Take up one idea.

Make that one idea your life - think of

it, dream of it, live on idea.

Let the brain, muscles, nerves, every

part of your body, be full of that idea,
and just leave every other idea alone.

This is the way to success. 1

Cholesterol , the most feared
among lipids, speaks:

“Consumed through
diet and produced in the
body;
Participate in innumerable
cellular functions;
And blamed I am, for no fault of
mine’’ 2
 CHOLESTEROL METABOLISM

Biosynthesis of cholesterol
About 1 gm of cholesterol is synthesized in the
body per day.
Site
 All nucleated cells particularly
 liver, adrenal cortex, testis, ovaries, brain,
placenta, aorta and skin.
 The enzymes are present in microsomes and
cytosol of the cells.
3
 Precursors
Acetyl-CoAs generated from the break down of
carbohydrates, fats and aminoacids act as
precursors of cholesterol.
 Acetyl-CoAs are transported from mitochondria
to cytosol by similar mechanism described for
fatty acid biosynthesis.
 HMP shunt generates NADPH required for
cholesterol synthesis.
 For the production of one mole of cholesterol, 18
moles of acetylCoA, 36 moles of ATP and 16
moles of NADPH are required. 4
 The synthesis of cholesterol may be learnt in 5 stages

1. Synthesis of HMG CoA

2. Formation of mevalonate (6C)
3. Production of isoprenoid units (5C)
4. Synthesis of squalene (30C)
5. Conversion of squalene to cholesterol (27C)

5
 1. Synthesis of β-hydroxy β –methylglutaryl
CoA (HMG CoA)
 Two moles of acetyl CoA condense to form acetoacetyl CoA.
 Another molecule of acetyl CoA is then added to produce HMG
CoA.
 These reactions are similar to that of ketone body synthesis.
 However, the two pathways are distinct, since ketone bodies are
produced in mitochondria while cholesterol synthesis occurs in
cytosol.
 Thus, there exist two pools of HMG CoA in the cell.
 Further, two isoenzymes of HMG CoA synthase are known.
 The cytosomal enzyme is involved in cholesterol synthesis
whereas the mitochondrial HMG CoA synthase participates in
ketone body formation. 6
2. Formation of mevalonate
 HMG CoA reductase is the rate limiting enzyme in
cholesterol biosynthesis.
 This enzyme is present in endoplasmic reticulum and
catalyses the reduction of HMG CoA to mevalonate.
 The reducing equivalents are supplied by NADPH.
3. Production of isoprenoid units
 In a three step reaction catalysed by kinases, mevalonate
is converted to 3-phospho 5-pyrophospho-mevalonate
which on decarboxylation forms isopentenyl
pyrophosphate (IPP).
 The latter isomerizes to dimethylallyl pyrophosphate
(DPP).
 Both IPP and DPP are 5-carbon isoprenoid units. 7
4. Synthesis of squalene
IPP and DPP condense to produce a 10-carbon
geranyl pyrophosphate( GPP).
Another molecule of IPP condenses with GPP to
form a 15-carbon farnesyl pyrophosphate (FPP).
 Two units of farnesyl pyrophosphate unite and
get reduced to produce a 30-carbon squalene

8
 5. Conversion of squalene to cholesterol

 Squalene undergoes hydroxylation and cyclization utilizing O2 and

NADPH and gets converted to lanosterol.
 The formation of cholesterol from lanosterol is a multi step
process with a series of about 19 enzymatic reactions.
 The following are the most important reactions

9
 The enzymes (about 19?) involved in the
conversion of lanosterol to cholesterol are
associated with endoplasmic reticulum.
 14-Desmethyl lanosterol, zymosterol,
cholestadienol and desmosterol are among the
intermediates in the cholesterol biosynthesis.
 The penultimate product is 7-dehydrocholesterol
which, on reduction, finally yields cholesterol.

10
11
12
13
14
 Immediate fate of endogenous cholesterol

1. Cholesterol synthesized with in the cells is either

esterified or released as free cholesterol.
2. In the liver and intestine dietary cholesterol is
esterified.
3. The esterification of cholesterol in the liver or
intestine or extrahepatic tissues is catalyzed by
Acyl-CoA-cholesterol acyl transferase (ACAT),
which is an intracellular enzyme.
Fatty acid is esterified to the OH group of
3-carbon of cholesterol. 15
 Transport of cholesterol

 Cholesterol is present in the plasma lipoproteins in two

forms
1. About 70-75% of it is in an esterified form with long
chain fatty acids.
2. About 25-30% as free cholesterol.
 This form of cholesterol readily exchanges between
different lipoproteins and also with the cell
membranes.

Role of LCAT : High density lipoproteins (HDL) and the

enzyme lecithin-cholesterol acyltransferase (LCAT) are
responsible for the transport and elimination of
cholesterol from the body. 16
 LCAT is a plasma enzyme, synthesized by the liver.
 It catalyses the transfer of fatty acid from the second
position of phosphatidyl choline (lecithin) to the hydroxyl
group of cholesterol.
 HDL-cholesterol is the real substrate for LCAT and this
reaction is freely reversible.
 LCAT activity is associated with apo-A1 of HDL.
 The cholesterol( cholesteryl) ester forms an integral part of
HDL.
 In this manner, the cholesterol from the peripheral tissues
is trapped in HDL, by a reaction catalysed by LCAT and
then transported to liver for degradation and excretion.
 This mechanism is commonly known as reverse
cholesterol transport. 17
Dietary and hepatic cholesterol transport

18
Extra hepatic tissue cholesterol transport. (Reverse
cholesterol transport)

19
Summary of major sources of liver cholesterol and its
utilization( values given in brackets are variable)

20
 Regulation of cholesterol synthesis
Cholesterol biosynthesis is controlled by the rate
limiting enzyme HMG CoA reductase at the
beginning of the pathway.
 HMG CoA reductase is found in association with
endoplasmic reticulum, and is subjected to
different metabolic controls.
1. Feedback control
2. Hormonal regulation
3. Inhibition by drugs

21
 1. Feedback control

 The end product cholesterol controls its own

synthesis by a feedback mechanism.
 Increase in the cellular concentration of
cholesterol reduces the synthesis of the enzyme
HMG CoA reductase.
 This is achieved by decreasing the transcription
of the gene responsible for the production of
HMG CoA reductase.

22
 2. Hormonal regulation
 The enzyme HMG CoA reductase exists in two
interconvertible forms.
 The dephosphorylated form of HMG CoA reductase is more
active while the phosphorylated form is less active.
 The hormones exert their influence through cAMP by a series
of reactions which are comparable with the control of the
enzyme glycogen synthase.
 The net effect is that glucagon and glucocorticoids favour the
formation of inactive HMG CoA reductase (phosphorylated
form) and, thus, decrease cholesterol synthesis.
 On the other hand, insulin and thyroxine increase
cholesterol production by enhancing the formation of active
HMG CoA reductase (dephosphorylated form).
23
Regulation of cholesterol synthesis

24
 3. Inhibition by drugs :
The drugs compactin and lovastatin
(mevinolin) are fungal products.
They are used to decrease the serum cholesterol level in
patients with hypercholesterolemia.
Compactin and lovastatin are competitive inhibitors
of the enzyme HMG CoA reductase and, therefore,
reduce cholesterol synthesis.
About 50 to 60% decrease in serum cholesterol level has
been reported by a combined use of these two drugs.

4. HMG CoA reductase activity is inhibited by bile

acids. Fasting also reduces the activity of this enzvme.
25
 Catabolism of cholesterol

 Humans lack enzyme system which can break

steroid nucleus of cholesterol.
 The steroid nucleus (ring structure) of the
cholesterol cannot be degraded to CO2 and H2O.
 Cholesterol (50%) is converted to bile acids
(excreted in feces), serves as a precursor for the
synthesis of steroid hormones, vitamin D,
coprostanol and cholestanol.
 The latter two are the fecal sterols, besides
cholesterol
26
 l. Synthesis of bile acids

 The bile acids possess 24 carbon atoms, 2 or 3 hydroxyl groups in the steroid nucleus
and a side chain ending in carboxyl group.
 The bile acids are amphipathic in nature since they possess both polar and non-polar
groups.
 They serve as emulsifying agents in the intestine and actively participate in the
digestion and absorption of lipids.
 The synthesis of primary bile acids takes place in the liver and involves a series of
reactions .
 The step catalysed by 7 a-hydroxylase is inhibited by bile acids and this is the rate
limiting reaction.
 Cholic acid and chenodeoxycholic acid are the primary bile acids and the
 Former is found in the largest amount in bile.
 On conjugation with glycine or taurine, conjugated bile acids (glycocholic acid,
taurocholic acid etc.) are formed which are more efficient in their function as
surfactants.
 In the bile, the conjugated bile acids exist as sodium and potassium salts which are
known as bile salts.
 In the intestine, a portion of primary bile acids undergoes deconjugation and
dehydroxylation to form secondary bile acids (deoxycholic acid and lithocholic acid). 27
These reactions are catalysed by bacterial enzymes in the intestine.
Formation of bile acids

28
 Enterohepatic circulation

 The conjugated bile salts synthesized in the liver accumulate in gall

bladder.
 From there they are secreted into the small intestine where they serve
as emulsifying agents for the digestion and absorption of fats and fat
soluble vitamins.
 A large portion of the bile salts (primary and secondary) are
reabsorbed and returned to the liver through portal vein.
 Thus the bile salts are recycled and reused several times in a day.
 This is known as enterohepatic circulation.
 A bout 15- 30 g of bile salts are secreted into the intestine each day
and reabsorbed.
 However, a small portion of about 0.5 g/day is lost in the feces.
 An equal amount (0.5 g/day) is synthesized in liver to replace the lost
bile salts.
 The fecal excretion of bile salts is the only route for the removal of 29
Overview of bile salt metabolism.

Enterohepatic circulation 30
 Cholelithiasis
 Bile salts and phospholipids are responsible for keeping the
cholesterol in bile in a soluble state.
 Due to their deficiency (particularly bile salts), cholesterol crystals
precipitate in the gall bladder often resulting in cholelithiasis-
cholesterol gall stone disease.
 Cholelithiasis may be due to defective absorption of bile salts
from the intestine, impairment in liver function, obstruction of
biliary tract etc.
 The patients of cholelithias is respond to the administration of bile
acid chenodeoxy cholic acid, commonly known as chenodiol.
 It is believed that a slow but gradual dissolution of gall stones
occurs due to chenodiol.
 For severe cases of cholelithiasis, surgical removal of gall bladder
is the only remedy 31
 Other catabolic fates of cholesterol

1. Another important catabolic fate of cholesterol

relates to steroid hormones.
2. Steroid hormones are synthesized in various
tissues using cholesterol as starting material.
Finally, they are excreted in urine after
conjugation.

32
 Formation of Steroid Hormones
1. Five classes of steroid hormones are synthesized from
cholesterol.
They are progesterone, testosterone, cortisol, aldosterone
and estradiol.
2. Corpus luteum and placenta synthesizes progesterone.
Testis and ovaries produce testosterone and estradiol.
Adrenal cortex produces aldosterone and cortisol.
3. NADPH is another important substance needed for
steroid hormone formation.
Fecal sterols
 A small amount of cholesterol present in bile is converted to
coprostanol and cholestanol by the intestinal bacteria and they
are excreted in feces as fecal sterols. 33
 Medical Importance of
cholesterol metabolism

 In healthy individuals, the total plasma cholesterol is in the

range of 150-200 mg/dl.
 In the new born, it is less than 100 mg/dl and rises to about
150 mg/dl within an year.
 The women have relatively lower plasma cholesterol which
is attributed to the hormones-estrogens.
 Cholesterol level increases with increasing age ( in women
particularly after menopause), and also in pregnancy.
 Plasma cholesterol is associated with different
lipoprotein fractions (LDL, VLDL and HDL)
34
 Medical Importance of cholesterol metabolism …..
 In adults,the normal LDL-cholesterol is about 80-
150 mg/dl while HDL-cholesterol is around 30-
60 mg/dl.
 Elevation in plasma HDL cholesterol is
beneficial to the body, since it protects the body
from atherosclerosis and coronarv heart diseases
(CHD).
 On the other hand, increase in LDL-cholesterol
is harmful to the body as it may lead to
various complications, including CHD.
35
Lipid profile reference values

36
You cannot escape the responsibility
of tomorrow by escaping it today
Abraham Lincoln

Worry does not empty tomorrow of

its sorrow. It empties today of its
strength.
Corrie Ten Boom

37
You cannot escape the responsibility
of tomorrow by escaping it today
Abraham Lincoln

Worry does not empty tomorrow of

its sorrow. It empties today of its
strength.
Corrie Ten Boom

38
Factors affecting plasma cholesterol

1. It increases with age

2. Physical activity
3. Life style
4. Dietary fat
5. Smoking
6. Genetic factors

39
 Hyper cholesterolemia

Increase in plasma cholesterol (> 200 mg/dl)

concentration is known as hypercholesterolemia
and is observed in many disorders .
Atherosclerosis,
Coronary Artery Disease,
Diabetes,
Xanthomatosis,
Nephrotic Syndrome,
Hypothyroidism And Obstructive Jaundice 40
 Hyper cholesterolemia and incidence of
coronary artery disease
• Though there are many lipids in plasma relative
risk of developing Coronary Artery Disease
(CAD) is related to raised plasma cholesterol
level.
• However, the most useful index of
coronary artery disease incidence is LDL:HDL
cholesterol ratio.
This ratio is used to predict incidence of
coronary disease.
41
Control of hypercholesterolemia

Several measures are advocated

to lower the plasma cholesterol
level.
1. Consumption of PUFA :
 Dietary intake of PUFA reduces the plasma
cholesterol level.
 PUFA will help in transport of cholesterol by LCAT
mechanism and its excretion from the body.
 The oils with rich PUFA content include cottonseed
oil, soyabean oil, sunflower oil, corn oil, fish oils
etc.

42
2. Dietary cholesterol : Cholesterol is
found only in animal foods and not in
plant foods.
 Dietary cholesterol influence on plasma
cholesterol is minimal.
 However, avoidance of cholesterol-rich foods is advocated to
be on the safe side.
3. Plant sterols : Certain plant sterols and their esters
(e.g. sitostanoel sters) reduce plasma cholesterol levels.
 They inhibit the intestinal absorption
of dietary cholesterol.
4. Dietary fiber : Fiber present in
vegetables decreases the cholesterol
absorption from the intestine.
43
5. Avoiding high carbohydrate diet :
Diets rich in carbohydrates
(particularly sucrose) should be
avoided to control hypercholesterolemia.
6. Impact of lifestyles : Elevation in plasma
cholesterol is observed in people with
Smoking, Abdominal Obesity,
Lack Of Exercise, Stress,
High Blood Pressure, Consumption of soft water
etc.
Therefore, adequate changes in the lifestyles will
bring down plasma cholesterol. 44
Impact of lifestyles

45
7. Moderate alcohol cosumption :
The beneficial effects of moderate alcohol
intake are masked by the ill effects of
chronic alcoholism.
Red wine is particularly beneficial due to its
antioxidants, besides low alcohol content.

46
 Cholesterol lowering drugs
(Hypocholesterolemic drugs)

 Since raised cholesterol level is associated with

development of coronary artery disease, several
drugs are used to lower blood cholesterol level.
 Lowering of plasma cholesterol level decreases
incidence of coronary artery disease.
 For example, at the age of 40, a decrease in
blood cholesterol level from 250 to 200mg%
lowers incidence of coronary artery disease by
50%. 47
1. Lovastatin (Mevinolinate) : It is a competitive
inhibitor of HMG-CoA reductase.
It reduces plasma cholesterol level with minimal side
affects.
Compactin or mevastatin is another competitive
inhibitor.
2. Nicotinic acid : It decreases plasma cholesterol by
interfering with the mobilization of free fatty acids.
3. Neomycin : It interferes with bile acid re-absorption
and absorption of dietary cholesterol.
As a result, elimination of cholesterol is more from
the body. This leads to decrease in plasma
cholesterol level.
48
4. Probucol : It also decreases blood cholesterol
level by increasing excretion of cholesterol and
bile acids.
5. Cholesteramine (Questran) : It lowers blood
cholesterol level by decreasing re-absorption of
bile acids.
6. Clofibrate (Astromid-S): It blocks cholesterol
formation in liver and increases excretion of
cholesterol and bile acids.
 As a result, blood cholesterol level is
decreased.
49
7. Dextro thyroxine (D-thyroxine)
It lowers blood cholesterol level by accelerating
cholesterol catabolism thereby increasing fecal
cholesterol excretion.
8. β-Sitosterol It is a plant sterol.
It decreases blood cholesterol by blocking
absorption of dietary cholesterol.
9. Plant lectins and gums
They lower blood cholesterol level by
interfering with absorption of cholesterol and
bile acids.
50
 Guava

10. Consumption of this tropical fruit for

three months bring down plasma
cholesterol
from 250 mg% to 200 mg%.

51
 Hypocholesterolemia

Plasma cholesterol level is decreased in

• Hyper Thyroidism,
• Liver Disease,
• Malabsorption Syndrome And
• Hemolytic Anaemia.

52
 FATTY LIVER
 The normal concentration of lipid (mostly phospholipid) in liver is
around 5%.

 In Liver is not a storage organ for fat unlike adipose tissue.
the normal
 However, in certain conditions lipids especially the TGLs accumulate
liver, Kupffer
excessively
cells contain in liver, resulting in fatty liver.
lipids
fattyinliver,
the droplets of triacylglycerols are found in the entire cytoplasm
of hepatic
form of cells.
droplets.
This causes impairment in metabolic functions of liver.
 In Fatty liver is associated with fibrotic changes and cirrhosis
 Fatty liver may occur due to two main causes.
1. Increased synthesis of triacylglycerols
2. Impairment in lipoprotein synthesis

53
 1. Increased triacylglycerol synthesis

• Mobilization of free fatty acids from adipose tissue

and their influx into liver is much higher than their
utilization.
• This leads to the overproduction of triacylglycerols
and their accumulation in liver.
• Diabetes mellitus, starvation, alcoholism and high
fat diet are associated with increased mobilization of
fatty acids that often cause fatty liver.
• Alcohol also inhibits fatty acid oxidation and, thus,
promotes fat synthesis and its deposition.
54
 2. Impaired synthesis of lipoproteins
• The synthesis of very low density lipoproteins( VLDL) actively takes place
in liver.
• VLDL formation requires phospholipids and apoprotein B.
• Fatty liver caused by impaired lipoprotein synthesis may be due to :
 a defect in phospholipid synthesis;
 a block in apoprotein formation
 a failure in the formation/secretion of lipoprotein.
• Among the three causes, fatty liver due to impairment in phospholipid
synthesis has been studied in some detail.
• This is usually associated with the dietary deficiency of lipotropic factors
such as choline, betaine, inositol etc.
• Deficiency of essential fatty acids leads to a decreased formation of
phospholipids.
• Excessive consumption of cholesterol competes with essential fatty acids
and impairs phospholipid synthesis.
55
 Certain chemicals (e.g. puromycin, ethionine,
carbon tetrachloride, chloroform, lead,
phosphorus etc.) that inhibit protein synthesis
cause fatty liver.
 This is due to a blockade in the synthesis of
apoprotein B required for VLDL production.

 Endocrine factors : Certain hormones like ACTH,

insulin, thyroid hormones, adrenocorticoids
promote depositon of fat in liver.

56
Development of
Fatty Liver

57
Fatty Liver

58
Fatty Liver

59
 Atherosclerosis
 Atherosclerosis is a complex disease characterized by thickening
or hardening of arteries due to the accumulation of lipids
(particularly cholesterol, free, and esterified) collagen, fibrous
tissue, proteoglycans, calcium deposits etc. in the inner arterial
wall.
 Atherosclerosis is a progressive disorder that narrows and
ultimately blocks the arteries.
 Infarction is the term used to indicate the stoppage of blood flow
resulting in the death of affected tissue.
 Coronary arteries-the arteries supplying blood to heart-are
the most commonly affected, leading to myocardial infarction
or heart attacks.
 The incidence of atherosclerosis and coronary heart diseases
are higher in developed countries (e.g. USA, U.K.) than in the 60
 Causes of atherosclerosis and CHD
 The development of atherosclerosis and the risk for the coronary heart
disease (CHD) is directly correlated with plasma cholesterol and LDL.
 On the other hand, plasma HDL is inversely correlated with CHD.
Disorders that may cause atherosclerosis
 Certain diseases are associated with atherosclerosis. These include :
 Diabetes Mellitus,
 Hyperlipoproteinemias,
 Nephrotic Syndrome,
 Hypothyroidism etc.
 Many other factors like Obesity, High Consumption Of Saturated
Fat, Excessive Smoking, Lack Of Physical exercise, hypertension,
stress etc., are the probable causes of atherosclerosis

61
ANATOMIC AND BIOCHEMICAL ASPECTS OF
ATHEROSCLEROSIS

62
63
64
65