lipemia and increases in FVIIa
compared with oleate [18]. Lindman et al. [104] reported
that long-term Mediterranean-type diet favorably modified the fasting levels of FVII (FVIIag, and FVIIa) in
individuals with 353Q genotype. FVII is coded by the
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gene on band 13q34, closely located to the gene for
factor X [88,90,105,106]. A strong contribution of the
FVII genotype to FVII levels has been observed, and
different FVII genotypes can result in up to several-fold
differences in mean FVII levels [83,105,107,108].
The major proportion of FVII circulates in plasma in
zymogen form, and the activation of the zymogen form
results in cleavage of the peptide bond between arginine
152 and isoleucine 153. Thirty different mutations have
been identified since the isolation of the FVII gene (F7).
Approximately two-thirds of the mutations seem to
affect the protease domain, indicating that loss of
protease function is the most common cause of the
clinical phenotype [109]. FVII activity is influenced by
mutations of F7 and by allelic polymorphic variations of
the gene. The R353Q polymorphism of the FVII gene
has been reported to modify the plasma levels of FVIIc,
FVIIa, and total FVII protein [110,111]. This polymorphism is characterized by a guanine to adenine
substitution resulting in replacement of the amino acids
arginine (R) by glutamine (Q) in codon 353 of FVII
protein [112]. Individuals heterozygous or homozygous
for the Q allele have been reported to have lower levels
of FVII than individuals homozygous for the more
common R allele [112].
5. Plasminogen activator inhibitor-1
PAI-1 is the major physiological inhibitor of the
plasminogen activators in the circulation and thereby
the principal inhibitor of the fibrinolytic system [113].
Postprandial triglyceridemia has been observed in many,
but not all, studies to increase PAI-1 plasma levels,
which would further strengthen the chances of thrombotic occlusion of a vessel after rupture of an atherosclerotic plaque [7,32,74,114,115]. Elevated PAI-1
activity has also been shown to be associated with
elevated fasting plasma triacylglycerol concentrations,
obesity, and the insulin resistance syndrome, and the
reduction in plasma triacylglycerol concentrations after
weight loss and a fat-modified diet results in increased
fibrinolytic activity [99,116]. Fig. 3 shows the relationship between PAI-1 and dietary lipids. The presence of a
4G allele at a common insertion–deletion polymorphism
in the promoter of the PAI-1 gene has been associated
with elevated plasma PAI-1 concentration and activity
[117]. Carriers of the 4G allele may be at increased risk
of ischemic heart disease, but this may be dependent on
an interaction with other environmental factors. In one
study, an increase in PAI-1 activity was reported 8 h
after a test meal very high in butter fat in subjects
carrying the 4G allele but not in those with the 5G/5G
genotype [73]. Fibrinolytic activity increased from
fasting values after high-oleate or high-palmitate meals
and did not appear to be affected by postprandial
385
Fig. 3. Fibrinolytic pathway and dietary lipids. Fibrinolytic pathway
can be activated by several processes, such as intrinsic, extrinsic, and
exogenous pathways. PAI-1 can inhibit these processes. PAI-1 can be
regulated by dietary fats. PAI-1, plasminogen activator inhibitor type
1, HMWK, high molecular weight kininogen, tPA, tissue plasminogen
activator, FXIIa, activated factor XII.
lipemia [7]. These observations are consistent with
reports of circadian variations in fibrinolytic activity.
This increase in fibrinolytic activity is consistent with the
decline in PAI-1 activity after the oleate meal [18,24].
These findings suggest that postprandial lipemia induced
by oils high in oleate or palmitate does not impair
fibrinolytic activity. Kozima et al. [114] reported that
PAI-1 antigen concentrations were elevated 8 h after the
consumption of 100 g butter. Oakley et al. [24], using a
crossover design, compared meals containing 95 g fat
provided either by high-oleate sunflower or a mixture of
oleate and medium-chain triacylglycerols or butter fat
with a low-fat test meal and found that PAI-1 declined
from fasting to the same extent with all the four
treatments. Byrne et al. [73] reported an increase in
PAI-1 activity after a high-fat meal (130 g) in subjects
who had an in-dwelling catheter. In this study, PAI-1
activity increased after the test meal between subjects
carrying the 4G allele and subjects homozygous for the
5G allele. PAI-1 activity was positively associated with
fasting plasma triacylglycerol concentrations. These
findings are consistent with the observation that weight
loss associated with decreased energy intake and regular
physical activity results in improvement in fibrinolytic
activity. There are reports that PAI-1 activity in 5G/5G
subjects is 40–50% lower than that in subjects who carry
one or more 4G alleles. However, the diurnal variations
appeared to be greater in subjects with one or more 4G
allele. This could be an important source of confounding
factors in studies assessing diet–genotype interactions
with regard to PAI-1. Meta-analysis of published studies
show that the PAI-1 promoter 4G variant is associated
with a 30% higher risk of myocardial infarction than
that in 5G/5G subjects [118], with little evidence of
heterogeneity of effect in subjects from different
countries who might be expected to have different
dietary habits.
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6. Dietary fatty acids and platelet function
Hyperactivity of platelets, and their adhesion and
aggregation at the site of injury in atherosclerotic vessel
walls, is critically important in the pathogenesis of CVD
[119–121]. Platelet activity is thought to play a major
role in the development as well as in the stability of
atherosclerotic plaques. In support of the pathophysiological role of platelets, platelet-inhibitory drugs such as
aspirin reduce the incidence of myocardial infarction,
stroke and death from CVD in secondary prevention
trials [122]. Various studies have shown that functional
and biochemical parameters of platelets are affected by
dietary fatty acids [123,124]. As mentioned earlier, the
TF:FVIIa complex activates coagulation cascade which
leads to fibrin formation. Although the production of
fibrin is usually considered to be the main purpose,
thrombin is also a potent platelet-aggregating agent
[125]. Thus, postprandial activation of hemostatic
factors may initiate platelet activation. Platelets are
activated in postprandial lipemia by several mechanisms
[6,126]. In vivo platelet activation in hypertriglyceridemic patients was reported by analysis of activationdependent platelet surface antigen, GP53 [127]. Plasma
LDLs also activate platelets by modulating Na+ /K+
antiport activity [128]. Postprandial platelet aggregation
response to ADP and collagen was lower in the butter
intake group compared to those of the control [114].
Stearic acid, 18:0 and trans-fatty acid diets similarly
affect platelet activation and endothelial PGI2 production [129]. Platelet aggregation response to collagen
increased after both diets, while ADP-induced aggregation showed no diet-induced changes [129,130]. While
oleic acid has neutral effect on platelet function [10,56],
PUFAs inhibit both collagen and ADP-induced platelet
aggregation, but no effect on arachidonic acid (AA)induced aggregation. AA provides adequate substrates
for synthesis of circulating vasoactive factors such as
prostacyclin (PGI2) (produced by endothelium) and
thromboxane A2 (TXA2) (produced by platelets). The
ratio of TXA2/PGI2 is an index of the relative activity of
the opposing stimuli that modulate vascular tone and
platelet activation. The ratio of TXA2/PGI2 in intervillous space could be involved in the mechanism of
initiating platelet function. In general, it seems that in
diseases where there is a tendency for thrombosis to
develop, TXA2 production is elevated whereas PGI2
production may be either elevated or reduced. The
opposite is found in some diseases associated with
increased bleeding tendency. To serve as the substrate
for synthesis of TXA2, AA is liberated from membrane
phospholipids by phospholipases (Fig. 4). During
activation, exogenous AA can also readily be taken up
by platelets. Increased expression of fatty acid translocase (FAT) or CD36 in platelets enhances AA uptake,
thus lead to increased TxA2 production [131]. PGI2
Fig. 4. Dietary lipids and platelet activation. Platelets can be activated
by different agonists (thrombin, ADP, collagen, TXA2) via their
respective receptors on platelet membrane surface. Activated phospholipase C (PLC) then cleaves phosphoinositol pyrophosphate (PIP2)
to release diacylglycerol (DAG) and inositol triphosphate (IP3). This
mobilizes Ca2+ which in turn activates phospholipase A2 (PLA2).
PLA2 then cleaves phospholipids (PL) to liberate arachidonic acid,
20:4n-6 (AA) or eicosapentaenoic acid,20:5n-3 (EPA) to produce
thromboxane A2 (from AA) or thromboxane A3 (from EPA).
Prostacyclin (PGI2), produced from AA in endothelium, inhibits
platelet aggregation through increasing cAMP levels in platelets via
activation of its receptor-linked adenylate cyclase.
strongly inhibits aggregation of platelets, an effect
mediated by stimulation of receptor-linked adenylate
cyclase which results in accumulation of cAMP [132].
Linoleic acid, 18:2n-6, rich diet increased PGI2 receptors
in human platelets compared with stearate or oleate
acid-rich diets without affecting platelet membrane
fluidity [56]. An increased amount of dietary n-3 fatty
acids reduces AA in tissue lipids by inhibiting its
synthesis from its parent molecule, linoleic acid. In
addition, eicosapentaneoic acid (20:5n-3) competitively
inhibit the oxygenation of AA via the cyclooxygenase
and lipoxygenase pathways. The replacement of TXA2
from AA with the less-potent TXA3 from EPA, leads to
a marked shift in the TXA2–PGI2 balance which may
act to produce an anti-aggregatory state. Modifying
platelet aggregation and subsequent adhesion to the
blood vessel affected by TXA2–PGI2 interactions
suggests a mechanism, already partially realized, for
preventing and treating circulatory diseases and tumor
metastasis. Dietary fatty acids thus may affect platelet
function by modulating AA levels in these cell membranes.
7. Conclusions
Dietary lipids are thought to influence the development of CVD via number of processes such as the
hemostatic system and platelet function [9,133,134]. In
the postprandial state, large triacylglycerol-rich particles
can support the assembly and function of coagulation
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complexes and seem to play a role in the activation of
factor VII, PAI-1, and platelets, and thus may explain
increased CVD risk associated with increased postprandial triglyceridemia. FVII coagulant activity modestly
decreases with reductions in saturated fatty acid intake
and thereby may contribute to the beneficial effects of
low saturated fatty acid diets. Oleic acid exerts
significant beneficial effects on atherosclerosis and
thrombosis [34,55,56,135]. The thrombogenic state
arises when an imbalance exists between procoagulant
and profibrinolytic activity. FVII appears to play a
major role in basal thrombin generation, whereas the
generation of the fibrinolytic enzyme plasmin is regulated by PAI-1. Reports of postprandial increases in
PAI-1 antigen and activity and the demonstration that
triacylglycerol-rich VLDLs stimulate the expression and
secretion of PAI-1 by endothelial cells in vitro may have
clinical significance for this disorder. However, many
studies investigating the postprandial effects of lipids
suffer limitation that the fat load given is fairly large and
unrepresentative of the typical fat content of a meal,
meaning that extrapolation of results to real-life
situations are not possible. Fundamental gains have
been recently made in our understanding of postprandial lipid metabolism in health and disease; however, its
relationships with the activation of hemostatic factors
are not yet fully understood. In order to improve our
knowledge in this area, sufficient sample size in future
studies are required to take into account of the genetic
variation (gene polymorphisms for VII, PAI-1), sex,
physical activity, stage of life factors, and sufficient
duration to account for adaptation for definitive
conclusions.
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