Cholesterol: Factors Determining Blood Cholesterol Levels
Z Rasic-Milutinovic and G Perunicic-Pekovic, University of Belgrade, Belgrade, Serbia
D Jovanovic, Institute of Public Health ‘Milan Jovanovic-Batut’, Belgrade, Serbia
N Simovic, Z Gluvic, D Ristic-Medic, and M Glibetic, University of Belgrade, Belgrade, Serbia
ã 2016 Elsevier Ltd. All rights reserved.
Introduction
Whole-body cholesterol balance is regulated by the net effects
of dietary cholesterol absorption, de novo cholesterol biosyn-
thesis, and whole-body cholesterol clearance, mostly by biliary
excretion from the liver.
In the intestinal tract, cholesterol originates from two
sources: food intake and biliary secretion into the duodenum.
Several proteins in the brush border membrane of enterocytes
are involved in mediating intestinal cholesterol absorption.
Whereas various transporters, including fatty acid translocase/
cluster determinant 36, scavenger receptor class B type I (SR-BI),
and Niemann-Pick C1-like 1 (NPC1L1), may influence choles-
terol uptake, the ATP binding cassette (ABC) transporter family,
including several cholesterol carriers (ABCA1, ABCB1, and
ABCG5/G8), act as efflux pumps favoring cholesterol export
out of absorptive cells into the lumen or basolateral compart-
ment. Among all the cholesterol transporters, the enriched
NPC1L1 protein in the apical membrane of enterocytes is con-
sidered essential for intestinal cholesterol absorption, and
genetic modifications of NPC1L1 in cultured intestinal cells
alter cholesterol uptake.
Although all tissues in the body are capable of synthesizing
cholesterol from acetyl coenzyme A (CoA), the liver is the main
site for de novo cholesterol synthesis and stores it as cholesterol
ester after esterification by acetyl-CoA acetyltransferase. The
major rate-controlling enzyme in hepatic cholesterol synthesis
is 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase,
which is used as a pharmacological target of statin treatment.
Cholesterol, as a water-insoluble molecule, needs to be
transported in the plasma associated with various lipoprotein
particles, such as chylomicrons, very low-density lipoproteins
(VLDLs), intermediate-density lipoproteins (IDLs), low-
density lipoproteins (LDLs), and high-density lipoproteins
(HDLs). Approximately 60–80% of cholesterol is transported
through the bloodstream in the core of LDL particle. On the
other hand, crucial molecules in cholesterol transport are apo-
lipoproteins located on the surface of LDL particles. Each LDL
particle contains one molecule of apoB, a lipoprotein respon-
sible for carrying cholesterol to peripheral tissues and binding
to LDL receptors. Since more than 90% of the removal of LDL
takes place in the liver, the liver determines the rates of LDL
clearance from plasma. Hence, the liver is the only organ
capable of eliminating excess cholesterol from the body, by
either secretion into bile or conversion into bile acids. The
movement of excess cholesterol from peripheral tissues to the
liver is a result of reverse cholesterol transport (RCT), which is
promoted by HDL particles.
The body maintains a stable cholesterol pool by regulating
mechanisms of absorption, synthesis, and elimination. The
dominant factor that determines cholesterol absorption in
Encyclopedia of Food and Health http://dx.doi.org/10.1016/B978-0-12-384947-2.00152-5
the small intestine is intake. Hence, when dietary cholesterol
intake is very low, its absorption is upregulated. Conversely, if
dietary intake is too high, absorption is decreased and biliary
excretion is intensified. The percent of cholesterol absorbed in
healthy subjects vary significantly from person to person from
29% to 80%. However, about 25% of the population has
exaggerated response to an overload of dietary cholesterol.
Additionally, among dietary and genetic factors, many physio-
logical and pathological conditions can influence plasma cho-
lesterol levels.
Aging
Numerous studies have demonstrated that regardless of phys-
ical activity levels and nutritional status, levels of plasma total
cholesterol rise progressively with age. Plasma LDL cholesterol
(LDL-C) levels increase progressively from young adulthood to
approximately age 60 in men and to age 70 in women. Pro-
longed intestinal transit time may be a factor for increasing
cholesterol absorption with aging. Slow intestinal transit is
associated with an increased rate of bacterial biotransforma-
tion of bile acids, with enhanced enterohepatic recirculation of
deoxycholic acid. At the same time, diet rich in cholesterol and
saturated fatty acids (SFA), usually presented in elderly sub-
jects, can be the reason for increased cholesterol absorption.
Another possible explanation could be a gradual reduction in
the rate of LDL clearance from the circulation, presumably as
the result of a reduced activity of LDL receptors, diminished
number of functioning hepatic LDL receptors, and prolonged
turnover time (‘downregulation’) of the recirculating LDL
receptors. In response to cholestyramine, a bile acid-binding
agent, the elderly can reach the same values of LDL clearance as
younger individuals, which explains that they still have the
capacity for ‘upregulation’ of hepatic LDL receptors. Another
explanation for reduced LDL receptor expression may be a
consequence of a reduced hepatic demand for cholesterol,
due to a reduced bile acid synthesis occurring with age. In
mice, aging increases biliary cholesterol secretion and reduces
level of hepatic bile acid synthesis, which hence increases the
susceptibility of developing cholesterol gallstones in elderly
animals. This finding may be explained with the decreased
activity of hepatic 7-a hydroxylase, an enzyme that metabolizes
cholesterol to biliary salts. Some of the rise in LDL-C levels
with age could be related to the sedentary lifestyle and increase
of body weight, which is typical in older population. In addi-
tion, various concomitant diseases (diabetes mellitus, hypo-
thyroidism, and nephropathy) and commonly used drugs
more frequently present in the elderly population are associ-
ated with hypercholesterolemia. Also, it has been shown that
growth hormone (GH) has key roles in cholesterol metabolism
53
54 Cholesterol: Factors Determining Blood Cholesterol Levels
and that its secretion is reduced with aging. Experiments per-
formed in rodents have demonstrated that the administration
of GH is able to completely reverse age-dependent increase in
plasma cholesterol and the reduced levels of bile acid synthesis
to the same level as seen in young animals.
Gender
Compared with men, women have lower levels of LDL-C and
VLDL cholesterol and higher HDL cholesterol (HDL-C) levels.
There is no difference in cholesterol absorption fraction
between men and women. Lower concentrations of LDL-C
are associated with accelerated LDL production and enhanced
LDL clearance, which may be explained with higher levels of
estrogens in women. Studies in rats have shown that estrogen
treatment is followed by an increase of hepatic LDL receptors
and a faster clearance of LDL particles. The sex difference in
HDL concentrations is associated with greater synthesis rate of
apolipoproteins A-I and A-II, major proteins of HDL particle
responsible for fat efflux from peripheral tissues to the liver. It
has been shown that postmenopausal women have higher
plasma cholesterol levels than premenopausal women of the
same age. In postmenopausal women, the decrease in plasma
estrogen levels after menopause may play a significant role in
the reduction of the clearance of LDL particles and subsequent
increase of LDL-C. Estrogen replacement treatment has been
shown to markedly decrease LDL-C in dyslipidemic postmen-
opausal women. Sexual dimorphism in cholesterol metabo-
lism cannot be explained only by the different levels of sex
hormones. There are studies that showed that surgically
induced menopause without hormone replacement therapy
has no effect on plasma cholesterol concentrations when com-
pared with surgical control group (hysterectomy with conser-
vation of the ovaries). There are seemingly many factors that
need to be explored in the future, and one of them is certainly
the difference in insulin action between men and women, with
higher rate of circulating insulin and therefore greater suppres-
sion of lipolysis in women. It is unlikely that differences in
body composition are responsible for this phenomenon,
because sex differences in cholesterol metabolism exist even
they are matched for percentage of body fat. Androgen action is
most likely not responsible for the sex differences in plasma
LDL-C concentration. Testosterone administration is associ-
ated with only modest reduction of LDL-C concentration
when given to hypogonadal men in replacement doses and
has no effect on LDL-C concentration in eugonadal men.
Genetic Factors
Serum lipid levels are associated with genetic factors. It has been
estimated that genotype participates with around 40–60% in the
serum total cholesterol variability. There is growing evidence
about association between 95 genetic loci and LDL-C, HDL-C,
and triglycerides, discovered in genome-wide association
studies. In the Framingham Heart Study (FHS), offspring and
third-generation cohorts (3110 participants) of middle-aged to
elderly adults with available genomic DNA were genotyped for
lipid single-nucleotide polymorphisms (SNPs), and genetic risk
scores (GRS) were calculated for each individual and lipid frac-
tion. The results showed modest association between lipid GRS
and corresponding lipid, which was the strongest with the long-
term average lipid measure, and between HDL-C GRS and TG
GRS. Lu et al. investigated whether common genetic variants in
genes involved in cholesterol metabolism could predict the
plasma cholesterol levels. They found that out of 361 SNPs in
243 genes, 23 SNPs were associated with plasma total choles-
terol levels. The results of the study with the multiple gene
approach reported that 10 out of 17 candidate genes were
associated with lipid levels in Caribbean Hispanic subjects,
where the genetic variants on three genes, APOA5, APOB, and
CYP7A1, accounted for the largest proportion of lipids varia-
tion. The longitudinal cohort of black and white siblings,
enrolled in the Bogalusa Heart Study, showed association of
long-term levels and trends of LDL-C with chromosomes 1
and 19. There are several evidences of strong connections
between ten common variants in the genes for LPL, CEPT, and
APO and plasma lipid concentrations in children according to
the Gene–Diet Attica Investigation on childhood obesity (GEN-
DAI). Significantly higher total cholesterol and LDL-C were
observed in APOE E4 carriers compared to E3/E3 homozygotes
and E2 carriers. The association of APOE genotype with total
cholesterol/HDL-C ratio was further modulated by body mass
index (BMI). Carriers of the cholesteryl ester transfer protein
(CETP) TaqIB B2 allele had significantly higher HDL-C and
lower total cholesterol/HDL-C ratio compared to B1/B1 indi-
viduals. Suggested potential prediction of lifelong exposure to
an adverse lipid profile in children is very important for apply-
ing precautionary principle and preventive measures.
Dietary Factors
Modern diet is characterized by the high intake of SFA, refined
starches and sugars, both known to have adverse effect on
serum lipids levels. In addition, the human diet contains a
large portion of oxidized fatty acids and oxidized cholesterol
because of the food processing (e.g., frying and heating).
Lipid Intake
It is clear that plasma cholesterol levels correlate to the quality
and quantity of dietary lipid intake. Tarahumara and Guate-
malan Indians who are consuming a diet low in fat exhibit low
serum total cholesterol and LDL-C. However, when these peo-
ple are placed on typical Western diet, their total cholesterol
and LDL-C increase and synthesis of VLDL increased, mainly
due to increased flow of free fatty acids (FFA) to the liver. In
subjects with increased BMI, it has been demonstrated that
excess body weight correlates with increased synthesis and
turnover of cholesterol in the adipose tissue.
SFA and Cholesterol
Effects of dietary fats and cholesterol on circulating cholesterol
levels, among others, depend on the type of fats and individual
characteristics. A high intake of dietary cholesterol increased
fasting LDL levels by
10% in a dose-dependent manner,
while 12% reduction of fasting LDL levels reduced coronary
 Cholesterol: Factors Determining Blood Cholesterol Levels
risk by 19%. It was estimated that each 100 mg increase in dietary
cholesterol intake resulted in an increase of 0.05 mmol l1 in
serum LDL-C concentration. On the other hand, very-low-fat
diets caused dyslipidemia (high triglycerides and low HDL-C
concentrations). In the ‘Great Fat Debate,’ scientists emphasized
that the adequate replacement of SFA in diet is crucial in terms of
reduction of LDL-C and cardiovascular risk. The general recom-
mendation is to minimize dietary saturated fat by displacing it
with unsaturated fat, primarily polyunsaturated. However, in
practice, people usually replace it with refined carbohydrates,
which also increase cardiovascular risk.
Polyunsaturated and Monounsaturated Fatty Acids
The beneficial effect of unsaturated fatty acids on lipid metab-
olism in man is well documented. Supplementation of diet
by linoleic acid (n6) leads to a decrease in total cholesterol,
LDL-C, and HDL-C levels and in LDL/HDL ratio. Lowering
effect on serum total cholesterol and LDL-C could come from
polyunsaturated and monounsaturated fatty acids from the
corn oil. Favorable fat content from the corn oil positively
influence HDL-C, rising its level and also increasing ratio
of HDL-C to total cholesterol and decreasing ratio LDL-C to
HDL-C. The (n3) fatty acids have an effect different from that
of the (n6) fatty acids, in that they enhance HDL-C levels. The
effects of n3 PUFA on circulating levels of plasma lipopro-
teins have been shown to be variable. No consistent changes
have been observed in LDL-C or HDL-C concentrations with
n3 PUFA consumption. Greater part of this variability is
attributed to a lack of control of confounding factors such as
dietary cholesterol, fat level, and fatty acid composition. The
most comprehensive study evaluating benefits of fish oil (i.e.,
EPA þ DHA) supplementation represents meta-analysis
comprising 47 placebo-controlled randomized trials, which
found clinically significant reduction of triglycerides (by
0.34 mmol l1), no change in total cholesterol, and slight
increases in HDL-C and LDL-C (by 0.01 and 0.06 mmol l1,
respectively) in hyperlipidemic subjects. Another meta-analysis
of 21 trials evaluating lipid outcomes after fish oil consump-
tion found net change in triglycerides (0.30 mmol l1), HDL-C
(0.04 mmol l1), and LDL-C (0.15 mmol l1) and no effect on
total cholesterol. According to previous reports, the mecha-
nisms by which dietary n3 PUFA may induce changes
in plasma LDL-C levels by decreasing absolute rates of LDL
synthesis and catabolism without any effect on the fractional
catabolic rate. Studies using rats have shown that consumption
of fish oils alters hepatic LDL receptor expression. Now, it is
known that the effect of EPA/DHA on blood lipids (including
cholesterol) is based on the action of these n3 PUFAs as
ligands of the various PPAR isoforms and on the modulation
of the signaling pathway of the transcription factor SREBP.
Principal transcription factor that binds the promoter region
of the genes coding for proteins controlling cholesterol
homeostasis is SREBP-2. However, the fact that since SREBP-2
is not directly ligated by DHA (EPA), a relationship between
PPARa ligation and SREBP-2 activation is presumed and is still
not unequivocally explained. The last relationship is possibly
species-dependent. Furthermore, the more efficient absorption
of dietary cholesterol by rodents compared to humans may
account for the differences in the extent of observed increases
55
in LDL-C. The limited but rather consistent increases reported
in LDL-C in humans consuming fish oils may be due to the
relatively small proportion of dietary cholesterol being deliv-
ered to the liver compared to the amount delivered to the livers
of hamsters. Improvement of HDL-C together with insulin
resistance index HOMA (homeostasis model assessment) was
noted in hemodialyzed patients, after EPA þ DHA supplemen-
tation. That was explained by probably activation of PPAR
isoforms and consequently improving insulin signaling on
postreceptor level. It was shown that consumption of fatty
seafood can modulate fasting insulin, ghrelin, and leptin dur-
ing an 8-week intervention in obese young adults. Effects were
partly gender-specific, and the most consistent effect on circu-
lating hormones was mediated by weight loss. PPARa agonists
are the center of a regulatory hub impacting fatty acid uptake,
fatty acid activation, intracellular fatty acid binding, mitochon-
drial and peroxisomal fatty acid oxidation, ketogenesis, triglyc-
eride turnover, lipid droplet biology, gluconeogenesis, and bile
synthesis/secretion.
Therefore, it is important to understand the effects of die-
tary n3 PUFA on cholesterol metabolism and circulating lipid
levels and their interrelation with other dietary components, so
that the beneficial effects of n3 PUFA are not compromised.
As to the influence of oleic acid (n9), controversial results
have been published. Some authors did not see modification
of HDL-C levels, but others showed an increase of HDL-C
especially after an olive oil regime. Significant increase of
HDL-C and apo A1 levels among walnut consumers without
modified regular diet was established. The increase of HDL-C
may be due to the fatty acid composition of walnuts, as
it provides mostly linoleic acid (n6), alpha-linolenic acid
(n3), and oleic acid (n9), or might be related to the nature
of the protein amino acids.
Dietary Fiber, Soy Protein, and Plant Sterols
The serum levels of total cholesterol, LDL-C, Apo A1, and Apo B
were significantly lower in one Chinese ethnic group, who
consume diet primarily based on corn and then on rice, soy,
buckwheat, sweet potato, and pumpkin products, compared
with another Chinese ethnic group, who primary consume rice
and then corn, broomcorn, potato, and taro products, which are
more harmful for lipid profile. Corn-based diet of the first group
is rich with dietary fiber that reduces serum total cholesterol
level in healthy and hyperlipidemic subjects and with plant
high-quality protein that might raise serum HDL-C levels and
promote the transportation and excretion of free cholesterol.
Consumption of soy protein significantly decreases concen-
trations of total cholesterol, LDL-C, and triglycerides in circula-
tion. It was shown that after 24 weeks of treatment based on
soybean, patients with combined hyperlipidemia, isolated
hypercholesterolemia, and isolated hypertriglyceridemia have
decreased LDL-C level by 38%, 32%, and 8%, respectively.
Results of the meta-analysis showed association of soy protein
with significant decreases in serum total cholesterol by 77%,
LDL-C by 5.25%, and triglycerides by 7.27% after short initial
period and significant increases in serum HDL-C by 3.03% after
more than 12 weeks of consumption. A better effect on the lipid
profile was found after intake > 80 mg. Dietary fiber from fruits,
vegetables, and whole-grain products lowers levels of total
56 Cholesterol: Factors Determining Blood Cholesterol Levels
cholesterol and LDL-C possibly through the bile acid metabo-
lism and alteration in serum sex hormone concentrations.
Plant sterols (around 2 g day1) have been shown to block
intestinal absorption of cholesterol and lower total plasma
LDL-C.
In nutritional epidemiology, examining the relation between
diet and its effect should not be focussed on the intake of single
nutrients, food items, or food groups, but should be focussed on
the overall diet and food preparation methods and eating pat-
terns. If we want to achieve healthy serum lipid levels and
prevent chronic diseases, we should follow general diet recom-
mendations to consume great amount of fruits, vegetables, nuts,
and fish; moderate amount of dairy and vegetable oils; and
whole-grain foods in place of refined starches and sugars and
to avoid sugar-sweetened beverages, processed meats, and foods
that contain partially hydrogenated vegetable oils.
Alcohol Consumption
Serum lipid level is associated with alcohol consumption.
Effects depend in part on the amount of consumed alcohol,
so that moderate intake protects individuals against cardiovas-
cular diseases. Alcohol consumption was the independent neg-
ative risk factor for insulin resistance and improved lipid
profiles that are known to be worsened by insulin resistance.
The increase in HDL-C and decrease in LDL-C in drinkers result
from the inhibition of CETP that promotes transfer of choles-
teryl ester from HDL to VLDL (a precursor of LDL) and LDL.
Inconsistent results among earlier studies may partly result
from variability in the prevalence of obesity among subgroups
and according to the amount or frequency of alcohol con-
sumption. Harmful effect of heavy alcohol consumption may
be attributable to increased triglyceride synthesis.
Coffee Consumption
Coffee is consumed as a beverage worldwide; however, its effect
as a cardiovascular risk factor is still controversial. Roasted
coffee contains naturally present antioxidants and others that
are formed during the roasting process. Chlorogenic acids and
caffeine may play a role in the inhibition of lipid peroxidation,
free radical scavenging, and anti-inflammatory activity. How-
ever, coffee also contains diterpenes, cafestol, and kahweol.
High consumption of these compounds can raise serum levels
of total cholesterol and LDL-C. Most of them are retained by the
paper filter, which substantially reduces the cholesterol-raising
effects. It should be mentioned that instant coffee was associ-
ated with lower serum concentrations of total cholesterol and
higher serum LDL-C level. Average change in total cholesterol
for each cup ranged from 0.007 to 0.026 mmol l1. When
examining the effects of coffee beverage on serum lipoprotein
levels, we should take into account coffee preparation such as
the use of milk, sugar, ice cream, and alcohol.
Physical Activity
The sedentary lifestyle is one of the principal risk factors of
highly prevalent illnesses such as type 2 diabetes,
cardiovascular disease, osteoporosis, and some cancers. Asso-
ciation between sedentary lifestyle and the current pandemic of
obesity and metabolic syndrome is clear. Attempt to exactly
measure the effect of sedentary lifestyle on metabolic syn-
drome and other cardiovascular risk factors, based on duration
of leisure-time physical activity, have shown that even 25 min
day1 produces benefits, better HDL-C function or higher level
of paraoxonase 1 activity. The difference for glycemia, total
cholesterol, and HDL-C level disappears after adjustment for
age, gender, and cigarette smoking. However, low physical
fitness among young adults has been shown to longitudinally
predict hypercholesterolemia and, among middle-aged adults,
hypertension. This association was attenuated when adjusted
for obesity.
Seasonal variation in physical activity has been reported to
coincide with seasonal changes in blood lipid levels, particu-
larly total cholesterol. Environmental changes in ambient tem-
perature, daylight, and monthly precipitation are thought to
induce seasonal changes in physical activity, particularly by
extreme environmental factors (e.g., hot or cold temperatures).
Significant increase in nonoccupational activity due to yard
work and exercise or recreational activities was noted during
the warmer months. Estimates of the amplitude of seasonal
variation in activity energy expenditure in this report were
consistent with those in the Framingham Offspring Study.
The FHS is a population-based prospective family study that
began in Framingham, MA, in 1948 with the recruitment of the
Original Cohort. In 1971, children of the Original Cohort,
called the Offspring Cohort, were enrolled, and finally, in
2002, the grandchildren of the Original Cohort were enrolled
making the FHS the longest-running family-based study in
history. For the past 62 years, investigators at the FHS have
collected data related to CVD and its risk factors. Recent public
health recommendations have noted the importance of envi-
ronmental factors as potential barriers to regular participation
in healthful levels of such activity.
Environmental Contaminants
There are increasing evidences of the role of environmental
contaminants (e.g., heavy metals and persistent pollutants) in
serum lipid level variation. Nonoccupational exposure to var-
ious chemicals can occur through contaminated drinking
water, foods, air, and cigarette smoking, and even low-level
exposure may be harmful to health. Hereafter, examples of the
influences of the most common contaminants on lipid metab-
olism will be described.
Arsenic is widely distributed in the environment and usually
contaminates drinking water sources. Experimental studies on
rats have shown an increase in total cholesterol level after
10–20 weeks of exposure to arsenic, added as arsenite or arse-
nate in drinking water. This effect becomes more significant
under high-cholesterol diet and when the exposure occurs
earlier in life. Mechanism by which arsenic modifies choles-
terol metabolism has not been yet elucidated. Possible way is
modulation of RCT that transfers cholesterol from the periph-
ery back to the liver by modifying the densities of cholesterols.
Altered lipid metabolism (low HDL-C, hypertriglyceride-
mia, and high total cholesterol and LDL-C level) may be a
 Cholesterol: Factors Determining Blood Cholesterol Levels
consequence of chronic cadmium exposure, possibly due to
decreased plasma lipoprotein lipase activity and increased
activity of HMG-CoA reductase.
The results of relationship between blood lead level and
serum cholesterol and lipoprotein levels are conflicting. Occu-
pational exposure to lead was positively associated with levels
of total cholesterol and HDL-C. Lead-exposed patients had
decreased total cholesterol and LDL-C and increased HDL-C
levels. Recently, an association between blood lead and total
cholesterol based on an age-adjusted model has been
confirmed.
Fat-soluble chlorinated organics, such as dioxins, furans,
polychlorinated biphenyls (PCBs), and chlorinated pesticides,
were related with unfavorable serum lipid levels. Correlation
between serum PCBs levels and plasma lipid levels was firstly
showed in occupational studies. The strong relationship
between PCBs levels and cholesterol and triglycerides was
reported with average value for the sum of PCB congeners of
4.2 mg. The proposed mechanisms by which PCBs affect serum
lipids are the activation of certain cytochrome P450 enzymes
and increased synthesis of lipids.
Perfluorooctanesulfonate (PFOS) used as surfactant in a wide
variety of commercial products has been recently recognized to
disrupt serum lipid level. Positive association between plasma
concentration of PFOS and serum concentration of HDL-C and
negative association with total cholesterol/HDL-C ratio and
triglycerides level were reported. The possible pathway is per-
oxisome proliferation, leading in hepatotoxicity and alteration
of lipids homeostasis.
It was postulated in the systematic association study about
broad environmental correlation to lipid levels. There was
favorable association of HDL-C (3–4% higher HDL-C) with
iron and mercury exposure and unfavorable association with
PCBs, dibenzofurans, organochlorine pesticides, and all per-
sistent organic pollutants. Multiple environmental factor anal-
ysis enabled better understanding of their relationship with
characteristics in the general population.
Cigarette Smoking
Cigarette smoking is a well-known risk factor for atherosclero-
sis and may influence serum lipid levels. Significant increase in
serum total cholesterol, triglycerides, VLDL, and LDL-C and
decrease in protective HDL were reported among chronic
smokers, hypertensives, and chronic smokers with high
blood pressure. However, confounding factors such as diet,
BMI, stress, alcohol consumption, and physical activity have
not been controlled in some studies. The effect of smoking on
the serum lipid profiles may be influenced by age, gender, and
different smoking statuses. It was found that smoking was
associated with lower total cholesterol and LDL-C levels in
elderly men and in middle-aged women and also with
decreased HDL-C levels in 65–74-year-old men and 55–64-
year-old women when compared with nonsmokers. The data
from meta-analysis were in contrast due to differences in study
populations and their dietary habits, physical activities, life-
style, or public health awareness. Positive association between
current smoking and dyslipidemia was reported in women but
not in men. Further, current female smokers in the age groups
57
between 20 and 34 years and of 50 years or older have had the
highest risk of dyslipidemia. The possible reason for gender
difference in the association between cigarette smoking and
unfavorable serum lipid levels could be an interaction of some
hormonal factors with components of the inhaled smoke. The
nicotine provokes the secretion of catecholamines and other
hormones (e.g., cortisol and GH) leading to an increased
serum concentration of FFA, which stimulates hepatic secre-
tion of VLDL and triglycerides. Cigarette smoke has great oxi-
dative potential and can promote oxidative modifications in
LDL and other biomolecules and may contribute to additional
endogenous oxidant formation, through its effects on the
inflammatory-immune response. Some natural antioxidants
such as dietary polyunsaturated fats and vitamin E are connect-
ing with lower risk for atherosclerosis, although they may
contribute to lipid oxidation in smokers. Further studies are
needed to explain the mechanism by which cigarette smoke
changes serum lipid levels and what are the most responsible
substances for these changes, since cigarette smoke besides
nicotine contains multiple toxic compounds.
Stress
Serum cholesterol levels are changing under emotionally
stressful situations. Numerous studies have demonstrated
that acute and chronic stressors are related in alterations in
cholesterol concentrations. Investigators have established a
negative link between cholesterol and psychological and
physical aggressions. However, there is a positive correlation
between cholesterol and psychological stress. This correlation
can be explained with increased peripheral fat tissue lipolysis
caused by heightened sympathetic nervous system activity and
increased levels of catecholamines, glucocorticoids, and gluca-
gon. The final result of these processes is increased release of
fatty acids into the circulation. In contrary, deficit of serotonin
and lower cholesterol levels have been implicated with physi-
cal aggression and increased incidence of accident, suicide, and
homicide. The possible explanation can be that in primitive
man, cholesterol served as a sentinel compound for survival.
Hence, when primitive man was experiencing lack of food, low
blood cholesterol was leading and preparing him for food
seeking and increased risk in hunting. Chronic stress induces
both functional and structural adaptations within the hypot-
halamo–pituitary–adrenal axis that are suggestive of long-term
alterations in neuroendocrine reactivity to subsequent
stressors. Experimental evidence of chronic stress-induced
hyperlipidemia in animal models has been documented by
significant increases of blood total cholesterol, LDLs, and tri-
glycerides and decrease in HDLs concomitant with increased
oxidative stress.
Diseases
Obesity
It is hard to interpret the influence of obesity itself on choles-
terol metabolism, due to the confounding of metabolic disor-
ders accompanied with this condition. Abnormalities, such as
hypertriglyceridemia, hyperglycemia, and insulin resistance,
58 Cholesterol: Factors Determining Blood Cholesterol Levels
commonly seen in obese population, may affect the distribu-
tion and size of lipoprotein particles independently of adipos-
ity. The typical dyslipidemia observed in obesity does not
include total cholesterol level disturbances. Obesity is charac-
terized by the higher development of small dense, more ath-
erogenic LDL particles. Viscerally, obese men were found to
have significantly reduced LDL receptor binding of lipopro-
teins compared with lean healthy controls. Although hyper-
cholesterolemia is not a concomitant feature of insulin
resistance and obesity, both of them are characterized by
decreased expression of hepatic LDL receptors due to higher
rates of hepatic cholesterol synthesis and diminished choles-
terol absorption.
Many studies show that total cholesterol and LDL-C con-
centrations respond more weakly to diets low in saturated fat
and cholesterol in obese than in lean subjects, due to large
amount of cholesterol in the enterohepatic pool in obese
people. Additional amount taken in with the diet would not
be recognized as small to activate hepatic LDL receptors, and
hepatic LDL receptors are most probably suppressed by this
large stream of endogenous cholesterol from enterohepatic
circulation. Therefore, the most effective way for the obese to
normalize their blood cholesterol is to lose weight. This shows
us that cholesterol metabolism is tightly regulated so that if
cholesterol synthesis is upregulated, cholesterol absorption is
diminished and vice versa.
Diabetes Mellitus and Metabolic Syndrome
Considerable attention has been focussed on dyslipidemia
accompanying diabetes and metabolic syndrome. Metabolic
syndrome is generally characterized by abdominal obesity,
insulin resistance, hypertension, and blood lipid disorders
including high TG and low HDL-C, high apoB, and small
dense LDL-C. Metabolic syndrome is associated with increased
endogenous cholesterol synthesis and reduced intestinal cho-
lesterol absorption predominantly as a consequence of visceral
obesity, independently of overall obesity. It has been proposed
that hyperinsulinemia in insulin resistance may upregulate the
expression of SREBP-1c, a transcription factor that stimulates
the synthesis of fatty acids and the production of VLDL
particles. However, SREBP-2, another transcription factor that
upregulates de novo cholesterol synthesis, does not appear to
be affected by hyperinsulinemia or hyperglycemia. Besides
elevated liver VLDL production, decreased postprandial
triglyceride metabolism represents a major pathway of the
hypertriglyceridemia that characterizes diabetic condition.
Increased cholesterol absorption has also been reported in
type 2 diabetes with slightly increased concentrations of total
cholesterol and LDL-C. It has been shown that changing car-
bohydrate content of a mixed meal altered the postprandial
accumulation of chylomicrons. Furthermore, a high glucose
level alters the genetic expression of various genes involved in
HDL metabolism in HepG2 cells, including human ABCA1,
SR-BI, and hepatic lipase.
Cushing Syndrome
It is well known that chronic overt hypercortisolism, as in
Cushing syndrome, is characterized by systemic alterations
leading to increased risk of metabolic and cardiovascular diseases.
Cortisol excess could inhibit insulin secretion, glucose uptake,
and glycogen synthesis; worsen insulin sensitivity; and increase
gluconeogenesis. However, it was hypothesized that adrenal inci-
dentaloma (the presence of adrenal mass and patient has no signs
of hormonal excess or obvious underlying malignancy) may be
itself an unrecognized manifestation of the metabolic syndrome.
The pattern of dyslipidemia in Cushing syndrome is the same as
in metabolic syndrome or in type 2 diabetes.
Hypothyroidism
Hypothyroidism is associated with increased TC and LDL-C
due to limited synthesis of the LDL hepatic receptors. Also, the
activity of HMG-CoA reductase is significantly lowered, which
may explain the poor response to hypolipemic treatment.
Acromegaly
Patients with acromegaly have a relative risk to present glucose
alterations, with a 2.6 times and 2.1 times higher risk of
impaired glucose tolerance and diabetes, respectively, than
the general population, and show a higher prevalence of hyper-
triglyceridemia and low HDL-C. Active acromegaly in women
is strongly associated with higher visceral adiposity dysfunc-
tion, insulin resistance, and the features of MetS; therefore,
more careful metabolic management is suggested in acrome-
galic women.
Chronic Renal Failure
The typical dyslipidemia in chronic renal failure is characterized
by hypertriglyceridemia and low levels of HDL-C, as the result
from decreased lipoprotein lipase activity. The decreased level
of hepatic lipase observed in renal failure may account for the
presence of IDLs and the high HDL2 subfraction. The pattern
of dyslipidemia depends on the degree of proteinuria and the
kind of terminal renal failure treatment. Total and LDL-C can
also be increased, with a predominance of the small dense LDL
in the event of proteinuria or peritoneal dialysis.
Drugs
Many drugs, besides lipid-lowering drugs, can affect serum cho-
lesterol levels. It has been reported that thiazide diuretics increase
total and LDL-C levels by 5–10% in a dose-dependent way. These
side effects are short term and not contraindication for their
use. Loop diuretics have a similar effect. In contrary, the use of
potassium-sparing diuretics and indapamide shows no changes
in cholesterol levels. The effects of beta-blockers on total
cholesterol and LDL-C are negligible. Furthermore, they could
decrease HDL-C by
5–20%. However, Celiprolol, a selective
beta1 blocker with weak beta2 sympathomimetic activity even
improves the lipid pattern. The only antihypertensive agents that
lower total and LDL-C levels are alpha1-blocking agents.
Oral estrogen preparations given to postmenopausal
women, premenopausal women, women with polycystic ovary
syndrome, men with prostatic carcinoma, and male-to-female
transsexuals reduce total and LDL-C and increase HDL-C levels.
 Cholesterol: Factors Determining Blood Cholesterol Levels
Combined (estrogen/progestogen) hormone replacement
therapy has similar effect. Tamoxifen, a selective receptor estro-
gen modulator, beneficially affects both total cholesterol and
LDL-C, by decreasing them, due to its partial estrogenic activity.
Danazol, a drug that is used in treatment of endometriosis,
induces an increase of LDL and decrease of HDL-C level. Iso-
tretinoin treatment increases LDL and total cholesterol levels
by
15% compared to pretreatment levels. Patients treated
with immunosuppressive therapy (cyclosporine, azathioprine,
and corticosteroids) show increased level of total cholesterol,
LDL-C, and HDL-C in spite of the combination of drugs and
gender of the patient. The largest effect on cholesterol metabo-
lism has cyclosporine in female population, and it is associated
with small dense, more atherogenic LDL particles. Tacrolimus
does not affect total cholesterol and LDL-C levels.
Protease inhibitors, especially ritonavir, increases total cho-
lesterol level by 30–40%.
Considering anticonvulsive therapy, carbamazepine seems
to have most effect on TC levels, which are more pronounced
in women and independent of the dosage. Contrary, valproic
acid is the only anticonvulsant with a more favorable effect on
the lipid profile.
Conclusions
In this article, we try to summarize all factors that determine
cholesterol balance in the body, from absorption, to synthesis,
to clearance. Some of them, as age, gender, and unbalanced
food with more saturated fats and refined carbohydrates, are
well known. However, there is growing amount of evidence
about the benefit effect of diet, which contains more fatty
seafood, corn, soy protein, olive oil, and dietary fiber from
fruits, vegetables, and whole grain. Maybe, it is possible to
improve, by epigenetic impact with regular diet, known spe-
cific genetic variants of genes involved in cholesterol metabo-
lism in childhood. We also emphasize that improvement of
low physical fitness could reduce hypercholesterolemia. In the
future, we have to pay attention to environmental contami-
nants (e.g., heavy metals and persistent pollutants) that are
able to influence lipid metabolism.
See also: Cereals: Dietary Importance; Cholesterol: Absorption,
Function and Metabolism; Fish: Dietary Importance and Health Effects;
Soy Beans: Dietary Importance.
59
Further Reading
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303(5661): 1201–1204.
Berrougui H and Khalil A (2009) Age-associated decrease of high-density lipoprotein-
mediated reverse cholesterol transport activity. Rejuvenation Research 12(2):
117–126.
Delgado M, Gutierrez A, Cano MD, and Castillo MJ (1996) Elimination of meat, fish,
and derived products from the Spanish– Mediterranean diet: effect of the plasma
lipid profile. Annals of Nutrition and Metabolism 40: 202–211.
Dennis PA, Ulmer CS, Calhoun PS, et al. (2014) Behavioral health mediators of the link
between posttraumatic stress disorder and dyslipidemia. Journal of Psychosomatic
Research 77: 45–50.
Eslick GD, Howe PRC, Smith C, Priest R, and Bensoussan A (2009) Benefits of fish oil
supplementation in hyperlipidemia: a systematic review and meta-analysis.
International Journal of Cardiology 136: 4–16.
Hu FB (2002) Dietary pattern analysis: a new direction in nutritional epidemiology.
Current Opinion in Lipidology 13: 3–9.
Hunter RF, Tullya MA, Donnelly P, Stevenson M, and Kee F (2014) Knowledge of UK
physical activity guidelines: implications for better targeted health promotion.
Preventive Medicine 65: 33–39.
Jump DB (2008) N-3 polyunsaturated fatty acid regulation of hepatic gene transcription.
Current Opinion in Lipidology 19: 242–247.
Kuller LH (2011) The great fat debate: reducing cholesterol. Journal of the American
Dietetic Association 111: 663–664.
Kikkawa K, Nakajima K, Shimomura Y, et al. (2015) Small dense LDL cholesterol
measured by homogeneous assay in Japanese healthy controls, metabolic
syndrome and diabetes patients with or without a fatty liver. Clinica Chimica Acta
438: 70–77.
Petel CJ, Cullen MR, Ioannidis JPA, and Butte AJ (2012) Systematic evaluation of
environmental factors: persistent pollutants and nutrients correlated with serum lipid
levels. International Journal of Epidemiology 41: 828–843.
Rasic-Milutinovic Z, Popovic T, Perunicic-Pekovic G, Arsic A, Borozan S, and
Glibetic M (2012) Lower serum paraoxonase-1 activity is related with linoleic and
docosahexanoic fatty acids in type 2 diabetic patients. Archives of Medical Research
43: 75–82.
Ravid Z, Bendayan M, Delvin E, et al. (2008) Modulation of intestinal cholesterol
absorption by high glucose levels: impact on cholesterol transporters, regulatory
enzymes, and transcription factors. American Journal of Physiology.
Gastrointestinal and Liver Physiology 295: G873–G885.
Ristic-Medic D, Ristic V, Tepsic V, et al. (2003) Effect of soybean Leci-Vita product on
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Relevant Websites
www.aace.com – AACE is American Association of Clinical Endocrinologists.
www.nice.org.uk – NICE is National Institute for Health and Care Excellence from UK.
www.ama-assn.org – AMA (American Medical Association) and AMA publications.
www.atsdr.cdc.gov – ATSDR is Agency for Toxic Substances and Disease Registry.
www.oldwayspt.org/programs/mediterranean-food-alliance – Oldway mediterranean
diet pyramid.