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The role of casein in the development of hypercholesterolemia

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Atherosclerosis remains the leading cause of severe cardiovascular complications such as cardio- and cerebrovascular events. Given that prevention and early intervention play important roles in the reduction of cardiovascular complications associated with atherosclerosis, it is critical to better understand how to target the modifiable risk factors, such as diet, in order to best minimize their contributions to the development of the disease. Studies have shown that various dietary sources of protein can affect blood lipid levels, a modifiable risk factor for atherosclerosis, either positively or negatively. This clearly highlights that not all proteins are "created equal." For example, consumption of diets high in either animal- or vegetable-based sources of protein have resulted in varied and inconsistent effects on blood cholesterol levels, often depending on the amino acid composition of the protein and the species investigated. Careful consideration of the source of dietary protein may play an important role in the prevention of atherosclerosis and subsequent cardiovascular complications. Given the recent focus on high protein diets, an emphasis on controlled studies in the area is warranted. The goal of this review is to present the current state of the literature that examines the effects of casein, a commonly utilized animal-based protein, on blood cholesterol levels and the varying effects noted in both animals and humans.
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MINI REVIEW
The role of casein in the development of hypercholesterolemia
Olivia Hanna Koury &Celena Scheede-Bergdahl &
Andreas Bergdahl
Received: 27 February 2014 /Accepted: 6 October 2014
#University of Navarra 2014
Abstract Atherosclerosis remains the leading cause of
severe cardiovascular complications such as cardio- and
cerebrovascular events. Given that prevention and early
intervention play important roles in the reduction of
cardiovascular complications associated with athero-
sclerosis, it is critical to better understand how to target
the modifiable risk factors, such as diet, in order to best
minimize their contributions to the development of the
disease. Studies have shown that various dietary sources
of protein can affect blood lipid levels, a modifiable risk
factor for atherosclerosis, either positively or negatively.
This clearly highlights that not all proteins are created
equal.For example, consumption of diets high in either
animal- or vegetable-based sources of protein have re-
sulted in varied and inconsistent effects on blood cho-
lesterol levels, often depending on the amino acid com-
position of the protein and the species investigated.
Careful consideration of the source of dietary protein
may play an important role in the prevention of athero-
sclerosis and subsequent cardiovascular complications.
Given the recent focus on high protein diets, an empha-
sis on controlled studies in the area is warranted. The
goal of this review is to present the current state of the
literature that examines the effects of casein, a common-
ly utilized animal-based protein, on blood cholesterol
levels and the varying effects noted in both animals and
humans.
Keywords Casein protein .Hypercholesterolemia .Soy
protein .Lipoprotein .Cardiovascular disease
Cholesterol and the development of atherosclerosis
Atherosclerosis lies at the root of many serious cardio-
vascular complications such as myocardial infarction,
stroke, gangrene, intermittent claudication, and limb
amputation [39]. The initiation of the atherosclerotic
process depends mainly on the state and function of
the endothelial layer, which represents the demarcation
between the vessel wall and the blood [15]. Endothelial
dysfunction is characterized by two aspects: a reduction
of the bioavailability of nitric oxide, which leads to
impaired vasoreactivity, and the activation of the endo-
thelial cells [7,51]. Taken together, these features induce
a pro-inflammatory, proliferative, and pro-coagulatory
state, all of which contribute to the progression of ath-
erogenesis [1]. Factors associated with endothelial dys-
function include smoking, oxidative stress, diabetes,
metabolic dysfunction, obesity, hypercholesterolemia,
and hypertension [20](Fig.1).
High-density lipoproteins (HDL) are considered to
be a negative risk factor for the development of cardio-
vascular disease and have been casually referred to as
goodcholesterol. The cardioprotective effects of HDL
J Physiol Biochem
DOI 10.1007/s13105-014-0365-9
O. H. Koury:A. Bergdahl (*)
Department of Exercise Science, Concordia University,
7141 Sherbrooke Street West, Montreal, QC H4B 1R6,
Canada
e-mail: andreas.bergdahl@concordia.ca
C. Scheede-Bergdahl
Department of Kinesiology & Physical Education,
McGill University,
475 Pine Avenue West, Montreal, QC H2W 1S4, Canada
are due to its role in reverse cholesterol transport (RCT),
a key process that regulates cholesterol clearance from
the systemic circulation. The purpose of RCT is the
removal of excess (free) cholesterol from peripheral
cells and reuptake by the liver for eventual bile salt
synthesis and excretion [8]. In the early stages of ath-
erosclerosis, a higher than normal concentration of cir-
culating low-density lipoproteins (LDL) results in their
penetration into the subendothelial layer of the blood
vessel. LDL, transported by apolipoprotein B (ApoB)
into the vascular wall, becomes biochemically modified
and, subsequently, triggers an inflammatory response
[21]. There are three histological features of the unstable
atheroma: (1) the large lipid core which is present when
the abovementioned RCT is incapable of regulating
blood cholesterol levels, (2) the abundance of inflam-
matory cells, and (3) a thin fibrous cap [17,22]. The
atheroma is not only a collection of cholesterol, waste,
and fibrotic tissue but is also a lesion composed of
endothelial and smooth muscle cells with infiltrating
leukocytes and other inflammatory cells [32]. Essential-
ly, the initial endothelial dysfunction leads to the fatty
streak formation and, ultimately, fibrous cap formation
[39].
The risk of developing atherosclerosis and conse-
quent ischemic heart disease increases with the presence
of pro-atherogenic substances such as intermediate den-
sity lipoproteins (IDL), low-density lipoproteins (LDL),
and very low-density lipoproteins (VLDL) [33]. Evi-
dence in the literature has suggested that certain proteins
appear to exert a greater effect on blood cholesterol
levels than others [50]. Given that the recent trend
towards high protein diets in the pursuit of weight loss
and reduction of chronic disease risk, it remains imper-
ative to fully appreciate the associations between certain
protein types and the potential for increased cardiovas-
cular disease risk. This increased risk may occur despite
successful weight loss. The goal of this review paper is
to examine whether casein, a dietary source of protein,
has an effect on blood cholesterol and whether it can be
considered a positive risk factor for the development of
atherosclerosis.
What is casein and does it have a role
in the atherosclerotic process?
Over the last five decades, there has been a steady
interest in the abilities of certain proteins to promote
either a pro- or anti-atherogenic effect. In particular,
casein has often been included in studies as an animal
source of protein [50]. Milk products contain two main
protein components: whey and casein. Whey protein
represents approximately 18 to 20 % of mammalian
milk protein, while casein represents the remaining
8082 % [4]. Casein is regarded as one of the most
Fig. 1 Schematic view of the arterial wall and the steps in ather-
oma formation. Risk factors such as a biochemical imbalance
(high LDL) trigger an endothelial activation beyond the normal
noxious stimuli. LDL enters the subendothelial layer and become
oxidized to allow attraction of monocytes, cytokines, and other
inflammatory cells to support the inflammatory process
O.H. Koury et al.
nutritive milk proteins, as it contains all common amino
acids and is rich in essential amino acids (EAA) [45].
Purified casein is produced from skim milk by a pro-
cessing technique where the protein is separated from
the whey, dried, and then resolubilized [9]. Isolated milk
casein forms micelle complexes when dispersed in the
water phase of milk. The micelle structures have five
different subunits of the casein subtype: α-casein, α-2
casein, β-casein, κ-casein, and γ-casein. Common
among these five structures are the calcium-phosphate
bonds that hold them together and that they all contain
salt and water [9].
The primary difference between casein, whey pro-
tein, and other high-quality proteins is the rate of digest-
ibility. Casein is considered to be a slow-digesting pro-
tein because it curdles or gels in the stomach, thus
delaying release in the intestines. This results in a grad-
ual but steady rise in blood amino acid concentration
following ingestion [9]. Since the blood amino acid
concentrations are kept relatively low, it slows but ex-
tends the rate of protein synthesis [16]. Casein also
demonstrates anti-catabolic properties, which simulta-
neously inhibits protein breakdown [4,6]. In situations
where weight loss is desired, the anti-catabolic proper-
ties of casein result in it being the preferred source of
protein for hypocaloric diets [5]. In light of these char-
acteristics, casein is attractive for many weight loss
programs that include high protein intake.
As early as the 1970s and 1980s, animal studies
reported that casein increased serum cholesterol levels,
thus playing a role in the development of atherosclero-
sis. Previously, it was believed that cardiovascular dis-
ease and atherosclerosis were a result of the amount of
fat in the diet and, in particular, the cholesterol and
saturated fats. In light of results seen in animal studies,
a high casein diet may also be considered a risk factor in
the development of atherosclerotic plaque. Casein-
mediated hypercholesterolemia has been shown to de-
velop independently of exogenous cholesterol and sat-
urated fat consumption [28]. Studies have been per-
formed in order to compare lipid profiles upon adher-
ence to diets that vary in amount of cholesterol,
cholesterol-free semi-purified diets, and various protein
sources. Early studies have shown that soy protein, a
source of vegetable protein, appears to play a protective
role in the vasculature and reduces the concentration of
total cholesterol and LDL, contrary to the detrimental
effects of casein [10]. A negative association between
soy protein intake and the development of coronary
heart disease and nonfatal myocardial infarctions was
also shown in a group of middle-aged and older Chinese
women [52], although these protective effects of soy are
not detected in all studies [24]. The association between
animal-based protein and cardiovascular disease is also
supported by a meta-analysis of five prospective studies
that compared mortality in vegetarians and non-vegetar-
ians. This analysis showed that subjects who consumed
animal protein had a 24 % higher mortality from ische-
mic heart disease, even after controlling for potential
confounding factors such as age, sex, smoking status,
alcohol, habitual exercise, education, and body mass
index [29]. Given the potential detrimental effects of
casein and other animal-based proteins in the develop-
ment of vascular disease, as suggested in studies such as
these, it is important to consider dietary protein source
when recommending high protein diets rather than con-
sidering all proteins equal.
The effects of casein in the animal model
Research conducted in male New Zealand white rabbits
by Huff and colleagues clearly demonstrated that chang-
es in body weight, plasma cholesterol, triglyceride
levels, as well as liver cholesterol occurred upon varying
the dietary protein source (i.e., either animal or plant
protein) [26]. The diet used in the Huff study was termed
alow-fat semi-purified diet,consistingofeither27%
casein or soy isolate, along with 60 % dextrose, 5 %
celluflour, 4 % salt mix, 3 % molasses, and 1 % corn oil.
The 16 animals were divided into 2 groups: 8 received a
diet rich in casein and 8 received a diet rich in soy
protein isolate. This low-fat semi-purified diet was giv-
en to both groups for 10 months, resulting in signifi-
cantly lower levels of mean plasma cholesterol in the
soy isolate group as compared to the casein semi-
purified group. After 10 months, the casein-fed animals
ended up with higher mean triglyceride levels, higher
liver cholesterol (Table 1), and developed atherosclerot-
ic lesions, particularly in the aortic arch region. Despite
the negative effects on plasma lipids and cholesterol,
casein-fed animals gained less weight than the soy-fed
animals (2.9 and 3.3 kg, respectively).
Plasma VLDL, LDL, and IDL levels were all signif-
icantly higher in the casein-fed versus the soy-fed ani-
mals (Table 2). Huff and colleagues concluded that this
hypercholesterolemic state must be the result of choles-
terol that is endogenously produced by the liver or
Effects of casein on blood lipid profile
intestine in response to the manipulation of dietary
protein source [26]. This significant rise in IDL, the
main transporter of cholesterol, has been observed under
similar conditions since although the underlying cause
remains speculative [44].
In the Huff study, it is interesting that both the casein
and soy diets lacked exogenous cholesterol and were
low in saturated fats. From these, it is evident that the
source of protein directly affects the distribution pattern
and concentration of cholesterol being transported in the
blood [26]. The amino acid compositionof the protein is
as important as the protein source [11]. It is known that
amino acids vary in their effects on serum cholesterol
concentrations, as well as further variations when
ingested as proteins [11]. Illustrating this concept, the
amino acids lysine and methionine contribute to the
development of hypercholesterolemia, whereas arginine
is able to counteract this effect [30,31]. The essential
amino acids found in casein have been hypothesized to
be responsible for the observed increase of total choles-
terol and LDL [11]. By replacing casein with isolated
soy protein, which has a different amino acid composi-
tion, the increases in total and LDL cholesterol content
in the serum associated with casein can be avoided [3].
Terpstra and colleagues reported similar results, but
their data also demonstrated the dose effect of casein fed
to Zucker strain rats [46]. Their study included six
groups of animals fed with either a commercial diet with
no cholesterol, a commercial diet with 1.2 % cholester-
ol, or four types of semi-purified cholesterol enriched
diets (20 % casein, 50 % casein, 20 % soybean, or 50 %
soybean (g/100 g of feed)). The results revealed a more
prominent hypercholesterolemic effect occurring in di-
ets with a higher percentage of casein. The same effect
was observed in rabbits [25,46], as well as in pigeons
[34,35].
Evidence in the literature supports the notion that the
casein-mediated cholesterol increases may be biphasic
in nature: extremely low and extremely high amounts of
casein in the diet appear to have the greatest impact on
blood cholesterol levels [27,40]. Increases in cholester-
ol were most apparent with either diets containing rela-
tively small amounts (5 %) or large amounts (40 to
60 %) of casein. Diets consisting of moderate amounts
of casein (i.e., 20 %) appeared to produce the smallest
effects [19]. Gender also appears to play a role: Female
rats were more predisposed to developing hypercholes-
terolemia in response to casein ingestion [47]. This
observation had also been previously reported by Filios
and colleagues [19] with blood cholesterol levels dou-
bling in magnitude in female versus male rats.
Research conducted by Hermus and colleagues fo-
cused on demonstrating the different combinations of
protein with gelatin on serum cholesterol levels and
body weight gain in rabbits [23]. The team set up four
experimental groups: (1) semi-purified diet containing
strictly casein as the protein source; (2) casein and
gelatin; (3) casein, gelatin, and fish protein; and (4)
casein, gelatin, fish protein, and soy protein. After
58 weeks of diet adherence, the group fed the diet
consisting of casein only demonstrated a growth-
retarding effect compared to the other groups who
achieved normal growth. Additionally, the casein group
Tabl e 1 The condition of the rabbits following the observance of
a casein- or soy-rich diet. Cholesterol and triglyceride contents in
the plasma and liver were all significantly elevated, excluding the
liver triglyceride (adapted from [26]withpermission)
Casein
(mg/dl)
Soy protein
(mg/dl)
Mean plasma cholesterol
a
(mg/dl) 247±12 66± 3
b
Liver cholesterol (mg/g wet wt) 6.6± 1 3.3± 0.2
b
Mean plasma triglyceride
a
(mg/dl) 95 ±4 58± 3
b
Liver triglyceride (mg/g wet wt) 7.0±0.7 6.6± 0.3
Lipid profile in rabbits fed either casein or soy protein diet for
10 months. Results are expressed as a mean ± SE for 8 rabbits in
each dietary group
a
The overall mean ± SE for the entire 10-month period
b
Significantly different from the casein-fed group P<0.01 from
Studentsttest
Tabl e 2 The varying distribution of plasma cholesterol that de-
veloped among the four lipoprotein classes: VLDL, IDL, LDL,
and HDL, as well as the total plasma concentration. Differences
with both diet groups in all lipoprotein classes are significant,
excluding the HDL (adapted from [26] with permission)
Density class Casein (mg/dl) Soy protein (mg/dl)
VLDL d< 1.006 76± 6 11±3
a
IDL 1.006<d > 1.019 132±14 25± 6
a
LDL 1.019<d > 1.063 46± 6 10±2
a
HDL 1.063<d>1.21 19±4 12±3
Total plasma concentration 275±25 58± 6
a
Plasma cholesterol distribution among lipoprotein classes. Results
are expressed as mean ± SE for 6 rabbits in each dietary group
a
Significantly different from the casein-fed rabbits (P<0.01) from
Studentsttest
O.H. Koury et al.
also achieved a hypercholesterolemic state that was
unseen in the other three experimental groups. This
study demonstrated that the addition of alternate protein
sources to the diet was able to blunt the hypercholester-
olemic effects of casein.
Overall, it is understood that the atherosclerotic pro-
cess can be initiated by hypercholesterolemia, with se-
rum total cholesterol and lipoproteins being well-
established risk factors for the disease [21]. Although
elevated concentrations of serum cholesterol contribute
to the development of fatty streaks, this is not the sole
reason for disease susceptibility [28]. Other known risk
factors, such as family history, obesity, chronic hyper-
glycemia, and physical and/or biochemical injuries,
have also been implicated [21,28]. To fully appreciate
the origins and mechanisms involved in the progression
of atherosclerosis, what has been learned from studies
involving possible dietary sources of cholesterol must
also be considered. When certain animals are fed with a
casein-rich diet, there is a higher correlation with lipo-
philic plaques and high serum cholesterol content than a
diet consisting of plant protein [28]. The lipoprotein
density concentration is also altered, depending on
whether a plant or animal protein source is considered
[37]. Theories suggest that soybean protein contain sa-
ponins, which are protective against hypercholesterol-
emia [42]. It is also thought that dietary fiber increases
absorption of bile acids in the intestine. This will result
in loss of bile acid through fecal excretion which will be
compensated by stimulation of hepatic conversion of
cholesterol into bile acids [41]. The main question is
how casein protein causes an elevation in cholesterol,
such that the protein source is as detrimental as the
source of fat [26]. What provokes this mechanism to
increase cholesterol to such a level as to induce athero-
genic plaque?
Many speculations and theories have been put forth
over the past 30 years as to how and why casein inges-
tion raises cholesterol levels and why certain species are
more susceptible to the effects of casein. The activity
and concentration of enzyme alkaline phosphatase play
an important role since it has the potential to dephos-
phorylate casein and prevent accumulation of
phosphopeptides [36]. In 1988, Van Der Meer and col-
leagues conducted studies that involved feeding both
rabbits and rats a similar diet that included elevated
casein content in order to investigate intestinal absorp-
tion and bile acid excretion. They reported that casein
induces a hypercholesterolemic effect in rabbits due to
low intestinal phosphatase activity and with a high
glycine conjugation of bile acids, whereas in the rat,
where little effect of casein was noted, the conjugation
of bile acids occurs primarily via other amino acids,
such as taurine [48].
Another potential factor that may contribute to the
effects of casein is the LDL receptors. It has been
reported that animals fed casein-enriched diet had a
downregulation of hepatic LDL receptors preceded by
an increase in plasma cholesterol [12]. Other studies
have also shown that casein stimulates LDL ApoB
synthesis, therefore increasing the circulating LDL [11].
What effect does casein have in a human model?
Contrary to the observations seen in animals, the major-
ity of intervention studies that have investigated the
effects of plant and animal protein on serum cholesterol
levels in humans have reported inconsistent effects. In
1983, Sacks and colleagues tested whether dairy protein
(casein) or soy protein would have an effect on plasma
cholesterol in 13 strict vegetarians. The study design
consisted of a 1-week pre-intervention period, during
which, baseline measurements such as body weight,
cholesterol profile, triglycerides, and VLDL-c/TG ratio
were measured. Following the baseline period, all 13
subjects were split into groups that followed two phases:
a diet enriched in casein for 20 days and then soy for
20 days or vice versa. Results yielded no significant
changes in LDL or protective HDL cholesterol from
baseline. Aswell, there was no difference oflipid profile
or lipoproteins in the soy and casein groups during their
40-day intervention [43].
Another study conducted by Van Raaij and col-
leagues looked at similar aspects, but in healthy non-
vegetarian subjects eating a westernsimulated diet.
All 69 participants began by eating a casein-soy or
cassoydiet for a control period of 10 days in order
to establish baseline measurements for the remainder of
the experimental design. In this cassoy diet, 65 % of the
protein content was a 2:1 mixture of casein and soy,
respectively. Following the 10-day control period, indi-
viduals were divided into three groups for 28 days:
maintenance cassoy diet, casein diet, or soy diet. Inter-
estingly, there were barely any changes seen between
the experimental casein and soy groups in regard to total
cholesterol. Subjects adhering to the casein-enriched
diet did not demonstrate any significant changes in
Effects of casein on blood lipid profile
lipoprotein fractions. On the other hand, the soy group
demonstrated improvements in the LDL and HDL con-
centrations as compared to the casein group, and the
reductions in LDL were also significant within the soy
group from their baseline measurements [49]. The im-
provements in LDL-c and HDL-c were also seen in
another study with participants eating a cholesterol-
enriched casein or soy diet [38]. VLDL concentrations
remained unchanged in both study groups.
Crouse and colleagues conducted a similar study
with healthy individuals having elevated LDL concen-
trations between 3.62 and 5.17 mmol/L. Subjects main-
tained a casein-rich diet or a soy-rich diet with varying
amounts of isoflavones for 9 weeks. Following this
dietary intervention, LDL-c and total cholesterol
lowered significantly from baseline in individuals in
the soy group, with a dose-dependent relationship be-
tween cholesterol improvements and isoflavone
amount. There was no significant improvement in
HDL-c or TG concentration between the groups [14],
suggesting that casein supplementation is not an effec-
tive intervention for individuals with pre-existing high
cholesterol.
From these studies performed on humans, the results
suggest that casein protein may not have such a pro-
nounced effect on cholesterol levels as seen in certain
animal models, such as rabbits. The studies share mixed
results and conclusions. A soy diet would be more
beneficial for lowering cholesterol levels in hypercho-
lesterolemic patients since casein-enriched diets demon-
strate few advantages in lowering LDL-c or TG. In
healthy subjects, on the other hand, it seems as though
casein and soy diets lack influence on cholesterol levels
[43]. However, it should be pointed out that, in order to
better mimic the study design in animals, the human
experiments would need to be conducted for longer
periods of time and/or administered at earlier periods
in their lives [49]. The important point here is to con-
sider whether the lack of effect is indeed a phenomenon
in the human model or whether it is due to limitations in
study design. Further work is needed in order to objec-
tively determine the safety of diets high in casein.
Clinical implications of a high casein diet
Meal replacements (MR) containing elevated amounts
of plant or animal protein have proven successful in
promoting weight loss in obese patients. In a
randomized controlled trial by Anderson and colleagues
[2], patients consuming a MR with high casein for
16 weeks had a tendency towards more weight loss
and greater fat loss than individuals on high soy diets.
Although associated with only modest weight loss, the
individuals consuming soy MR showed promising im-
provements in their cardiovascular risk profile (i.e.,
LDL, TC, visceral fat, and systolic blood pressure).
The period following weight loss is crucial to success-
fully sustain weight reduction, and for this, high casein
diets have been found to be useful [13].
Attention must also be drawn to the popular use of
protein supplementation following exercise training.
Postprandial protein synthesis has been studied, and
the data indicates that amino acids dictate future protein
synthesis, breakdown, and oxidation [6]. Protein shakes
of whey and casein are frequently used to maintain and
increase muscle mass, hence protein synthesis or anab-
olism following exercise. As compared to whey protein,
ingestion of casein protein in a meal or drink may only
induce a small increase in protein synthesis, but is
associated with a substantial decrease in protein break-
down [6]. These physiological processes are possible
due to the retarded increase in plasma AA concentra-
tions. Without the pronounced hyperaminoacidemic
peak associated with whey, casein offers a longer last-
ingrise in AA levels and sustains protein breakdown
inhibition. Casein supplementation, compared to whey,
has been shown to improve body composition resulting
in decreased percent body fat; an increase of lean mass;
and greater muscle strength in legs, chest, and shoulders
[18]. These effects are most likely due to caseinsanti-
catabolic property. Depending on individual aims or
motives, athletes may opt for casein as their choice of
protein supplementation for the aforementioned
reasons.
Conclusion
Casein is not only naturally present in foods containing
dairy such as milks and cheeses but is also extensively
utilized in its purified form as a powdered protein sup-
plement. For decades, saturated fats, and cholesterol
have been deemed responsible for the development of
cardiovascular disease and conditions such as athero-
sclerosis and the clogging of arteries.Studies have
also found that casein protein is just as aversive as fats
for some animal species. Casein can have a negative
O.H. Koury et al.
impact on the serum cholesterol concentration and raise
it to levels that pose a severe danger to the lipid profile.
There have been speculations that casein is responsible
for the disruption of bile acid binding in the small
intestine, leaving elevated levels of free bile acids to
be re-absorbed. It is key to clearly understand whether
hypercholesterolemia is enough to induce atherosclero-
sis and simulate endothelial dysfunction and to what
extent does itraise cholesterol and cause atherosclerosis.
Another important aspect that would require further
investigation is the possibility that humans may mani-
fest the same hypercholesterolemic dangers of casein if
given for longer periods of time comparable to animal
studies. Although healthy humans are assumed to be
less sensitive to dietary modifications than animals,
there may be changes noted if the human studies would
parallel animal studies in terms of time periods and
administration [49]. Would a diet low in fats but high
in animal protein be harmful to individuals and pose
cardiovascular risks? The potential dangers of casein
should serve as a red flag for dieters, trainers, physi-
cians, or nutritionists alike, especially when considered
for populations who may already be considered at risk
for cardiovascular complications. In regard to supple-
mentation, patients in a rehabilitation setting due to
conditions such as cancer cachexia or sarcopenia may
also be administered large doses of soy, whey, or casein.
Also of concern are people who exercise train and
consume exceptionally high concentrations of
whey or casein protein supplementation in order
to increase protein synthesis and muscle mass.
Understanding the implications of a high casein
protein diet is vital in order to assess the health
status and long-term lipid profile of an individual
adhering to such a diet.
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O.H. Koury et al.
... Furthermore, isoflavones can have weak estrogenic effect and can reduce the severity of symptoms associated with menopause, without eliciting any negative side effects [30,49]. Isoflavones reduce blood cholesterol by as much as 35%, suggesting their potential as cholesterol-lowering agents [50], while casein, an animal protein, has been found to increase blood cholesterol [51]. In people with insufficient protein intake, protein is generated from accumulated fat [1]. ...
... Furthermore, isoflavones prevent bone reabsorption and increase bone density to prevent osteoporosis, which is common in older women [20,59]. The physiological roles of isoflavones are summarized in Figure 6. has been found to increase blood cholesterol [51]. In people with insufficient protein intake, protein is generated from accumulated fat [1]. ...
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In addition to providing nutrients, food can help prevent and treat certain diseases. In particular, research on soy products has increased dramatically following their emergence as functional foods capable of improving blood circulation and intestinal regulation. In addition to their nutritional value, soybeans contain specific phytochemical substances that promote health and are a source of dietary fiber, phospholipids, isoflavones (e.g., genistein and daidzein), phenolic acids, saponins, and phytic acid, while serving as a trypsin inhibitor. These individual substances have demonstrated effectiveness in preventing chronic diseases, such as arteriosclerosis, cardiac diseases, diabetes, and senile dementia, as well as in treating cancer and suppressing osteoporosis. Furthermore, soybean can affect fibrinolytic activity, control blood pressure, and improve lipid metabolism, while eliciting antimutagenic, anticarcinogenic, and antibacterial effects. In this review, rather than to improve on the established studies on the reported nutritional qualities of soybeans, we intend to examine the physiological activities of soybeans that have recently been studied and confirm their potential as a high-functional, well-being food.
... Management of hypercholesterolemia is of a high importance in the prevention of cardiovascular events 5,6 . A number of cholesterol-lowering medications, such as statins, PSCK9 inhibitors, fibrates, and bile acid sequestrants are available to treat hypercholesterolemia. Yet, they have been linked to a variety of side effects 7 . ...
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Background: Hypercholesterolemia and oxidative stress consider the main causes for atherosclerotic cardiovascular diseases, that are one of the major non-communicable diseases responsible for more than a third of deaths in Saudi Arabia. Cholesterol-lowering medications as Atorvastatin® (ATOR) are linked to a variety of side effects. Achillea fragarntissima (AF) is a valuable medicinal plant in Saudi Arabia with potent antioxidant activity. Aim: The current study was performed to determine the efficacy of AF in the treatment of hypercholesterolemia through the antioxidant metabolic pathway. Methodology: Dried aerial parts of AF were extracted by ethanol (70%). Induction of hypercholesterolemia in rats was induced through feeding a high fat-cholesterol diet (HFCD) for 8 weeks. Rats were assigned to two main groups; control group (Cont, n=10) rats fed a standard diet, and hypercholesterolemic group (HFCD) (n=40) rats fed HFCD. The HFCD group was further assigned after measured lipid profile to confirm the induction of hypercholesterolemia to HFCD; HFCD+AF (hypercholesterolemic rats treated orally with 500 mg/kg AF); HFCD+ ATOR (hypercholesterolemic rats treated orally with 20 mg/kg ATOR, as a reference drug); and HFCD+AF+ATOR (hypercholesterolemic rats treated orally with AF+ ATOR). Different treatments were ingested to rats for 4 weeks. Results: The results revealed that the HFCD group showed significant hyperlipidemia (elevation of serum TC, TG, LDL-C, and VLDL-C levels concurrent with a reduction in serum HDL-C level); significant disturbance in liver functions (elevation in serum ALT, AST, and ALP enzymes activities); and significant oxidative stress (elevation in hepatic MDA level with a reduction in hepatic SOD activity) compared with the Cont group. Besides, hepatic central vein section showed deposition of large lipid within hepatocytes and abundant focal cell necrosis. Oral treatment with AF, ATOR, and the mixture of the drug and AF produced significant hypocholesterolemia, antioxidant, and improved liver function enzymes, with normalized hepatic central vein tissue compared with the HFCD group. The mixture of AF+ATOR had a superior effect than either treatment alone. Conclusion: In hypercholesterolemic rats, AF may be used to prevent atherosclerosis through improving lipid profile levels, protecting against hepatic oxidative stress, and ameliorating hepatic functions. Thus highlighting its valuable effects in the treatment of atherosclerotic cardiovascular diseases. Keywords: Achillea fragarntissima, lipid profile, hepatic oxidative stress, hepatic function, hypercholesterolemia.
... However, whether or not this observed increase in risk is driven by protein per se is unclear and difficult to define. On the other hand, soy protein was claimed by the FDA (1999) to decrease cardiovascular disease risk through a cholesterol-lowering effect, whereas casein was thought to be hypercholesterolemic (10). In addition, given the current increased environmental impact of animal proteins, plant proteins are likely to be favored in the future for human consumption, given their lower environmental impact (11,12). ...
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Dietary protein may play an important role in the prevention of metabolic dysfunctions. However, the way in which the protein source affects these dysfunctions has not been clearly established. The aim of the current systematic review was to compare the impact of plant- and animal-sourced dietary proteins on several features of metabolic syndrome in humans. The PubMed database was searched for both chronic and acute interventional studies, as well as observational studies, in healthy humans or those with metabolic dysfunctions, in which the impact of animal and plant protein intake was compared while using the following variables: cholesterolemia and triglyceridemia, blood pressure, glucose homeostasis, and body composition. Based on data extraction, we observed that soy protein consumption (with isoflavones), but not soy protein alone (without isoflavones) or other plant proteins (pea and lupine proteins, wheat gluten), leads to a 3% greater decrease in both total and LDL cholesterol compared with animal-sourced protein ingestion, especially in individuals with high fasting cholesterol concentrations. This observation was made when animal proteins were provided as a whole diet rather than given supplementally. Some observational studies reported an inverse association between plant protein intake and systolic and diastolic blood pressure, but this was not confirmed by intervention studies. Moreover, plant protein (wheat gluten, soy protein) intake as part of a mixed meal resulted in a lower postprandial insulin response than did whey. This systematic review provides some evidence that the intake of soy protein associated with isoflavones may prevent the onset of risk factors associated with cardiovascular disease, i.e., hypercholesterolemia and hypertension, in humans. However, we were not able to draw any further conclusions from the present work on the positive effects of plant proteins relating to glucose homeostasis and body composition.
... At present, several lipid-lowering drugs are available to combat hypercholesterolemia including statins, bile acid sequestrants, fibrate and PSCK9 inhibitors, but those drugs are highly associated with several adverse events (Bao et al. 2012). Recently, researchers are concentrated more on natural dietary proteins, which might positively influence the blood lipid levels without any adverse effects (Matthan et al. 2007;Koury et al. 2014). ...
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Context: Royal jelly (RJ) has been reported for its health promoting factors such as antioxidant, anti-inflammatory and lipid lowering activities. Objective: The present randomized, placebo-controlled study examines the hypolipidemic beneficial effect of RJ through evaluating anthropometric measurements, lipid profile and various hormone levels in mildly hypercholesterolemic participants. Materials and methods: Forty subjects with mild hypercholesterolemia (180–200 mg/dL) were randomly selected and divided into two groups as experimental or placebo, who requested to intake nine capsules (350 mg/capsule) of RJ or placebo/day, respectively, for three months with one month of follow-up without any supplementation. Results: No significant changes were noted in any of the anthropometric parameters like body weight, waist and body fat. The serum total cholesterol (TC; 207.05–183.15 mg/dL) and low-density lipoprotein cholesterol (LDL-c; 126.44–120.31 mg/dL) levels were reduced significantly (p < 0.05) after administration of RJ. However, triglyceride (TG) and high-density lipoprotein cholesterol (HDL-c) levels were not considerably altered. Moreover, three months of RJ consumption significantly ameliorated (p < 0.05) the concentration of sex hormones like dehydroepiandrosterone sulphate (DHEA-S; 1788.09–1992.31 ng/mL). Also, intake of RJ did not elicit any hepatic or renal damage. Discussion and conclusion: Intervention with RJ for three months considerably lowered the TC and LDL-c levels through improving the levels of DHEA-S and thus alleviates the risk of cardiovascular disease (CVD).
... Additionally these choices include increased fiber content which increase the absorption, and thus loss of bile acids through defecation [9]. This loss is compensated by increased hepatic modulation of plasma cholesterol into bile acids [15] with a subsequent reduction in serum cholesterol and thus a lower risk of CVD in vegans. ...
... Additionally these choices include increased fiber content which increase the absorption, and thus loss of bile acids through defecation [9]. This loss is compensated by increased hepatic modulation of plasma cholesterol into bile acids [15] with a subsequent reduction in serum cholesterol and thus a lower risk of CVD in vegans. ...
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Kardiyovasküler hastalıklar ile diyet ilişkisini araştıran çalışmalar genellikle karbonhidrat ve yağ kaynaklarına odaklanmıştır. Bu çalışmadaki amaç, kardiyovasküler hastalıklara, diyetsel protein kaynaklarının etkilerini incelemektir. Hayvansal ve bitkisel protein kaynakları, (süt ve süt ürünleri, yumurta, et, tavuk, balık, baklagiller ve tahıllar) farklı besin matriksine sahip olmaları sebebiyle lipid metabolizmasına ve kardiyometabolik risklere farklı etki ederler. Kardiyovasküler hastalıkların beslenme tedavisinde, süt ürünleri, tam tahıllar, yağlı tohumlar, tavuk, balık ile meyve ve sebzelerin tüketimi arttırılırken; yağ içeriği yüksek olan hayvansal kaynaklı besinlerin, işlenmiş kırmızı et, rafine şeker içeren yiyecek ve içeceklerin tüketiminin kısıtlanması genel bir beslenme önerisidir. Güncel kanıtlar, bitkisel protein ağırlıklı beslenmeyi desteklemektedir. Studies investigating the relationship between cardiovascular diseases and diet have generally focused on carbohydrate and fat sources. The aim of this study is to examine the effects of dietary protein sources on cardiovascular diseases. Animal and plant protein sources (milk and dairy products, eggs, meat, chicken, fish, legumes and cereals) have different effects on lipid metabolism and cardiometabolic risks due to their different nutritional matrix. In the nutritional treatment of cardiovascular diseases, the consumption of dairy products, whole grains, oil seeds, chicken, fish, fruits and vegetables is increased; restriction of consumption of foods of animal origin with high fat content, processed red meat, refined sugar-containing foods and beverages is a general nutritional recommendation. Current evidence supports a plant-based diet.
Thesis
Afin d’évaluer la qualité alimentaire et l’efficacité métabolique des aliments mixtes combinant différentes sources protéiques végétales ou des sources protéiques végétales/animales, deux aliments de base, les pâtes alimentaires et les gels laitiers, ont été choisis comme vecteurs et ont été enrichis par des farines ou des protéines de légumineuses. La structure de la fraction protéique des aliments mixtes a été étudiée à l’échelle moléculaire. La relation entre cette structure et la digestibilité in vitro et in vivo des protéines a été évaluée. L’effet de la formulation et/ou du procédé de fabrication de ces aliments mixtes sur le métabolisme protéique in vivo a été étudié chez des rats jeunes en croissance et des rats âgés. Le changement de la formulation des pâtes alimentaires, c'est à dire l’incorporation de trois farines de légumineuses différentes (féverole, lentille ou pois cassé), génère des modifications de structure du réseau protéique influençant la digestibilité des protéines. Les études animales montrent que la qualité alimentaire des pâtes enrichies en légumineuses est comparable à celle d’une protéine animale comme la caséine et ce, quel que soit le type de légumineuses utilisé. La rétention protéique corporelle et la synthèse protéique musculaire des rats âgés, consommant des régimes iso- protéiques à base de pâtes alimentaires enrichies en légumineuses ou de caséine, sont comparables. Elles restent cependant inférieures à celles induites par les protéines solubles du lait. L’utilisation de gels laitiers enrichis en protéines de féverole chez le rat a révélé un effet de la formulation et du procédé de gélification sur la digestion et la rétention protéiques. La digestibilité in vivo des protéines est plus élevée chez les rats consommant le régime contenant le gel fermenté mixte composé de protéines de caséine et de féverole comparativement à son homologue de même composition mais acidifié par voie chimique. La rétention protéique est encore améliorée chez les rats ayant consommé le régime contenant le gel fermenté composé de protéines de caséine, de féverole et de lactosérum. Ces aliments enrichis en légumineuses, riches en protéines, équilibrés en acides aminés indispensables commencent à être disponibles sur le marché. Ils pourraient être proposés à la population âgée notamment dans des situations physiopathologiques impliquant une perte de protéines corporelles.
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During the prevention and treatment of cardiovascular diseases, first cause of deaths in the world, diet has a vital role. While nutrition programs for the cardiovascular health generally focus on lipids and carbohydrates, effects of proteins are not well concerned. Thus this review is written in order to examine effect of proteins, amino acids, and the other amine consisting compounds on cardiovascular system. Because of that animal or plant derived proteins have different protein composition in different foods such as dairy products, egg, meat, chicken, fish, pulse and grains, their effects on blood pressure and regulation of lipid profile are unlike. In parallel amino acids made up proteins have different effect on cardiovascular system. From this point, sulfur containing amino acids, branched chain amino acids, aromatic amino acids, arginine, ornithine, citrulline, glycine, and glutamine may affect cardiovascular system in different metabolic pathways. In this context, one carbon metabolism, synthesis of hormone, stimulation of signaling pathways and effects of intermediate and final products that formed as a result of amino acids metabolism is determined. Despite the protein and amino acids, some other amine consisting compounds in diet include trimethylamine N-oxide, heterocyclic aromatic amines, polycyclic aromatic hydrocarbons and products of Maillard reaction. These amine consisting compounds generally increase the risk for cardiovascular diseases by stimulating oxidative stress, inflammation, and formation of atherosclerotic plaque.
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Evidence supports that a high proportion of calories from protein increases weight loss and prevents weight (re)gain. Proteins are known to induce satiety, increase secretion of gastrointestinal hormones, and increase diet-induced thermogenesis, but less is known about whether various types of proteins exert different metabolic effects. In the Western world, dairy protein, which consists of 80% casein and 20% whey, is a large contributor to our daily protein intake. Casein and whey differ in absorption and digestion rates, with casein being a "slow" protein and whey being a "fast" protein. In addition, they differ in amino acid composition. This review examines whether casein, whey, and other protein sources exert different metabolic effects and targets to clarify the underlying mechanisms. Data indicate that whey is more satiating in the short term, whereas casein is more satiating in the long term. In addition, some studies indicate that whey stimulates the secretion of the incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide more than other proteins. However, for the satiety (cholecystokinin and peptide YY) and hunger-stimulating (ghrelin) hormones, no clear evidence exists that 1 protein source has a greater stimulating effect compared with others. Likewise, no clear evidence exists that 1 protein source results in higher diet-induced thermogenesis and promotes more beneficial changes in body weight and composition compared with other protein sources. However, data indicate that amino acid composition, rate of absorption, and protein/food texture may be important factors for protein-stimulated metabolic effects.
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The speed of absorption of dietary amino acids by the gut varies according to the type of ingested dietary protein. This could affect postprandial protein synthesis, breakdown, and deposition. To test this hypothesis, two intrinsically 13C-leucine-labeled milk proteins, casein (CAS) and whey protein (WP), of different physicochemical properties were ingested as one single meal by healthy adults. Postprandial whole body leucine kinetics were assessed by using a dual tracer methodology. WP induced a dramatic but short increase of plasma amino acids. CAS induced a prolonged plateau of moderate hyperaminoacidemia, probably because of a slow gastric emptying. Whole body protein breakdown was inhibited by 34% after CAS ingestion but not after WP ingestion. Postprandial protein synthesis was stimulated by 68% with the WP meal and to a lesser extent (+31%) with the CAS meal. Postprandial whole body leucine oxidation over 7 h was lower with CAS (272 ± 91 μmol⋅kg−1) than with WP (373 ± 56 μmol⋅kg−1). Leucine intake was identical in both meals (380 μmol⋅kg−1). Therefore, net leucine balance over the 7 h after the meal was more positive with CAS than with WP (P < 0.05, WP vs. CAS). In conclusion, the speed of protein digestion and amino acid absorption from the gut has a major effect on whole body protein anabolism after one single meal. By analogy with carbohydrate metabolism, slow and fast proteins modulate the postprandial metabolic response, a concept to be applied to wasting situations.
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The effects of different dietary levels of several proteins on the serum cholesterol concentration of the rat have been determined. With diets containing casein, serum cholesterol concentration was lowest when the protein level was 30–40%. The cholesteremic effects of fibrin and pork were similar to that of casein. Zein exerted a marked hypercholesteremic effect which could be counteracted by replacing it in part with casein. A soybean protein (Drackett) fed at high levels led to lower, and fed at lower levels, led to higher serum cholesterol concentrations than were observed with comparable levels of casein.Wheat gluten fed to rats on a hypercholesteremic regimen caused a marked lowering of serum cholesterol concentration. However, when cholesterol and cholic acid were excluded from the diet, the substitution of wheat gluten for casein as the dietary protein caused a rise in serum cholesterol concentration. Extraction of wheat gluten with absolute ethanol led to the separation of lipid-like material possessing cholesterol-lowering activity. The extracted wheat gluten had a marked hypercholesteremic effect.
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Experimental work has elucidated molecular and cellular pathways of inflammation that promote atherosclerosis. Unraveling the roles of cytokines as inflammatory messengers provided a mechanism whereby risk factors for atherosclerosis can alter arterial biology, and produce a systemic milieu that favors atherothrombotic events. The discovery of the immune basis of allograft arteriosclerosis demonstrated that inflammation per se can drive arterial hyperplasia, even in the absence of traditional risk factors. Inflammation regulates aspects of plaque biology that trigger the thrombotic complications of atherosclerosis. Translation of these discoveries to humans has enabled both novel mechanistic insights and practical clinical advances.
Chapter
Blood cholesterol and LDL levels are well-established risk factors for cardiovascular disease and, in particular, coronary heart disease. In recent years, the role of LDL in the pathogenesis of atherosclerosis, the underlying cause of coronary heart disease, has been studied extensively. These studies have highlighted the complexity of atherosclerotic processes and identified oxidative damage and inflammation as important components of the process. In addition, the formation and possible involvement of various oxidized lipids in atherosclerosis have been identified by the studies. The oxidized lipids include the products of oxidative enzymes, located in the vasculature, as well as nonspecific oxidation products. Many of these lipids have been found in atherosclerotic plaque and have potent bioactivities. Moreover, these oxidation products and, reactive oxygen and nitrogen species, have been linked with cellular signaling pathways that can influence the development of atherosclerosis.