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Cholesterol Metabolism

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Fadhil Jawad Altu'ma

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 Cholesterol Metabolism

Prof. Dr. Fadhil Jawad Al-Tu’ma . Ph.D.

Professor of Molecular and Clinical Biochemistry
College of Medicine – University of Kerbala

Objective:
1. Appreciate the importance of cholesterol as an essential structural component of cell
membranes and as a precursor of all other steroids in the body, and indicate its
pathological role in cholesterol gallstone disease and atherosclerosis development.
2. Identify the five stages in the biosynthesis of cholesterol from acetyl-CoA.
3. Understand the role of 3-hydroxy-3-methylglutaryl CoA reductase (HMG-CoA
reductase) in controlling the rate of cholesterol synthesis and explain the mechanisms
by which its activity is regulated.
4. Appreciate that cholesterol balance in cells is tightly regulated and indicate the
factors involved in maintaining the correct balance.
5. Explain the role of plasma lipoproteins, including chylomicrons, very low density
lipoprotein (VLDL), low-density lipoprotein (LDL), and high-density lipoprotein
(HDL), in the transport of cholesterol between tissues in the plasma.
6. Name the two main primary bile acids found in mammals, outline the pathways by
which they are synthesized from cholesterol in the liver, and understand the role of
cholesterol 7α-hydroxylase in regulating the process.
7. Appreciate the importance of bile acid synthesis not only in the digestion and
absorption of fats but also as a major excretory route for cholesterol.
8. Indicate how secondary bile acids are produced from primary bile acids by intestinal
bacteria.
9. Identify the lifestyle factors that influence plasma cholesterol concentrations and thus
affect the risk of coronary heart disease.
10.Understand that the class of lipoprotein in which cholesterol is carried is important in
determining the effects of plasma cholesterol on atherosclerosis development, with
high levels of VLDL or LDL being deleterious and high levels of HDL being
beneficial.
11.Give examples of inherited and noninherited conditions affecting lipoprotein
metabolism that cause hypo- or hyperlipoproteinemia.

Introduction:
Cholesterol is one of the most highly recognized molecules in human biology, in part
because of a direct relationship between its concentrations in blood and tissues and the
development of atherosclerotic vascular disease. Cholesterol, which is transported in the
blood in lipoproteins because of its absolute insolubility in water, serves as a stabilizing
component of cell membranes and as a precursor of the bile salts and steroid hormones.
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Precursors of cholesterol are converted to ubiquinone, dolichol, and, in the skin, to
cholecalciferol, the active form of vitamin D. As a major component of blood
lipoproteins, cholesterol can appear in its free, unesterified form in the outer shell of these
macromolecules and as cholesterol esters in the lipoprotein core.
Cholesterol (free and esterified with long chain fatty acids) the most abundant steroid in
human tissue ( liver , 0.3% ; skin, 0.3% ; brain and nervous tissues, 2% ; intestine, 0.2% and
adrenal gland, 10% ) and is an extremely important biological molecule that has roles in
membrane structure as well as being a precursor for the synthesis of the steroid hormones,
vitamin D and bile acids. Both dietary cholesterol (500-700 mg/day) and that synthesized
de novo are transported through the circulation in lipoprotein particles (chylomicrones,
VLDL , LDL and HDL) in which cholesterol (free and esterified , the form in which
cholesterol is stored in cells) combined with specific apo-proteins.
The synthesis and utilization of cholesterol must be tightly regulated in order to prevent
over-accumulation and abnormal deposition within the body. Of particular importance
clinically is the abnormal deposition of cholesterol and cholesterol-rich lipoproteins in the
coronary arteries. Such deposition, eventually leading to atherosclerosis, is the leading
contributory factor in diseases of the coronary arteries.

Cholesterol structure , it composed perhydrocyclopentanophenanthrene

nucleus with different methyl, aliphatic side chain and hydroxyl groups.
Biosynthesis of Cholesterol:
Slightly less than half of the cholesterol in the body derives from biosynthesis de novo
(from the beginning) by virtually all tissues in humans, although liver, intestine, adrenal
cortex, and reproductive tissues including ovaries, testes and placenta make the largest
contributions to the body cholesterol pool. The liver plays a central role in the regulation of
the body cholesterol balance which is a series of transport, biosynthetic, and regulatory
mechanism. Biosynthesis in the liver accounts for approximately 10%, and in the intestines
approximately 15%, of the amount produced each day. Cholesterol synthesis occurs in the
cytoplasm and microsomes from the two-carbon acetate group of acetyl-CoA. It was
estimated that nearly 50% of the daily cholesterol production is converted to bile acids and
salts and secreted in bile. Most of this re-absorbed and re-used by way of entero-hepatic
circulation. About 0.5 – 1.0 g/day is used for the biosynthesis of steroid hormones (about
40 mg/day). A small part of cholesterol (about 50 mg/day) in adult is excreted also from
the surface of the skin. Feeding a diet containing 0.5 % cholesterol to an animal results in
a 95% inhibition of hepatic cholesterol biosynthesis. In general , an adult on a low-

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cholesterol diet typically synthesizes about 800 mg of cholesterol/day in the liver cells as a
major site and by the intestinal cells.
The process of cholesterol biosynthesis has five major steps:

1. Three molecules of acetyl-CoA are condensed and converted to 3-hydroxy-3-methyl-

glutaryl-CoA (HMG-CoA).
2. HMG-CoA reductase catalyzed the conversion of HMG-CoA to mevalonate is the
rate –limiting step in cholesterol biosynthesis in which cholesterol act as an allosteric
inhibitor of gene expression of the enzyme, provides rapid feedback control of
cholesterol biosynthesis within cells and also affected by different statin drugs as
competitive inhibitors with mevalonate for bindings to HMG-CoA reductase (e.g.
lovastatin and mevastatin which are used to decease high plasma cholesterol levels).

Metabolic Pathway of Cholesterol Biosynthesis.

3. Mevalonate is converted in several enzymatic steps to the isoprene based molecule,

isopentenyl pyrophosphate (IPP) and is the key five-carbon isoprenoid intermediate in
cholesterol biosynthesis, with the concomitant loss of carbon dioxide. IPP is also
precursors in the synthesis of coenzyme Q (ubiquinone) and dolichol , which function in
the synthesis of carbohydrate side chains in glycoproteins and another important
biomolecules such as vitamin E , K and carotinoids.
4. Squalene, a 30-carbon molecule is formed by several condensation reactions involving
isopentenyl ptrophosphate.

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5. Conversion of Squalene to cholesterol (a 27- carbon molecule) requires several
reactions , some of them with unknown mechanism till now and involved the reducing
equivalent NADPH and molecular oxygen ( mixed – oxygenase system).

The acetyl-CoA utilized for cholesterol biosynthesis is derived from an oxidation reaction
(e.g., fatty acids or pyruvate) in the mitochondria and is transported to the cytoplasm by the
same process as that described for fatty acid synthesis (see the Figure below). Acetyl-CoA
can also be derived from cytoplasmic oxidation of ethanol by acetyl-CoA synthetase. All
the reduction reactions of cholesterol biosynthesis use NADPH as a cofactor. The
isoprenoid intermediates of cholesterol biosynthesis can be diverted to other synthesis
reactions, such as those for dolichol (used in the synthesis of N-linked glycoproteins,
coenzyme Q (of the oxidative phosphorylation) pathway or the side chain of heme a.
Additionally, these intermediates are used in the lipid modification of some proteins.

Pathway for the movement of acetyl-CoA units from within the mitochondrion to the
cytoplasm (citrate shuttle) for use in fatty acid and cholesterol biosynthesis. Note that
the cytoplasmic malic enzyme catalyzed reaction generates NADPH which can be used
for reductive biosynthetic reactions such as those of fatty acid and cholesterol
synthesis.

Regulating Cholesterol Biosynthesis :

Normal healthy adults synthesize cholesterol at a rate of approximately (1.0 g/day) and
consume approximately (0.3 g/day). A relatively constant level of cholesterol in the body
(150 - 200 mg/dL) is maintained primarily by controlling the level of de novo synthesis.
The level of cholesterol synthesis is regulated in part by the dietary intake of cholesterol.
Cholesterol from both diet and synthesis is utilized in the formation of membranes and in
4
the synthesis of the steroid hormones and bile acids (see below). The greatest proportion of
cholesterol is used in bile acid synthesis (50%).
The cellular supply of cholesterol is maintained at a steady level by three distinct
mechanisms:
1. Regulation of HMG-CoA reductase activity and levels.
2. Regulation of excess intracellular free cholesterol through the activity of acyl-CoA :
cholesterol acyltransferase, ACAT.
3. Regulation of plasma cholesterol levels via LDL receptor-mediated uptake and HDL-
mediated reverse transport.
Regulation of HMG-CoA reductase activity is the primary means for controlling the level
of cholesterol biosynthesis. The enzyme is controlled by four distinct mechanisms:
A. Feed-back inhibition,
B. Control of gene expression,
C. Rate of enzyme degradation and
D. Phosphorylation-dephosphorylation.
The activity of HMG-CoA reductase is additionally controlled by the cAMP signaling
pathway. Increases in cAMP lead to activation of cAMP-dependent protein kinase, PKA. In
the context of HMGR regulation, PKA phosphorylates phosphoprotein phosphatase
inhibitor-1 (PPI-1) leading to an increase in its activity. PPI-1 can inhibit the activity of
numerous phosphatases including protein phosphatase 2C and HMG-CoA reductase
phosphatase which remove phosphates from AMPK and HMGR, respectively. This
maintains AMPK in the phosphorylated and active state, and HMGR in the phosphorylated
and inactive state. As the stimulus leading to increased cAMP production is removed, the
level of phosphorylations decreases and that of dephosphorylations increases. The net result
is a return to a higher level of HMGR activity.
Since the intracellular level of cAMP is regulated by hormonal stimuli, regulation of
cholesterol biosynthesis is hormonally controlled. Insulin leads to a decrease in cAMP,
which in turn activates cholesterol synthesis. Alternatively, glucagon and epinephrine,
which increase the level of cAMP, inhibit cholesterol synthesis.
The ability of insulin to stimulate, and glucagon to inhibit, HMG-CoA reductase
activity is consistent with the effects of these hormones on other metabolic pathways. The
basic function of these two hormones is to control the availability and delivery of
energy to all cells of the body.
Long-term control of HMGR activity is exerted primarily through control over the
synthesis and degradation of the enzyme. When levels of cholesterol are high, the level of
expression of the HMGR gene is reduced. Conversely, reduced levels of cholesterol activate
expression of the gene.

5
 Insulin also brings about long-term regulation of cholesterol metabolism by increasing
the level of HMG-CoA reductase synthesis.
The stability of HMG-CoA reductase is regulated as the rate of flux through the
mevalonate synthesis pathway changes. When the flux is high the rate of HMGR
degradation is also high. When the flux is low, degradation of HMGR decreases. This
phenomenon can easily be observed in the presence of the statin drugs.

The Utilization of Cholesterol :

Cholesterol is transported in the plasma predominantly as cholesteryl esters associated
with lipoproteins. Dietary cholesterol is transported from the small intestine to the liver
within chylomicrons. Cholesterol synthesized by the liver, as well as any dietary
cholesterol in the liver that exceeds hepatic needs, is transported in the serum within LDLs.
The liver synthesizes VLDLs and these are converted to LDLs through the action of
endothelial cell-associated lipoprotein lipase. Cholesterol found in plasma membranes can
be extracted by HDLs and esterified by the HDL-associated enzyme LCAT. The
cholesterol acquired from peripheral tissues by HDLs can then be transferred to VLDLs and
LDLs via the action of cholesteryl ester transfer protein (apo-D) which is associated with
HDLs. Reverse cholesterol transport allows peripheral cholesterol to be returned to the liver
in LDLs. Ultimately, cholesterol is excreted in the bile as free cholesterol or as bile salts
following conversion to bile acids in the liver.

Bile Acids Synthesis and Utilization :

The ring structure of cholesterol cannot be metabolized to CO2 and water in humans.
Rather, the intact sterol ring is eliminated from the body by:
1. Conversion to bile acids, which are excreted in feces.
2. Secretion of cholesterol into the bile, which transports it to the intestine
for elimination.
Bile salts are primarily used to emulsify fatty acids and monoacylglycerols and package
them into micelles, along with fat-soluble vitamins, phospholipids and cholesteryl esters,
for re-absorption by villi in the small bowel. The end products of cholesterol utilization are
the bile acids, synthesized in the liver (primary bile acid; cholic and chenodeoxycholic
acid). Bile acids contain 24 carbons with two or three hydroxyl groups and a side chain that
terminates in a carboxyl group. The -COOH has a pKa of about 6, and therefore is not fully
ionized at physiologic pH. The bile acids are amphipathic in that all the -OH groups are in
α- orientation (lie above the plane of the ring) and the methyl group are β- orientation (lie
below the plane of the ring). Therefore, the molecules have both a polar and a non-polar
faces and can acts as emulsifying agents in the intestine, helping to prepare dietary TG and
other lipids for degradation by pancreatic digestive enzymes.

6
 Synthesis of bile acids is one of the predominant mechanisms for the excretion of excess
cholesterol. However, the excretion of cholesterol in the form of bile acids is insufficient to
compensate for an excess dietary intake of cholesterol.

Biosynthesis of the 2 primary bile acids, cholic acid and chenodeoxycholic acid. The
reaction catalyzed by the 7α-hydroxylase is the rate-limiting step in bile acid synthesis
which is ascorbate-dependent enzyme and is inhibited by cholic acid. Conversion of
7α-hydroxycholesterol to the bile acids requires several steps not shown in detail in
this image. Only the relevant co-factors needed for the synthesis steps are shown.
The most abundant bile acids in human bile are chenodeoxycholic acid (45%) and cholic
acid (31%). These are referred to as the primary bile acids. Within the intestines the primary
bile acids are acted upon by bacteria and converted to the secondary bile acids, identified as
deoxycholate (from cholate) and lithocholate (from chenodeoxycholate). Both primary and
secondary bile acids are reabsorbed by the intestines and delivered back to the liver via the
portal circulation.

Structure of the conjugated cholic acids

Within the liver the carboxyl group of primary and secondary bile acids is conjugated via
an amide bond to either glycine or taurine before their being re-secreted into the bile
7
canaliculi. Taurine is an end product of cysteine catabolism. The ratio of the glycine to
taurine forms in the bile is approximately (3:1) and are called bile salts. Bile salts are more
effective detergents than bile acids because of their enhanced amphipathic nature. These
conjugation reactions yield glycoconjugates and tauroconjugates, respectively. Bile acids
are carried from the liver through these ducts to the gallbladder, where they are stored for
future use. The ultimate fate of bile acids is secretion into the intestine, where they aid in
the emulsification of dietary lipids. In the gut the glycine and taurine residues are removed
and the bile acids are either excreted (only a small percentage) or reabsorbed by the gut and
returned to the liver. This process of secretion from the liver to the gallbladder, to the
intestines and finally re-absorption is termed the entero-hepatic circulation. The
following figure indicate an overview of bile salt metabolism.
Clinical Significance of Bile Acid Synthesis:
Bile acids perform four physiologically significant functions:
1. Their synthesis and subsequent excretion in the feces represent the only significant
mechanism for the elimination of excess cholesterol.
2. Bile acids and phospholipids solubilize cholesterol in the bile, thereby preventing
the precipitation of cholesterol in the gallbladder.
3. They facilitate the digestion of dietary triacylglycerols by acting as emulsifying
agents that render fats accessible to pancreatic lipases.
4. They facilitate the intestinal absorption of fat-soluble vitamins.

The movement of cholesterol from the liver into the bile must be accompanied by the
simultaneous secretion of phospholipids and bile salts. If this coupled process is disrupted
and more cholesterol enters the bile than can be solubilized by the bile salts and lecithin
present, the cholesterol may be precipitated in the gallbladder initiating the occurrence of
cholesterol gallstone disease ( the disease is called cholethiasis ).

Lipoprotein Metabolism and Their Clinical Disorders

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 Because lipids are hydrophobic and essentially insoluble in the water of the blood,
cholesterol, cholesterol esters, TGs and phospholipids, must be transported through the
bloodstream packaged as lipoproteins. These macromolecules are water-soluble. Each
lipoprotein particle is composed of a core of hydrophobic lipids such as cholesterol esters
and TGs surrounded by a shell of polar lipids (the phospholipids), which allows a hydration
shell to form around the lipoprotein (see below). This occurs when the positive charge of
the nitrogen atom of the phospholipid (phosphatidylcholine, phosphatidylethanolamine, or
phosphatidylserine) forms an ionic bond with the negatively charged hydroxyl ion of the
environment. In addition, the shell contains a variety of apoproteins that also increase the
water solubility of the lipoprotein. Free cholesterol molecules are dispersed throughout the
lipoprotein shell to stabilize it in a way that allows it to maintain its spherical shape. The
major carriers of lipids are chylomicrons, VLDL, and HDL. Metabolism of VLDL will lead
to IDL and LDL. Metabolism of chylomicrons leads to chylomicron remnant formation.

Through this carrier mechanism, lipids leave their tissue of origin, enter the bloodstream,
and are transported to the tissues, where their components will be either used in synthetic or
oxidative process or stored for later use. The apoproteins not only add structural stability of
the particle but have other functions as well: (1) they activate certain enzymes required for
normal lipoprotein metabolism and (2) they act as ligands on the surface of the lipoprotein
that target specific receptors on peripheral tissues that require lipoprotein delivery for their
innate cellular function.
Therefore, lipoproteins are considered to fall into four major classes:
1. Chylomicrons (the least dense form)
2. VLDL (very low density lipoproteins)
3. LDL (low density lipoproteins
4. HDL (high density lipoproteins)
In addition, there are two minor classes: IDL (intermediate density lipoproteins, which
are intermediate between VLDL and LDL), and chylomicron remnants, which are the
residual protein and lipid after the completion of TG extraction from chylomicrons.
The following table indicate the characteristics of the major lipoproteins.

9
 Lipoproteins classes differ in the relative amounts of lipid and the protein they contain as
shown in the following table. As the lipid: protein ratio decreases, particles become smaller
and more dense in the following order: Chylomicron> VLDL > LDL > HDL.
Whereas, the following table indicate protein content of various lipoprotein
particles:
Lipoprotein Chylomicron VLDL IDL LDL HDL2 HDL3
particle
% Protein 1-2 7-10 10-12 20-22 33-35 55-57
content
Apolipoproteins or apoproteins:
The proteins present in lipoproteins are called apolipoproteins or simply apoproteins.
(The prefix “apo-” means without, with apolipoprotein referring to the protein without the
lipid). Ten principal apoproteins have been characterized. Their tissue source, molecular
mass, distribution within lipoproteins, and metabolic functions are shown in table listed
below. Each class of lipoprotein has a specific function determined by its apolipoprotein
content, its tissue of origin, and the proportion of the macromolecule made up of TGs,
cholesterol esters, free cholesterol, and phospholipids. The apoproteins play a major role in
the regulation of cellular interactions with the lipoproteins. Some apoproteins are permanent
parts of the particles; others are capable of transferring from one lipoprotein to another.
Apoproteins interact with cell surface receptors to allow transport of lipids into cells. In
addition, some of the apoproteins modulate (either activate or inhibit) enzyme activities
related to lipids, and assist in the transfer of the lipids from one lipoprotein to another, or
from the lipoprotein to the cell.
Apoproteins are classified by structure and function into classes from A to H, with most
classes having subclasses as shown in the following table. The Apo-A forms (comprised of
several different gene products) are found in chylomicrons and HDL. The Apo-C forms
(especially Apo-C-II) and Apo-E are found in HDL, VLDL, and chylomicrons; these
apoproteins are released as part of HDL, and are transferred to VLDL and chylomicrons
while in circulation. Apo-B-100 is found in VLDL and LDL, while Apo B-48 is found in
chylomicrons. Apo B-48 is required for secretion of chylomicrons from intestinal mucosa
into the lymphatics and from there into the peripheral circulation ) :-
The following table indicates the characteristics of the major apoproteins.
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Chylomicrons:
Chylomicrons are assembled in the intestinal mucosa as a means to transport dietary
cholesterol and TGs to the rest of the body. Chylomicrons are, therefore, the molecules
formed to mobilize dietary exogenous lipids. The predominant lipids of chylomicrons are
TGs (which contain long chain fatty acids). The apolipoproteins that predominate before
the chylomicrons enter the circulation include apoB-48 and apoA-I, -A-II and IV. ApoB-
48 combines only with chylomicrons (see the figure below which indicate the Molecular
structure of a chylomicron. The surface is a layer of phospholipids, with head groups
facing the aqueous phase. Triacylglycerols sequestered in the interior (yellow) make up
more than 80% of the mass. Several apolipoproteins that protrude from the surface (B-48,
C-III, C-II) act as signals in the uptake and metabolism of chylomicron contents. The
diameter of chylomicrons ranges from about 100 to 500 nm.).

Clinical Significances of Lipoprotein Metabolism:

Fortunately, few individuals carry the inherited defects in lipoprotein metabolism that
lead to hyper- or hypolipoproteinemias (see Tables below for brief descriptions). Persons
11
suffering from diabetes mellitus, hypothyroidism and kidney disease often exhibit
abnormal lipoprotein metabolism as a result of secondary effects of their disorders. Insulin
and thyroid hormones positively affect hepatic LDL-receptor interactions; therefore, the
hypercholesterolemia and increased risk of atherosclerosis associated with uncontrolled
diabetes or hypothyroidism is likely due to decreased hepatic LDL uptake and
metabolism.
A greater complication results from cholesterol deposition within the arteries, leading to
atherosclerosis, the major contributing factor of nearly all cardiovascular diseases.

Plasma Lipids:

Total plasma lipids is 400–600 mg/dl which include the following fractions and are
complexed with apoproteins due to their water insolubility :

Lipid Parameters mg/dl

Total cholesterol, TC 150-220
HDL – cholesterol, male (HDL-C) 30-60
HDL – cholesterol, female 35-75
LDL – cholesterol, 30-39 yr (LDL-C) 80-175
Triacylglycerol, male 50-200
Triacylglycerol, female 40-150
Free fatty acids, FFA 10-20

In peripheral laboratories, a lipid profileorplasma lipids is assessed by estimating the

following fraction in plasma :

1. Total cholesterol ; 2. HDL-cholesterol ; 3. LDL-cholesterol

4. Triglyceride, TG ; 5. Phospholipid.

The sample of serum or plasma should be taken after 12-24 hours of fasting. In normal
person, cholesterol level varies from 150-220 mg/dl. It should be preferably below 200
mg/dl. Concentration between 200-220 mg/dl are deemed borderline ; between 220-240
mg/dl is considered as elevated and above 240 mg/dl has definite risk for heart attack.
According to previous table, HDL has a protective effect on the development of
atherosclerosis. The opposite is true with regard to LDL.

Clinical Application :

Serum cholesterol is increased in the following conditions :

1- Diabetes mellitus, because acetyl-CoA pool is increased and more molecules are
channeled to cholesterol.
2- Obstructive jaundice, where excretion of cholesterol through bile is blocked .
3- Hypothyroidism, where the receptors for HDL on liver cells are decreased, and so
excretion is not effective .
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4- Frederickson's type ll hyperlipoproteinemia which is a hereditary autosomal
dominant condition.
5- In nephritic syndrome, where there is albumin loss through urine, globulins are
increased as a compensatory mechanism. When lipoproteins are increased, cholesterol is
correspondingly increased.

Risk factors for Coronary Artery Diseases ( CAD ):

1. Serum cholesterol value should be preferably below 200 mg/dl. Values around 220
mg/dl will have moderate risk and values above 240 mg/dl indicate active treatment.
2. LDL-cholesterol level: Blood levels under 130 mg/dl are desirable. Levels between 130
and 159 are borderline; while above 160 mg/dl carry definite risk. Hence LDL is
Badcholesterol.
3. HDL-cholesterol level: Levels above 160 mg/dl protects against heart disease. Hence
HDL is Goodcholesterol. A level below 35 mg/dl increases the risk of CAD. For every
1 mg/dl drop in HDL, the risk of heart disease rises 3%. Predictive value is increased
when total cholesterol / HDL ratio is considered ; a ratio more than 3.5 is dangerous.
Similarly, LDL/HDL ratio more than 3.5 is also deleterious.
4. Apoprotein level:Maintenance of A-I / A-II ratio of more than 3 : 1 ensures influx of
cholesterol from cells to liver. Apo A-I is a measure of HDL-C and apo B measure LDL-
C. Apo A-I is the most reliable index with predictive value in patients with cardiac
diseases.
5. Cigarette smoking: Nicotine of cigarette will cause lipolysis and thereby increases the
acetyl CoA and cholesterol synthesis. Nicotine also causes transient constriction of
coronary and carotid arteries. Smoking tobacco causes damage to endothelial cells due
to free radicals present in tobacco smoke. It is estimated that each puff of a cigarette
produces 1014 free radicals. In addition, the resultant lack of oxygen causes damage or
death to neurones, and nicotine and carbon monoxide, both present in tobacco smoke,
cause an increase in blood pressure.
6. Hypertension: Systolic blood pressure more than 160 mm further increases the risk of
CAD. Atherosclerosis may lead to hypertension. Hypertension causes damage to
endothelial cells due to the shear stress as the blood flows through the arteries, especially
at positions where arteries branch.
7. Diabetes Mellitus: In the absence of insulin, hormone sensitive lipase is depressed,
more free fatty acids are formed, these are catabolised to produce acetyl CoA. These
cannot readily utilized, as the availability of oxaloacetate is reduced and citric acid cycle
is sluggish. So acetyl CoA pool is increased, and are channeled into cholesterol
synthesis.Glycation of LDL prolonged its half-life. Oxidized LDL is taken up by non-
specific endocytosis, and further leading to atherosclerosis.
8. Serum Triglyceride level : Normal level is 50 – 200 mg/dl. Blood level more than 200
mg/dl is injurious to health.
9. Homocysteine level : An increase of 5 micromole/L of homocysteine in serum elevates
coronary artery risk by as much as cholesterol increase of 20 mg/dl.

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