The possible roles of food-derived bioactive peptides in reducing the
risk of cardiovascular disease
Kati Erdmann, Belinda W.Y. Cheung, Henning Schröder⁎
Department of Pharmaceutics, College of Pharmacy, University of Minnesota, Minneapolis, MN 55455, USA
Received 2 October 2007; accepted 26 November 2007
Vascular diseases such as atherosclerosis, stroke or myocardial infarction are a significant public health problem worldwide. Attempts to
prevent vascular diseases often imply modifications and improvement of causative risk factors such as high blood pressure, obesity, an
unfavorable profile of blood lipids or insulin resistance. In addition to numerous preventive and therapeutic drug regimens, there has been
increased focus on identifying dietary compounds that may contribute to cardiovascular health in recent years. Food-derived bioactive
peptides represent one such source of health-enhancing components. They can be released during gastrointestinal digestion or food
processing from a multitude of plant and animal proteins, especially milk, soy or fish proteins. Biologically active peptides are considered to
promote diverse activities, including opiate-like, mineral binding, immunomodulatory, antimicrobial, antioxidant, antithrombotic,
hypocholesterolemic and antihypertensive actions. By modulating and improving physiological functions, bioactive peptides may provide
new therapeutic applications for the prevention or treatment of chronic diseases. As components of functional foods or nutraceuticals with
certain health claims, bioactive peptides are of commercial interest as well. The current review centers on bioactive peptides with properties
relevant to cardiovascular health.
© 2008 Published by Elsevier Inc.
Keywords: Antihypertensive; Antioxidant; Antithrombotic; Bioactive peptides; Cardiovascular disease; Hypocholesterolemic/hypotriglyceridemic
exert — beyond their nutritional value — a physiological,
hormone-like effect in humans. They are found in milk, egg,
meat and fish of various kinds as well as in many plants.
Bioactive peptides are inactive within the sequence of their
parent protein and can be released by enzymatic hydrolysis
either during gastrointestinal digestion or during food
processing (e.g., cheese ripening and milk fermentation).
but in some cases may consist of more than 20 amino acids.
Following digestion, bioactive peptides can either be
absorbed through the intestine to enter the blood circulation
intact and exert systemic effects, or produce local effects in
the gastrointestinal tract. Depending on the sequence of
amino acids, these peptides can exhibit diverse activities,
including opiate-like, mineral binding, immunomodulatory,
antimicrobial, antioxidant, antithrombotic, hypocholestero-
lemic, and antihypertensive actions [1–4]. Many of the
known bioactive peptides are multifunctional and can exert
more than one of the effects mentioned [5–7]. Because of
their health-enhancing potential and safety profiles they may
be used as components in functional foods or nutraceuticals.
However, milk proteins are currently the main source of
several biofunctional peptides and daily intake of milk and
milk products has proved to be physiologically important to
both neonates and adults [8–10].
This review centers on bioactive peptides with proper-
ties relevant to cardiovascular health including effects on
blood pressure, oxidative stress, hemostasis, appetite and
2. Cardiovascular disease and nutraceuticals
Cardiovascular disease (CVD) is the single leading cause
of death for both males and females in the United States
Available online at www.sciencedirect.com
Journal of Nutritional Biochemistry xx (2008) xxx–xxx
⁎Corresponding author. Tel.: +1 612 625 5695; fax: +1 612 624 6695.
E-mail address: email@example.com (H. Schröder).
0955-2863/$ – see front matter © 2008 Published by Elsevier Inc.
ARTICLE IN PRESS
and other technologically advanced countries in the world.
In lesser-developed countries it generally ranks among the
top five causes of death. The World Health Organization
estimates that by 2020, heart disease and stroke will have
surpassed infectious diseases to become the leading cause
of death and disability worldwide . Consequently, there
has been an increased focus on improving diet and lifestyle
as a strategy for CVD risk reduction. Current dietary advice
to reduce risk of CVD includes substituting saturated fat
with carbohydrate without changing the protein content. In
the USA, the DASH-diet (Dietary Approaches to Stop
Hypertension), which is rich in fruits, vegetables and low-
fat dairy products, is recommended to meet this objective.
The DASH-diet is based on a reduced intake of saturated
fat that is replaced by carbohydrate. Such high-carbohy-
drate, low-protein diets are known to reduce blood pressure
and low-density lipoprotein (LDL) cholesterol [8,12], but
also to reduce high-density lipoprotein (HDL) cholesterol
levels and to raise fasting triglycerides [13,14]. Recent
evidence suggests that an increased consumption of protein,
particularly plant protein, may further lower the risk of
hypertension and CVD [15,16]. The OmniHeart (Optimal
Macro-Nutrient Intake to Prevent Heart Disease) trial
demonstrated that partial substitution of carbohydrate with
protein sources low in saturated fat can lower blood
pressure, improve lipid levels, facilitate short-term weight
loss and reduce the risk of CVD . The mechanisms by
which protein could exert its beneficial effects include an
increased intake of biologically active amino acids or
These and other findings have increased the awareness of
the critical link between diet and health. Moreover, they have
led to the development of nutritionally enhanced food
products designed to suit specific health concerns, particu-
larly with relevance to the management of lifestyle-related
diseases. Such foods, termed functional foods or nutraceu-
ticals, are generally defined as products that have been
satisfactorily demonstrated to have positive effects on one or
more functions in the body, beyond their nutritional proper-
ties, in a way which is relevant to either an improved state of
health and well-being and/or a reduction of disease risk.
They should remain as foods or beverages and not in
pharmaceutical forms such as tablets or capsules. As part of a
normal dietary regimen they must demonstrate their effects
in amounts that are reasonably expected to be consumed in
the diet. The physiologically active components of func-
tional foods are either added or enriched by modification of
the usual manufacturing process. Consequently, increasing
attention has focused on identifying dietary compounds,
from plants (i.e., phytochemicals) as well as animals (i.e.,
zoochemicals), for promotion of specific health benefits
[20,21]. Based on observations made in human studies over
the last several years such as the already mentioned
OmniHeart trial, bioactive peptides have gained scientific
interest as constituents of nutraceuticals for their potential in
disease prevention and health improvement.
3. Antihypertensive (ACE inhibitory) peptides
Elevated blood pressure is one of the major independent
risk factors for CVD [22,23]. Angiotensin I-converting
enzyme (ACE) plays a crucial role in the regulation of
blood pressure as it promotes the conversion of angiotensin
I to the potent vasoconstrictor angiotensin II as well as
inactivates the vasodilator bradykinin (Fig. 1). By inhibit-
ing these processes, synthetic ACE inhibitors have long
been used as antihypertensive agents. In recent years, some
food proteins have been identified as sources of ACE
inhibitory peptides and are currently the best known class
of bioactive peptides . These nutritional peptides have
received considerable attention for their effectiveness in
both the prevention and the treatment of hypertension. The
main sources of ACE inhibitory peptides are dairy products
and fish, but they are also derived from plant (e.g., soy,
wheat), meat and egg. Potent ACE inhibitory peptides from
caseins and whey proteins are termed casokinins and
lactokinins, respectively [2,24–26].
Numerous studies in spontaneously hypertensive rats
(SHR) as well as in hypertensive human volunteers have
been performed to determine the antihypertensive effects of
food-derived ACE inhibitors. These in vivo studies have
demonstrated that several ACE inhibitory peptides signifi-
cantly reduce blood pressure, either after intravenous or oral
administration. ACE inhibitory peptides with documented in
vivo antihypertensive effects are listed in Table 1. An
important observation from these trials is that the peptides
being studied have little or no effect on blood pressure of
normotensive subjects suggesting that they exert no acute
hypotensive effect. Therefore, ACE inhibitory peptides
could be applied as initial treatment in mildly hypertensive
individuals or as supplemental treatment. They would also
represent a low-cost alternative treatment for hypertension.
Another advantage is that these peptides have not been
associated with the harmful side effects reported for
synthetic ACE inhibitors such as dry cough, skin rashes
and angioedema, probably due to the lower ACE inhibitory
activity determined in vitro [24,38].
Fig. 1. The renin–angiotensin system.
2 K. Erdmann et al. / Journal of Nutritional Biochemistry xx (2008) xxx–xxx
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The potency of an ACE inhibitor is usually expressed as
an IC50value, which is the inhibitor concentration leading to
derived ACE inhibitors have moderate inhibitory potencies,
usuallywithinan IC50range of100–500μmol/L.Due to
the incomplete and often unknown bioavailability of the
ACE inhibitory peptides following oral administration, it is
difficult and unreliable to predict the in vivo antihypertensive
effect based on measured inhibitory activity in vitro. In order
to produce antihypertensive effects in vivo the peptides have
to be absorbed intact through the intestine and reach the
cardiovascular system in an active form. In this regard,
specific structural properties play an important role. Most of
the ACE inhibitory peptides are short peptides with only two
to nine amino acids. It has been demonstrated that di- or
tripeptides, especially those with C-terminal proline or
hydroxyproline residues, are generally resistant to degrada-
tion by digestive enzymes [40,41]. In addition, short peptides
consisting of two or three amino acids are absorbed more
rapidly than free amino acids [42,43]. The ACE inhibitory
tripeptides IPP and VPP, for example, were detected in the
aorta of SHR, following oral administration of fermented
diet can also be absorbed intact through the intestine and
produce biological effects, although the potency of the
peptides decreases as the chain length increases .
However, binding to ACE appears to be strongly influenced
by the C-terminal sequence of the peptides. It has been
postulated that proline, lysine or arginine is preferred as C-
terminal residue and thus contributes to the ACE inhibitory
potency . Furthermore, studies in SHR revealed that
dipeptides with a C-terminal tyrosine residue produced a
slow but prolonged decrease in systolic blood pressure
compared to dipeptides with phenylalanine at the C-terminal.
In contrast, dipeptides with C-terminal phenylalanine caused
a more rapid reduction and a shorter duration of action .
Table 2 presents examples of structural properties of selected
In vivo comparative studies with captopril, a clinically
used ACE inhibitor, have shown that ACE inhibitory
peptides with antihypertensive effect exhibit higher in vivo
activity than would be expected from their in vitro activity.
The exact mechanisms underlying this observation have not
yet been identified. Fujita and Yoshikawa  suggested that
bioactive peptides have higher tissue affinities and are
subject to a slower elimination than captopril.
However, these peptides may influence blood pressure by
mechanisms other than the established ACE inhibition. The
release of vasodilatory substances like prostaglandin I2,
NO  or CO  could also contribute to the blood
pressure-lowering effects of various ACE inhibitory pep-
tides. Recently, Nurminen et al.  reported that the
antihypertensive effect of α-lactorphin, a peptide with
opiate-like and ACE inhibitory properties, was mediated
through the vasodilatory action of binding to opioid
receptors. Furthermore, inhibition of chymase by ACE
inhibitory peptides has been suggested to provide an
additional antihypertensive effect as well .
4. Antioxidant peptides
Oxidant stress, the increased production of reactive
oxygen species (ROS) in combination with outstripping
endogenous antioxidant defense mechanisms, is another
significant causative factor for the initiation or progression of
several vascular diseases. ROS can cause extensive damage
to biological macromolecules like DNA, proteins and lipids
. Specifically, the oxidative modification of LDL results
in the increased atherogenicity of oxidized LDL [65,66].
Therefore, prolonged production of ROS is thought to
contribute to the development of severe tissue injury .
Dietary consumption of antioxidants appears to provide
further benefits to the endogenous antioxidant defense
strategies in the fight against oxidative stress [68–70]. In
addition to the well-known dietary antioxidants like vitamin
C, vitamin E, polyphenols and carotenoids, other dietary
Examples of ACE inhibitory peptides with in vivo antihypertensive effects
Origin Sequence/nameIC50(μmol/L) SubjectsReference
IPA (β-lactosin A)
ALPM (β-lactosin B)
MNPPK (myopentapeptide A)
ITTNP (myopentapeptide B)
SHR, humans [27,28]
Fish (sardine muscle)
Fish (bonito muscle)
Meat (chicken muscle)SHR 
Meat (porcine muscle) SHR 
3K. Erdmann et al. / Journal of Nutritional Biochemistry xx (2008) xxx–xxx
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compounds have generated particular interest as defenses
against oxidative damage. Recent studies have shown that
peptides with antioxidant properties can be released from
food sources such as milk casein , whey protein , egg
[73,74] and soy protein . Table 3 lists some examples of
bioactive peptides derived from different protein sources.
Some peptides derived from hydrolyzed food proteins
exert antioxidant activities against enzymatic (lipoxygen-
ase-mediated) and nonenzymatic peroxidation of lipids and
essential fatty acids [49,76–78]. The exact mechanisms
behind these effects are not fully understood. The
antioxidant properties of these peptides have been
suggested to be due to metal ion chelation, free radical
scavenging and singulet oxygen quenching . However,
through the investigation of synthetic histidine-containing
peptides, Chen et al.  demonstrated that none of these
properties can be correlated solely with the antioxidant
activity of the tested peptides. Therefore, overall antiox-
idant action is most likely attributed to the cooperative
effects of the mechanisms mentioned . Another
plausible mode of action may be the induction of genes
which protect cells from damage by ROS. Previously, our
laboratory has shown that the biofunctional dipeptide MY,
derived from sardine muscle, stimulates expression of the
antioxidant defense proteins heme oxygenase-1 (HO-1) and
ferritin in endothelial cells (Fig. 2). These genomic actions
of MY have been associated with a sustained cellular
protection from oxidative stress . The antioxidant
activity of whey-derived peptides and whey itself has been
linked with the presence of cysteine-rich proteins which
promote the synthesis of glutathione, a potent intracellular
antioxidant . In a study by Rival et al. , caseins and
casein-derived peptides were found to inhibit lipoxygenase,
an enzyme which catalyzes the peroxidation of unsaturated
fatty acids such as linoleic acid.
The antioxidant activity has been attributed to certain
amino acid sequences . High amounts of histidine and
some hydrophobic amino acids are related to the antiox-
idant potency . The activity of histidine-containing
peptides is thought to be connected to hydrogen-donating
ability, lipid peroxyradical trapping, and/or the metal ion
chelating ability of the imidazole group . The addition
of a leucine or proline residue to the N-terminus of a
histidine–histidine dipeptide would enhance antioxidant
activity. According to Chen et al. , peptides with a Pro-
His-His sequence showed the greatest antioxidant activity
among all tested peptides and had synergistic effects with
nonpeptidic antioxidants. The hydrophobicity of the
peptide also appears to be an important factor for its
antioxidant activity due to increased accessibility to
hydrophobic targets (e.g., lipophilic fatty acids) .
Furthermore, there is some evidence that the antioxidant
effect of certain amino acids is greater when they are
incorporated in dipeptides [87,88]. For example, the
constituent amino acids of the histidine containing dipep-
tide carnosine and related agents are far less effective
antioxidants than their parent proteins . As another
example, milk casein has been reported to inhibit the
lipoxygenase-mediated lipid autoxidation, whereas the free
amino acids could not substitute for casein as the antioxidant
. The results suggest a crucial role of the peptide bond
and/or specific structural features of the peptides regarding
antioxidant potency. In contrast, recent results on the
antioxidant effect of whey protein hydrolysates indicated
Structural properties of selected biofunctional peptides
Activity Structural elementsRemarks Reference
ACE inhibitory Pro or hydroxy-Pro as C-terminus Usually resistant to degradation
by digestive enzymes
Preferred C-terminal residues with
contribution to the ACE inhibitory potency
Dipeptides with a C-terminal Tyr produced
a higher antihypertensive effect compared
to dipeptides with C-terminal Phe
Contribution to the antioxidant potency
Pro, Lys or Arg as C-terminus
Tyr or Phe as C-terminus
Antioxidant High amounts of His and
hydrophobic amino acids
Peptides with a Pro-His-His sequence
Peptides with a Pro-His-His sequence
showed the greatest antioxidant activity
among all tested peptides
Important for the antithrombotic activity
Antithrombotic Ile108, Lys112and Asp115
residues of casoplatelin
Low ratios of methionine–glycine
and lysine–arginine in the dietary protein
High amounts of hydrophobic amino acids
Positive correlation with antithrombotic activity
Favors a hypocholesterolemic effect
Hydrophobic peptides can bind bile acids
and thereby enhance the fecal steroid excretion
Peptide length influences CCK-releasing activity
(different among each dietary protein)
Necessary condition for CCK release through
direct binding to intestinal cells
Antiobesity Peptide length
Multiple Arg residues 
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that the peptide linkage or structural peptide conformation
can also attenuate the antioxidant activity of the
constituent amino acids . Thus, peptide conformation
can lead to both synergistic and antagonistic effects in
regard to the antioxidant activity of free amino acids.
Further research examining the structure–activity relation-
ship in peptides is needed.
5. Antithrombotic peptides
Another complication related to CVD is the inclination to
develop thrombosis due to abnormalities in coagulation.
Increased occurrence of thrombosis has been linked to
platelet hyperreactivity, high levels of hemostatic proteins
(e.g., fibrinogen), defective fibrinolysis and hyperviscosity
of the blood [91,92]. Hence, antithrombotic drugs are
commonly used to reduce platelet aggregation and enhance
Indeed, it has been proved that there is a significant
amount of molecular similarities between the mechanisms
involved in milk clotting, defined by the interaction of κ-
casein with chymosin, and blood clotting, defined by the
interaction of fibrinogen with thrombin . To date, food-
derived peptides with antithrombotic properties are mainly
the result of enzymatic hydrolysis of bovine κ-casein.
Recently, antithrombotic peptides have been isolated from
human and sheep κ-casein as well [51,94].
The main antithrombotic peptide MAIPPKKNQDK,
isolated from the soluble C-terminal fragment (caseinogly-
comacropeptide) of bovine κ-casein, corresponds to the
residues 106 to 116 of κ-casein and is termed casoplatelin.
This undecapeptide inhibits both the aggregation of ADP-
activated platelets as well as the binding of human fibrinogen
γ-chain to its receptor region on the platelet surface. Smaller
fragments of this peptide, known as casoplatelins, can also
affect platelet function although they have much lower
inhibitory activity than the complete fragment .
Three amino acid residues (Ile108, Lys112, Asp115) of the
aforementioned undecapeptide seem to be important for the
antithrombotic effect, because they are homologous in
positions to the γ-chain sequence of human fibrinogen.
Therefore, antithrombotic activity is influenced by the
competition for platelet receptors between casoplatelin and
the γ-chain of human fibrinogen . Furthermore, a
correlation between sugar level and antithrombotic activity
has been suggested since the human κ-caseinoglycomacro-
peptide, which is richer in sugars than that in bovine, is
reportedly more potent .
It is thought that milk protein-derived antithrombotic
peptides are absorbed intact into the bloodstream. Human
and bovine κ-caseinoglycomacropeptides, two antithrombo-
tic peptides derived from the corresponding κ-caseins, have
been detected at physiologically active concentrations in the
plasma of newborn children following ingestion of breast
milk or cow milk-based formula, respectively .
Furthermore, a peptide derived from human lactoferrin,
KRDS, which holds structural similarities to fibrinogen α-
chain, has been shown to inhibit platelet aggregation but to a
lesser extent than the fibrinogen analogue, RGDS [96,97]. It
is likely that KRDS and RGDS have different mechanisms of
action and/or their binding sites are different and sequence
specific. Inhibition of platelet aggregation by KRDS has
been associated with an inhibition of the release of the dense
granule protein serotonin, whereas RGDS did not exhibit a
similar inhibition .
In vivo antithrombotic activities have been shown for
the κ-casein-derived undecapeptide  as well as for the
lactoferrin-derived tetrapeptide . In addition, no
detectable toxic effect has been reported. Hence, case-
inoglycomacropeptide could potentially be used to treat or
prevent thrombosis. In contrast, the RGDS sequence has
been found to induce detachment of endothelial cells in
vitro and therefore serious concerns exist regarding the
toxicity of this sequence in vivo. The related peptide KRDS
does not appear to have the same potential detrimental
effects as RGDS possibly due to their different modes of
6. Hypocholesterolemic and hypotriglyceridemic
An unfavorable profile of blood lipids is another
important risk factor for the genesis of various CVDs.
Many studies have found a positive correlation between
hypercholesterolemia and/or hypertriglyceridemia and the
likelihood for developing CVD [92,101,102]. Not surpris-
ingly, treatment for hyperlipidemia-accelerated diseases
Fig. 2. The heme oxygenase (HO) enzyme reaction: HO-1 is an inducible
enzyme that catalyzes the degradation of the toxic heme moiety. This
process leads to generation of carbon monoxide (CO), free iron and
biliverdin; the latter is subsequently converted to bilirubin by biliverdin
reductase (BVR) [79,80]. CO and bilirubin have been causally linked to a
higher resistance against cardiovascular disease [81–83]. Furthermore, the
HO-1-dependent release of free iron during heme catabolism results in the
up-regulation of ferritin protein expression . Induction of HO-1 and
ferritin is considered to be an adaptive and beneficial response to oxidative
stress in a wide variety of cells.
5 K. Erdmann et al. / Journal of Nutritional Biochemistry xx (2008) xxx–xxx
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often includes the improvement of serum lipid distribution
through diet modifications.
It is generally known that several dietary proteins can
improve blood lipid profiles. To date, hypocholesterolemic
properties have been reported for soy [103,104], whey
[105,106] and fish protein , capable of altering the
plasma profile from atherogenic to cardioprotective. In
contrast, bovine casein tends to cause species-dependent
hypercholesterolemia and atheromatous plaques in animal
studies [107,108]. The exact mechanisms responsible for the
hypocholesterolemic effects have not been fully identified,
but evidence suggests that the specific amino acid composi-
tion of dietary proteins probably influences the effect of the
protein source on plasma cholesterol levels. It has been
reported that dietary proteins with low ratios of methionine–
glycine and lysine–arginine, such as soy and fish protein,
favor a hypocholesterolemic effect [52–54]. In contrast,
bovine casein tends to elevate cholesterol levels probably
due to its high ratios of methionine-glycine and lysine-
Of the limited number of peptides reported to have
hypocholesterolemic effects, dietary soy protein has received
the most attention. Published data offer a range of possible
mechanism of action in soy protein's ability to reduce total
plasma cholesterol including induction of LDL receptor
expression, increase of bile acid synthesis and excretion as
well as decrease in steroid absorption from the intestine. In
addition, changes in the endocrine status such as alteration in
the insulin–glucagon ratio and in thyroid hormone concen-
trations havealso beenreported.Although these effects
have not been attributed to specific soy constituents, several
studiessuggestthat peptides derivedfromsoyproteinmaybe
the bioactive components. When amino acid mixtures
mimicking soy protein were fed to rats or rabbits, the
resulting blood cholesterol levels were significantly lowered
but not as low as those that were fed with the intact protein
[110,111]. It has also been shown that soy protein hydro-
lysates reduce total cholesterol levels more effectively than
intact soy protein [104,112]. Several more reports indicate
that hydrophobic peptides derived from soy protein can bind
bile acids thereby enhancing fecal steroid excretion which
may contribute to the hypocholesterolemic activity [55,56].
Recently, LPYPR, a peptide derived from soy glycinin,
was found to produce serum cholesterol-lowering effects in
mice following oral administration . LPYPR is
structurally homologous to enterostatin (VPDPR), an
endogenous peptide exhibiting hypocholesterolemic and
anorectic effects . Another glycinin-derived peptide
with cholesterol-lowering activity is IAVPGEVA . In
vitro measurements have shown that both LPYRP and
IAVPGEVA inhibited 3-hydroxy-3-methylglutaryl coen-
zyme A reductase (HMGR) which is a known key enzyme
in cholesterol biosynthesis. Investigations on the structure–
activity relationship revealed that the hydrophobic region of
both peptides is a required structural element for their
biological activity. The maximum length of the hydrophobic
sequence was stated to be four amino acids. Moreover, the
proline residue seems to be a key component and can be
located at both the C-terminus and in any other position of
the amino acid sequence except the N-terminus .
Several peptide fragments obtained from the subunits of
β-conglycinin are considered to possess hypocholesterole-
mic activity. The regulation of cholesterol homeostasis has
been proposed to be due to the activation of LDL receptors
and LDL degradation in liver cells at least in vitro.
Preliminary data evidently suggest a positive modulation
of LDL receptor induced by a specific sequence correspond-
ing to the positions 127–150 of β-conglycinin . Duranti
et al.  reported a marked up-regulation of liver β-very
low-density lipoprotein (VLDL) receptors and a significant
decrease in plasma triglycerides in hypercholesterolemic rats
after oral treatment with the α′-subunit of β-conglycinin.
They hypothesized that peptides arising from digestion elicit
the biological effect .
As for the observed hypotriglyceridemic activity, there is
some evidence that dietary protein may affect lipogenesis in
the liver. Iritani et al.  have shown that oral
administration of soy protein to rats reduced the concentra-
tions of triglycerides in plasma and more prominently in
liver. These effects were associated with significant reduc-
tions in the activities of hepatic lipogenic enzymes indicating
that soy protein reduces liver triglycerides or fat in part by
inhibiting hepatic fatty acid synthesis . Furthermore,
dietary soy protein appeared to cause a stimulation of
lipolysis and fatty acid utilization . In mice, Moriyama
et al.  demonstrated that β-conglycinin reduced serum
triglyceride levels by the acceleration of β-oxidation,
suppression of fatty acid synthesis and increased fecal
excretion of triglycerides. They concluded that some specific
β-conglycinin peptides might be responsible for these
multiple events . Remarkable hypotriglyceridemic
activities in different animal species were also achieved by
the administration of hydrolyzed globin. VVYP, VYP and
VTL were identified as the effective constituent peptides.
The hypotriglyceridemic effect of these peptides was
associated with decreased intestinal fat absorption as well
as an enhanced lipolysis of triglycerides . The
hypotriglyceridemic effect of hydrolyzed globin has also
been demonstrated in humans .
Numerous studies have shown that milk whey protein, in
contrast to milk casein, decreases serum cholesterol similar
to soy protein [106,124,125]. This effect was more marked
with the whey peptide fraction than with the intact whey
protein . Nagaoka et al.  identified IIAEK as the
hypocholesterolemic peptide derived from bovine milk β-
lactoglobulin. In animal studies, IIAEK, which is also termed
lactostatin, exhibited a greater hypocholesterolemic effect
than β-sitosterol. Following oral administration to rats, total
serum cholesterol levels were significantly lower, whereas
HDL concentration and atherogenic index (HDL cholesterol/
total cholesterol) were significantly higher than in the group
fed with β-sitosterol. These effects have been speculated to
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ARTICLE IN PRESS
be at least in part due to a decrease of micellar solubility of
cholesterol which leads to lower intestinal cholesterol
absorption . Recent data have shown that lactostatin
is capable of inducing the gene transcription of human
cholesterol 7α-hydroxylase (CYP7A1), a cholesterol-meta-
bolizing enzyme, resulting in hypocholesterolemic effects.
This new site of action involves Ca and MAPK-dependent
signaling pathways. Further results imply that the C-terminal
side of lactostatin, especially the glutamyl–lysine sequence,
is crucial for the induction of human CYP7A1 transcription.
However, an amino acid mixture constituently equivalent to
lactostatin failed to induce the CYP7A1 gene .
7. Antiobesity peptides
In many industrial countries obesity is a serious health
issue that has been associated with higher incidence of CVD
and related disorders . Hyperinsulinemia, insulin
resistance and abnormalities in lipid metabolism have all
been linked to obesity. Lipoprotein profile obtained in obese
subjects revealed a pattern of higher levels of triglycerides,
elevated LDL-cholesterol and low HDL-cholesterol. Restric-
tion of caloric intake and increasing physical exercise are
recommended for the treatment of adiposity. Both weight
loss and exercise can also improve insulin resistance and
associated dyslipidemia [129,130].
It is generally accepted that protein is the most satiating
macronutrient [131,132]. Besides inducing the feeling of
satiety, a high-protein diet promotes thermogenesis leading
to a faster rate of caloric metabolism. Diets rich in protein are
known to suppress food intake and facilitate short-term
weight loss even more effectively than high-carbohydrate
diets and thus can be used in the management of obesity.
However, some evidence suggests that different sources of
dietary protein in low-calorie diets produce varying effects
on metabolism and therefore strongly influence weight loss.
For example, the ingestion of plant protein such as soy is
effective in reducing body weight and in improving
cardiovascular risk factors. In contrast, the regular intake
of protein sources rich in saturated fat and cholesterol such as
red meat and eggs may increase the risk of CVD [131,133].
Nevertheless, reliable information on the long-term effects of
high-protein diets on overall health is not yet available.
Ingestion of soy, casein and whey protein has all been
shown to hold antiobesity or anorectic properties with the
effect of soy protein in reducing body weight more superior
than that of casein and whey protein [134–136]. The
mechanisms by which proteins exert anorectic actions are
still unclear. Several studies speculate that peptides released
from dietary proteins during digestion can initiate several
satiety signals from the gut and thus prevent further food
intake. Because these peptides act at the intestinal site they
do not need to be absorbed into the systemic circulation.
Pupovac and Anderson  conclude that the induction
of satiety by peptides derived from soy and casein protein is
mediated by independent activation of both opioid and
cholecystokinin (CCK)-A receptors. The pivotal role of
opioid and CCK-A receptors in the regulation of food intake
is well recognized. Peptides with opioid-like activities affect
food intake by the delay of gastric emptying and intestinal
transit . CKK is an important physiologic endocrine factor
that regulates appetite and gastric emptying. The stimulation
of CCK release contributes to appetite suppression in the
central nervous system as well as in the periphery [138,139].
In regard to soy protein, it has been shown that the decline
in body fat and food intake was more significant with the soy
peptide fraction than with the intact protein indicating that
hydrolysis of soy protein is important in its effect of weight
reduction [135,140]. Furthermore, amino acid mixtures
simulating soy and casein protein were not effective in
releasing CCK from mucosal cells [57,141,142]. These
results indicate that peptides released from dietary proteins
contribute to the initiation of satiety signals. Nishi et al. 
hypothesize that the peptide length might be an important
factor in CCK-releasing activity. The optimal peptide size
seems to be different among each dietary protein. Well-
Examples of bioactive peptides derived from food
Activity OriginSequence/name Reference
Antioxidant Fish (sardine muscle)
Egg (egg white)
MHIRL, YVEEL, WYSLAMAASDI
MAIPPKKNQDK (casoplatelin) and smaller fragments
Several peptide fragments
(e.g., sequence corresponding to the residues 127–150)
VVYP, VYP, VTL
7 K. Erdmann et al. / Journal of Nutritional Biochemistry xx (2008) xxx–xxx
ARTICLE IN PRESS
digested soy protein for instance is more effective than less-
digested one on CCK liberation. In contrast, larger peptides
of casein hydrolysate seem to be involved in the direct
stimulation of CCK release .
corresponding to the residues 51–63 of β-conglycinin as the
bioactive appetite suppressant in soy protein. This peptide
CCK release. Further investigations on the binding activities
of several synthetic model peptides indicate that multiple
arginine residues are a necessary condition for CCK release
through direct binding to brush border membrane .
Several studies have shown that satiety associated with
casein ingestion involves both opioid and CCK regulation
[137,142]. Proteolysis of milk casein releases bioactive
peptides relevant to hunger regulation including casomor-
phins and caseinoglycomacropeptide. Casomorphins are
peptides with opioid-like activities that are known to
interact with gastric opioid receptors to slow gastrointestinal
motility and prevent further food intake . In addition,
they influence appetite regulation by modifying the
postprandial levels of metabolic hormones involved in
satiety . Peptides with opioid activity have been
reviewed extensively elsewhere [39,147]. Caseinoglycoma-
cropeptide, a 64-amino acid fragment from the C-terminal
end of bovine casein, has been shown to exert CCK-
releasing activity via direct reaction with the small intestine
and therefore act as an appetite suppressant [143,144]. In
addition, caseinoglycomacropeptide has also been found to
control food intake in animals at least in part through opioid
Protein-induced satiety may also be mediated through the
glucagon-like peptide-1 (GLP-1) signaling pathway. In rats
as well as in humans it has been demonstrated that activation
of GLP-1 receptor is involved in casein- and whey-induced
suppression of food intake [149,150]. Peptides released from
digested protein appear to provide this satiety signal, because
neither intact proteins nor free amino acid mixtures
stimulated the release of GLP-1 .
Above and beyond the stimulation of satiety through
bioactive peptides, lipid-lowering effects as well as increas-
ing metabolic rate are also beneficial in fighting obesity.
Another possible mode of action is the modulation of
adipose genes that contribute to the homeostasis of
metabolism and vascular functions. In the case of soy
protein, Nagasawa et al.  have shown that it raises
adiponectin mRNA expression in mice. Adiponectin is an
adipose-specific plasma protein possessing antiatherogenic
and anti-insulin-resistance properties . Soy protein may
also reduce adiposity by modulating the expression of
nuclear transcription factors, specifically the peroxisome
proliferator-activated receptors (PPARs) and sterol regula-
tory element binding proteins (SREBPs) that are principal
regulators of fatty acid metabolism and cholesterol home-
ostasis [121,153,154]. Further evidence suggests that the
ingestion of soy and whey protein improves insulin
resistance which is a hallmark of obesity [136,154]. It
remains to be determined whether specific bioactive peptides
are responsible for the abovementioned effects.
Bioactive peptides have been shown to possess properties
that may be advantageous to cardiovascular health. These
effects include theloweringof bloodpressureand lipid levels
as well as reducing free radical formation. Evidence for
beneficial effects of bioactive peptides has also been raised
under conditions of obesity and enhanced thrombosis
(Table 3). Since CVD is a significant public health problem
in maintaining a healthy population. As part of a food product
or as a nutraceutical they have a chronic rather than an acute
effect on health. Numerous products that contain bioactive
peptides are already on the market (Table 4). Until now,
peptides have been observed in vitro or in animal model
systems.Human clinicalstudies are limitedornonexistent and
the optimal plasma levels of bioactive peptides have not been
Examples of commercially available functional foods carrying bioactive peptides (modified from Hartmann and Meisel )
Brand name ManufacturerRemarks Bioactive peptidesHealth claim
Calpis Co., Japan
Kanebo Ltd., Japan
BioZate Whey protein
Hypocholesterolemic CholesteBlockKyowa Hakko, JapanSoft drink Soy-derived peptides bound
8 K. Erdmann et al. / Journal of Nutritional Biochemistry xx (2008) xxx–xxx
ARTICLE IN PRESS
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