Fat and Health
Some Aspects of the Relationships of
Serum Lipids to Health
Prof. Walter K.K. Ho
Department of Biochemistry,
The Chinese University of Hong Kong
<b080707@mailserv.cuhk.edu.hk>
INTRODUCTION
Lipids, the scientific name for fats,
form an important class of biological
molecule found universally in all higher living
organisms.
In mammals the four most
important classes of lipid are fatty acid,
triglyceride, cholesterol and phospholipid.
One important property of all lipids is that
they are slightly soluble or completely
insoluble in water. The degree of solubility is
highly dependent on the nature and the
number of polar group present in the
molecule. Thus, fatty acids are more soluble
than triglycerides because they have a free
ionizable carboxyl group. The different
degrees of solubility are highly related to the
functional role of the various types of lipids.
In additional to the four major classes
of lipids, a variety of other lipids are also
found in living systems. Examples of them
include the plasmalogens, gangliosides,
prostaglandin and the fat-soluble vitamins.
In general, these lipids are only present in
small quantities.
the form of fat.
Most of the fat reserves found in the
body are stored in the adipose tissue. This
tissue is made up of individual fat cells called
adipocytes and it has been estimated that there
are 25 billion of them in our body. The
number of adipocytes is an important factor in
determining the amount of fat a person can
store. Various experimental evidence indicate
that the number of adipocytes is determined
during childhood. An over supply of dietary
fat during youth may lead to a proliferation of
adipocytes; because of this an excess accumulation of fat may be unavoidable in later years.
Membrane Components
Phospholipids and cholesterol are
integral components of biological membranes.
Their primary function is to provide a uniform
surface structure where other membrane
components (e.g., proteins and glycoproteins)
can be anchored. The earlier concept that
biological membranes are inert and static has
proved untrue. Experimental findings indicate
that lipids in the membrane play important
roles in the regulation of cellular functions.
Examples of these include orientation of
receptors, cell-cell interaction, membrane
transport, signal transduction, and enzyme
activation.
FUNCTIONAL ROLE OF LIPIDS
Others
Fuel for the body's metabolism
Other than the roles as fuel and
membrane components, lipids are also
involved in some less well known but still
important biological functions. Examples of
these are the emulsification of fat for
digestion, the activation and inactivation of
the immune system, the supply of precursors
for the synthesis of vitamins and hormones
and cellular signal transduction.
The major function of triglyceride and
fatty acids is to supply and store energy for
metabolism.
Compared with proteins and
carbohydrates, the molecular structure of
lipids offers a more efficient way of storing
energy. The amount of energy produced by a
complete break down of 1g of fat is
approximately twice that of 1g of protein or
carbohydrate. The normal fuel reserve in an
adult man is 166,000 kcal and 85% of it is in
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TRANSPORTATION OF LIPIDS
In mammals as well as in other
vertebrates the site of lipid absorption or
synthesis may not be the site of metabolism
and storage.
Thus, lipid absorbed in the
intestine must somehow be transported
through the circulatory system to other
organs.
Since lipids are not soluble in
aqueous systems, a means of transport is
required and is provided by a class of
macromolecules
named
the
serum
lipoproteins. The lipoproteins are basically
complexes of proteins and lipids. By virtue
of the ability of the proteins to interact with
both lipid and water, lipids can be solubilized
and transported in the bloodstream in
lipoprotein form. Thus, without lipoproteins,
the transportation of lipids may be impaired.
A typical example of this is the case of
abetalipoproteinemia. Patients affected with
this disease cannot synthesize lipoprotein and
because of this there is an accumulation of fat
in both the liver and the intestine.
Classification of the serum lipoproteins
Human serum lipoproteins are
generally classified into four major categories.
They are the chylomicrons, the very low
density lipoproteins (VLDL), the low density
lipoproteins (LDL) and the high density
lipoproteins (HDL).
Chylomicrons
Chylomicrons are the largest of the
serum lipoproteins. They are secreted mainly
by the gastro-intestinal tract during the
absorption of dietary fat. Chemically,
chylomicrons are composed predominantly of
triglyceride with smaller amounts of
phospholipid,
unesterified
cholesterol,
cholesteryl ester and proteins. The size of
chylomicrons ranges from 750 to 10,000 Å
with molecular weights between 1,000 to
10,000 million daltons. Because of their large
size, chylomicrons are easily seen as a milky
emulsion in the serum after a fatty meal.
Very low density lipoproteins (VLDL)
VLDL are triglyceride rich particles
derived mainly from the liver. The main
function of this class of lipoprotein is the
transport of liver triglyceride to peripheral
tissue for storage or metabolism. The chemical
composition of VLDL is predominantly
triglyceride with smaller amounts of
phospholipid, cholesterol and protein. The
hydrated density of VLDL is between 0.95 to
1.006 gm/ml and the molecular weight is
between 5 to 6 million daltons. Data from
electron microscopy indicates that the VLDL
particle is spherical with diameters ranging
from 300 to 800 Å.
Low density lipoproteins (LDL)
Serum LDL are characterized by their
high cholesterol content, particularly in the
form of cholesteryl ester. This class of
molecule is derived mainly from the
breakdown of VLDL during which hydrolysis
of
VLDL-triglyceride
occurs.
The
physiological function of LDL appears to be
related to cholesterol transport. It has been
suggested
that
the
development
of
atherosclerosis (a process whereby blood
vessels get clotted up with fiberous cholesterol
deposits) is significantly related to increased
blood level of this class of lipoproteins. The
chemical composition of LDL is approximately
25% protein, 10% triglyceride, 8% unesterified
cholesterol, 37% cholesteryl ester and 22%
phospholipid. Physical features defining this
class of lipoproteins include hydrated density
ranging from 1.006 to 1.063 gm/ml, molecular
weight from 2.1 to 2.6 million daltons and a
mean diameter of 212 Å.
High density lipoproteins (HDD)
Serum HDL are the smallest of all the
major lipoproteins. They are made up of
approximately 50% protein and 50% lipid. Of
the lipid components present, phospholipid
and cholesteryl ester predominate.
The
source of HDL is believed to be the liver.
Since part of the protein moiety in HDL is
common with VLDL there may be a
metabolic connection between them. The risk
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of atherosclerosis has been found to be
inversely related to the concentration of HDL.
It has been hypothesized that these
lipoproteins may act as carrier to transport
cholesterol from peripheral tissue to the liver
for metabolism. Physically, the size of the
HDL particles ranges from 75 to 100 Å with
molecular weights from 200,000 to 400,000
daltons. The hydrated density of HDL is
between 1.063 and 1.21 gm/ml. HDL has
been subdivided into two classes, HDL2 and
HDL3. The beneficial effect of HDL in
reverse cholesterol transport appears to be
associated with HDL3.
Absorption and transportation of dietary fat
A major source of fat is from dietary
intake. Absorption of fat occurs in the
intestine. Fat is first emulsified into small
micelles by the action of bile salts and then
hydrolyzed by the action of various enzymes
from the pancreas. Triglyceride is first broken
into free fatty acids and monoglycerides while
cholesteryl esters and phospholipids are
broken down into fatty acids, free cholesterol
and phosphoglycerol. The fatty acids and
other lipid components are then absorbed into
the mucosal cells of the intestine. The exact
mechanism of this uptake is unknown.
Once inside the intestinal cells, lipid
components are reassembled back into
triglyceride,
cholesteryl
ester
and
phospholipid.
Subsequently, triglyceride
together with a small amount of phospholipid,
cholesteryl ester and cholesterol are
complexed to a specific protein (B-protein) in
the endoplasmic reticulum to form
chylomicrons.
The chylomicrons are
transported to the other side of the intestinal
cells and ejected into the lymphatic system.
All chylomicrons thus secreted will gradually
enter the bloodstream via the thoracic duct.
Since the chylomicrons are very large
particles, their presence in the blood will
produce
a
milky
appearance.
This
phenomenon can usually be observed two
hours after a fatty meal.
Once inside the bloodstream, the
chylomicrons are transported to the adipose
tissue where their triglyceride moiety is
broken down into fatty acids and
monoglyceride by the action of an enzyme,
lipoprotein lipase.
The fatty acids and
monoglycerides are absorbed into the
adipocytes. Triglyceride is resynthesized
inside the cells and stored as fat droplets.
Chylomicrons which are not picked up by the
adipose tissue will be metabolized by the liver
and their lipid moiety resecreted in the form
of VLDL.
Transportation of endogenous fat
Although the bulk of fat in the body
comes directly from the diet, there are
situations in which other dietary components,
viz., carbohydrate, can be converted to fat in
the liver and stored in the adipose tissue. This
phenomenon usually comes about when there
is an excess of caloric intake.
The transport of triglyceride from the
liver to the adipose tissue is the main function
of VLDL. VLDL are synthesized in the liver
very much the same way as chylomicrons are
synthesized in the intestine. VLDL is
secreted into the bloodstream directly from
the liver and then transported to the adipose
tissue. Like the chylomicrons, VLDL is
broken down by lipoprotein lipase. The fatty
acids released are absorbed, reassembled into
triglyceride and stored in the form of fat
droplets. As the process of triglyceride
removal continues, the VLDL particles
become smaller and smaller with their relative
cholesterol content increasing. Eventually,
these particles will be transformed into
intermediate LDL and LDL .
Transportation of cholesterol
In contrast to triglyceride, the reason
why cholesterol transport is required in the
bloodstream is still by and large unknown.
Cholesterol is an important component of
biological membranes, therefore it is present
in almost every organ. Most tissues have the
capability to synthesize cholesterol but do not
possess the ability to metabolize or degrade it.
Thus, it has been hypothesized that some form
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of transportation system is required to channel
peripheral cholesterol to the liver for
breakdown and excretion. Since the LDL and
HDL are the major carriers of cholesterol in
the bloodstream, it has been suggested that
they may play a crucial role in channeling
cholesterol from one organ to another. As
HDL is believed to play a crucial role in
reverse cholesterol transport to the liver, its
level in the blood stream has gained wide
medical attention as a negative risk factor for
development of CHD.
blood products, fibrous tissue and calcium
deposits) and associated changes in the media
or middle portion of the arterial wall.
Atherosclerosis is a continuous process
throughout life and normally it will not lead to
any clinical symptoms until the fourth decade.
The risk of atherosclerosis has been shown to
associate with smoking, high blood pressure,
physical inactivity and elevated serum
cholesterol level.
Of the four factors
mentioned, the elevation of serum cholesterol
is believed to be the most direct cause because
cholesterol is a major component in the
hardened areas (called plaques) of the arteries.
The lipid theory of atherosclerosis
LIPIDS AND HEALTH
As mentioned in the Introduction,
lipids are involved in maintaining a number of
vital functions in our body. Because of this,
the inability to synthesize or absorb lipid will
undoubtedly affect our general health. For
example the storage of triglyceride in the
adipose tissue provides us the necessary
energy supply during starvation. If our body
does not have such a vital fuel reserve,
mobilization of protein may be necessary.
Because proteins are important components of
cellular functions, the deprivation of proteins
during starvation may lead to permanent
cellular and tissue damage.
As in the case of lipid deficiency, an
abundance of lipids in our circulatory system
and adipose tissue can also affect our health.
In contrast to starvation, this aspect of overnutrition has become a major health problem
in modern industrial societies.
Atherosclerosis
Atherosclerosis is the process usually
referred to as hardening of the arteries.
Basically it is a form of degenerative change
in the inner lining (intima) of the arteries.
There is focal accumulation of lipids (with or
without complex carbohydrates, blood and
The cause of atherosclerosis has been
under active investigation in the past 50 years.
The interest in the process is probably due to
the high incidence of diseases, such as
coronary heart disease and stroke, caused by
it. At the moment, a number of theories have
been proposed to account for the events
leading to the development of atherosclerosis.
However, none of them have been proven to
be adequate and acceptable. The lipid theory
proposes that the basic mechanism of
atherosclerosis is due to the infiltration of
serum lipids into the intimal layer of the
arterial wall. There are 3 events that are key
to the formation of early atherosclerotic
lesions. The first is infiltration of LDL
particles through the endothelium into the
intimal layer of the blood vessel wall. The
LDL particles are then oxidized. Macrophages
in the intima can ingest a limited number of
LDL particles through their normal LDL
receptor. However, once LDL is oxidized, the
uptake is increased significantly and not
regulated. This leads to the formation of foam
cells in the intima. Foam cells are a major
component of the early atherosclerotic lesion.
The accumulation of monocytes and
macrophages is also critical in the formation
of an early atherosclerotic lesion. Endothelial
cells express glycoproteins that allow
monocyte adhesion to the endothelial surface.
Oxidized LDL stimulates endothelial cells to
produce a monocyte hemotactic factor. As a
result, monocytes enter the intima and
differentiate into macrophages. These
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macrophages produce cytokines that stimulate
endothelial cells to produce adhesive
glycoproteins and thus recruiting more
monocytes. Macrophages also produce growth
factors that result in the proliferation of
smooth muscle cells. The combination of
these events result in the formation of a fatty
streak or early atherosclerotic lesion. Since
the initial and subsequent events are
positively
related
to
serum
LDL
concentration, it is not surprising that many
epidemiological studies performed in the past
30 years have already established that a high
cholesterol level means high risk in the
development of coronary heart disease. Fig. 1
summarizes the different stages of
atherosclerosis leading to the final outcome of
a blocked artery in coronary or stroke patients.
Figure 1
Potential routes of treatment
The treatment of atherosclerosis can
be divided into two phases, prevention and
cure. In the case of prevention, measures are
taken before the development of any signs or
symptoms. Examples of preventive treatment
include low fat low cholesterol diet, intake of
monounsaturated fat, keeping the body weight
within normal range, exercise, no smoking
and frequent monitoring of serum lipid levels.
In contrast to prevention, there is presently no
good method to reverse the process of
atherosclerosis once it is developed.
Potentially, there are means by which one can
manipulate
the
serum
lipoprotein
transportation system to halt or reverse this
process. For example, the drug lovastatin, an
inhibitor of a key enzyme in the synthesis of
cholesterol, can be used to reduce serum
cholesterol level by up to 30%. Clinical use of
this drug as well as other cholesterol lowering
drug has provided evidence that if serum
cholesterol could be maintained at a low level
(e.g. below 200 mg/100ml) the course of
atherosclerosis can actually be reversed. In
recent years, the concept of preventing LDL
from oxidation has also gained wide attention
in the treatment of atherosclerosis. Since the
infiltration of oxidized LDL into the intima is
believed to be the initiation process of
atherosclerotic lesion, the intake of food or
drug that can prevent oxidation appears to be
an attractive means of slowing down such a
process. In a number of clinical studies, the
intake of greater than 100 units of vitamin E
per day has been shown to be beneficial.
Modern surgical procedures have also
played an important role in the treatment of
coronary blood vessel blockage due to
atherosclerosis. The two most common
techniques used are coronary by-pass surgery
and angioplastin. In the former, the surgeon
graft a vein from the leg and construct a bypass blood vessel in the heart so that blood
can flow over the blocked area. In the latter, a
balloon catheter is inserted into the blocked
blood vessel and pressure is applied to crush
the plaque into small pieces to restore full
blood flow. Although both of these
procedures have saved millions of patients
from dying from heart attacks, they cannot
prevent the course of atherosclerosis.
Therefore, a healthy living style is still the
best method in keeping our blood vessels
clear.
SELECTED REFERENCES
Connor, W. E. (1968) Dietary sterols: Their
relationship to atherosclerosis. J. Am. Dietetic
Assoc. 52: 202-208.
Brewer, H. B., Gregg, R. E., Hoeg, J. M. and
Fojo, S. S. (1988) Apolipoproteins and
lipoproteins in human plasma: an overview.
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Clin. Chem. 34/8(B): B4-b8.
McGill, H. C. (1988) The pathogenesis of
atherosclerosis. Clin. Chem. 34/8B: B33-B39.
Brown M. S. and Goldstein, J. L. (1986) A
receptor-mediated pathway for cholesterol
homeostasis. Science 232: 34-47.
Muldoon, M. F., Manuck, S. B. and
Matthows, K. A. (1990) Lowering cholesterol
concentrations and mortality: a quantitative
review of primary prevention trials. Brit. Med.
J. 301: 309-314.
Diaz, M. N., Brei, B., Vita, J. and Keaney, J.
F.
(1997)
Mechanisms
of
disease:
antioxidants and atherosclerotic heart disease.
New Engl. J. Med. 337: 408-416.
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