Synthesis and catabolism of cholesterol; cholesterol and coronary artery disease

1. Metabolism of Cholesterol
R. C. Gupta
Professor and Head
Department of Biochemistry
National Institute of Medical Sciences
Jaipur, India

2. Cholesterol can be synthesized only by
animals
It is present in all animal cells
It circulates in blood as a component of
various lipoproteins

3. Cholesterol serves many important functions
It is required for the formation of membranes,
steroid hormones, vitamin D3, bile salts etc
An excess of cholesterol in the body can be
harmful as it promotes atherosclerosis

4. Cholesterol is both taken in diet and is
synthesized in the body
Endogenous synthesis is inversely
related to the dietary intake
A high intake decreases the endogenous
synthesis

5. The major sites for cholesterol synthesis
in human beings are liver, skin and
intestinal mucosa
All the reactions occur in cytosol except
for a hydroxylation reaction which occurs
in endoplasmic reticulum

6. Acetyl CoA provides all the carbon atoms
for cholesterol synthesis
ATP is required as a source of energy
NADPH, molecular oxygen and micro-
somal hydroxylase system are required
for a hydroxylation reaction

7. A carrier protein is required to bind some
of the intermediates
The carrier protein is ‘squalene and sterol
carrier protein’

8. The reactions of cholesterol synthesis
can be divided into four stages:
• Conversion of acetyl CoA into six-
carbon compound, mevalonate
• Conversion of mevalonate into five-
carbon isoprenoid units
• Conversion of six isoprenoid units into a
30-carbon compound, squalene
• Conversion of squalene into cholesterol

9. Two molecules of acetyl CoA react to form
acetoacetyl CoA
Another acetyl group is added to form b-
hydroxy-b-methylglutaryl CoA (HMG CoA)
HMG CoA is reduced to mevalonate
Reactions of the first stage

11. Mevalonate undergoes three successive
phosphorylations to form mevalonate-3-
phospho-5-pyrophosphate
The latter is converted into two types of
isoprenoid units
The units are isopentenyl pyrophosphate
and 3,3-dimethyl allyl pyrophosphate
Reactions of the second stage

13. Two isoprenoid units form geranyl pyro-
phosphate, a 10-carbon compound
Geranyl pyrophosphate and one isoprenoid
unit form15-carbon farnesyl pyrophosphate
Two molecules of farnesyl pyrophosphate
form 30-carbon squalene
Reactions of the third stage

15. Squalene is oxidized to squalene oxide
Squalene oxide is cyclized to lanosterol
By a series of reactions, lanosterol is
converted into cholesterol
Reactions of the fourth stage

17. HMG CoA reductase (HMGR) is the
regulatory enzyme
It is regulated by multiple mechanisms
Both the activity and the amount of the
enzyme can be regulated
Regulation

18. HMG CoA reductase exists in a:
▪ Dephosphorylated form (active)
▪ Phosphorylated form (inactive)
AMP-activated protein kinase (AMPK)
phosphorylates the enzyme
Protein phosphatase 1 (HMGR phos-
phatase) dephosphorylates the enzyme

19. Activity of protein phosphatase 1 (PP1) is
regulated by protein kinase A
Protein kinase A (PKA) is activated by
cAMP
Thus, hormones that affect cAMP concen-
tration regulate cholesterol synthesis

20. Glucagon increases cAMP concentration,
and activates PKA
PKA phosphorylates a regulatory subunit of
protein phosphatase 1
This results in inhibition of protein
phosphatase 1
HMGR remains inactive and cholesterol
synthesis is decreased

21. Insulin causes a decrease in cAMP
concentration
As a result, PKA remains inactive; protein
phosphatase 1 is not inhibited
Protein phosphatase 1 dephosphorylates
inactive HMGR to its active form
Cholesterol synthesis is increased

23. Cholesterol synthesis is also regulated by
repression and derepression
Excess of cholesterol represses the
synthesis of HMG CoA reductase
This decreases cholesterol synthesis
Decreased cholesterol level derepresses
the synthesis of HMG CoA reductase

24. HMGR contains a sterol-sensing domain
(SSD) which monitors sterol level in the cell
Increased sterol levels cause ubiquitination
of HMGR
Ubiquitinated HMGR is rapidly degraded by
proteasome
This decreases cholesterol synthesis

25. The entry of cholesterol into cells is also
precisely regulated
LDL is the major carrier of cholesterol
to extra-hepatic tissues
LDL is taken up by the cells with the help
of LDL receptors

26. LDL receptors are present on the cell
membrane
Binding of LDL to its receptor is followed
by receptor-mediated endocytosis
Both LDL and its receptor enter the
cell

27. As LDL enters the cell, the number of LDL
receptors on the cell decreases
Thus, the receptor is down-regulated
Downregulation of the receptor decreases
further entry of LDL in the cell

28. The major pathway for catabolism of
cholesterol is its conversion into bile acids
and bile salts in liver
Cholesterol is first converted into 7-a-
hydroxycholesterol by 7-a-hydroxylase
7-a-Hydroxylase is a part of microsomal
hydroxylase system
Catabolism of cholesterol

30. Most of the 7-a-hydroxycholesterol
is converted into cholic acid
Cholic acid can combine with:
Glycine to form glycocholic acid
Taurine to form taurocholic acid

31. Some of the 7-a-hydroxycholesterol is
converted into chenodeoxycholic acid
This can combine with glycine to form
glycochenodeoxycholic acid
It can combine with taurine to form tauro-
chenodeoxycholic acid

33. Glycocholic acid, taurocholic acid, glyco-
chenodeoxycholic acid and taurocheno-
deoxycholic acid are primary bile acids
Their Na+ and K+ salts are known as bile
salts
Bile salts are formed in liver, and are
excreted through bile into the intestine

34. Most of the bile salts entering the
intestine are reabsorbed into portal blood
These are brought to liver, and are re-
excreted into the intestine by the liver
This is known as enterohepatic circulation
of bile salts

35. Intestinal bacteria convert unabsorbed bile
salts into secondary bile acids and sterols
Deoxycholic acid and lithocholic acid are the
main secondary bile acids
Coprostanol is the main sterol formed from
bile salts
These are excreted in the faeces

37. Atherosclerosis is a condition in which
cholesterol and some other substances are
deposited in the walls of blood vessels
Lumen of the affected vessel is narrowed
This impedes blood flow and decreases the
supply of blood to the affected organ
Serum lipids and atherosclerosis

38. Lumen of
artery
Atherosclerotic
plaques

39. Coronary arteries are affected most
commonly leading to coronary artery
disease (CAD)
Involvement of cerebral arteries causes
cerebral thrombosis
Arteries supplying blood to lower limbs
may be affected resulting in peripheral
vascular disease

40. Risk of CAD is increased by a number of
conditions and habits
These conditions and habits are known
as coronary risk factors
Some of the coronary risk factors are
modifiable but others are not

41. The modifiable coronary risk factors
include:
• Dyslipidaemia
• High blood pressure
• Diabetes mellitus
• Obesity
• Smoking
• Lack of physical activity
• Unhealthy diet
• Stress

42. The association between dyslipidaemia
and CAD has been proved in many studies
There is a positive correlation between
high serum cholesterol and CAD
The risk is modestly increased by elevated
serum triglycerides

43. Cholesterol is present in plasma mainly in
LDL and HDL
It is elevated LDL-cholesterol which
increases the risk of CAD
High HDL-cholesterol has a protective
effect

44. Serum lipids ‒ desirable, borderline risk and high risk
levels
≥ 240High
risk
Borderline
risk
Desirable
Trigly-
cerides
(mg/dl)
LDL
cholesterol
(mg/dl)
HDL
cholesterol
(mg/dl)
Total
cholesterol
(mg/dl)
<200 ˃ 60 (females)
˃ 50 (males)
200-239 50-60 (females)
40-50 (males)
˂ 50 (females)
˂ 40 (males)
<100
100-159
≥ 160
<150
150-199
≥ 200

45. Measurements of apo A-I and apo B in
plasma may also be informative
A rise in apo B level indicates an
increased risk of CAD
A rise in apo A-I indicates a decreased
risk

46. Lp (a) is another risk factor for CAD
It is an abnormal variant of LDL
Lp (a) is formed when apo (a) forms a
disulfide bond with apo B-100 of LDL
Apo (a) is an apolipoprotein having a
structural resemblance with plasminogen

47. Apo (a) competes with plasminogen for
binding to fibrin
It decreases fibrinolysis
Some people have an elevated level of
plasma Lp (a)
Levels above 30 mg/dl increase the risk
of premature CAD

48. Control of coronary risk factors requires:
Dietary
measures
Pharmacological
measures

49. The dietary measures to control
coronary risk factors include:
Reduction in fat intake
Reduction in cholesterol intake
Replacement of SFA with PUFA
Dietary measures

50. Pharmacological measures include use of
drugs that decrease serum cholesterol
Common hypocholesterolaemic drugs are:
(i) bile acid-binding resins, (ii) nicotinic acid
and (iii) inhibitors of HMG CoA reductase
A fourth class, fibric acid derivatives, is more
effective in reducing serum triglycerides
Pharmacological measures

51. Bile acid-binding resins include colestipol
and cholestyramine
They bind bile acids in the intestine
preventing their reabsorption
Enterohepatic circulation of bile acids is
interrupted

52. Decreased reabsorption necessitates
increased synthesis of bile acids from
cholesterol in the liver
Thus, more cholesterol is diverted to bile
acid synthesis resulting in a decrease in
serum cholesterol level

53. Nicotinic acid (niacin) in large doses
decreases the level of serum cholesterol
Mechanism of action of nicotinic acid is
unclear
It decreases the secretion of lipoproteins
containing apo B-100 from liver

54. Statin family of drugs competitively
inhibits HMG CoA reductase
This decreases endogenous synthesis of
cholesterol
Statins are the most effective hypo-
cholesterolaemic drugs
They also cause a modest decrease in
serum triglycerides

55. Lovastatin and mevastatin are the oldest
members of the statin family
The newer members include atorvastatin,
fluvastatin, simvastatin etc

56. Fibric acid derivatives include clofibrate,
fenofibrate, gemfibrozil etc
They activate lipoprotein lipase which
hydrolyses the triglycerides present in the
lipoproteins
VLDL and triglyceride concentrations are
decreased
Cholesterol is modestly decreased