Metabolism of Cholesterol
Objective
•
At the end of this lecture, student will be able to
–
Explain regulation of cholesterol synthesis
–
Explain cholesterol
degradation
–
Describe
the cause, risk factors and control of Hypercholesterolemia
Metabolism of Cholesterol
•
Cholesterol is found exclusively in animals, hence
it is often called as animal sterol
•
The total body content of cholesterol in adult 140
mg/dl around 2g /kg body weight
•
Cholesterol is amphipathic in nature, since it
possesses both hydrophilic and hydrophobic regions in the structure
Function of cholesterol
Cholesterol is essential to life – important functions are
•
It is the structural component of cell membrane
•
Cholesterol is the precursor for the synthesis of
all other steroids in the body. These include steroid hormones, vitamin D and
bile acids
•
Essential ingredient in the structure of
lipoproteins in which form the lipids in the body are transported
•
Fatty acids are transported to liver as cholesteryl
esters for oxidation
Cholesterol Biosynthesis
•
About 1 g of cholesterol is synthesized per day in
adults
•
Almost all the tissues of the body participate in
cholesterol biosynthesis
•
Enzymes involved in cholesterol synthesis are found
in the cytosol and microsomal fractions of the cell
•
For the production of one mole of cholesterol, 18
moles of acetyl CoA, 36 moles of ATP and 16 moles of NADPH are required
•
The synthesis of cholesterol may be carried out 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)
Regulation of cholesterol
synthesis
•
Cholesterol biosynthesis is controlled by the rate
limiting enzyme HMG CoA reductase
1. Feedback
control:
•
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
↑
cholesterol level → ↓ HMG CoA reductase activity
↓
cholesterol level → ↑ HMG CoA reductase activity
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
•
Glucagon and glucocorticoids favour the formation of
inactive HMG CoA reductase (phosphorylated form) hence decrease cholesterol
synthesis
•
Insulin and thyroxine increase cholesterol
production by enhancing the formation of active HMG CoA reductase
3.
Inhibition by drugs:
•
Drugs like compactin and lovastatin are fungal
products, used to decrease the serum cholesterol level in patients with
hypercholesterolemia
•
It competitively inhibits HMG CoA reductase and
↓cholesterol synthesis
4. HMG
CoA reductase activity is inhibited by bile acids
•
Fasting also reduces the activity of this enzyme
Degradation of Cholesterol
•
Cholesterol cannot be degraded to CO2
& H2O.
•
Cholesterol (50%) is converted to bile acids
(excreted in faeces)
•
Serves as a precursor for the synthesis of steroid
hormones & vitamin D
Synthesis of bile acids
•
Bile acids possess 24 carbon atoms, 2 or 3 hydroxyl
groups in the steroid nucleus and a side chain ending in carboxyl group
•
Bile acids are amphipathic in nature since they
possess both polar and non-polar groups
•
Serve as emulsifying agents in the intestine and
actively participate in digestion & absorption of lipids
•
The synthesis of primary bile acids takes place in
the liver
•
7-α-hydroxylase is inhibited by bile acids and it is
the rate limiting reaction
•
Primary bile
acids are Cholic acid and Chenodeoxycholic acid
•
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, portion of primary bile acids undergoes
deconjugation and dehydroxylation to form secondary bile acids (deoxycholic
acid and lithocholic acid), catalysed by bacterial enzymes in the intestine
Enterohepatic circulation
•
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 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
•
About 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.
•
This is the only route for the removal of
cholesterol from the body
Cholelithiasis
•
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 cholelithiasis respond to the
administration of bile acid chenodeoxy cholic acid, commonly known as
chenodiol.
•
lt 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
Synthesis of steroid Hormones
from cholesterol
Cholesterol is the precursor for the synthesis of 5 classes of steroid
hormones
1. Glucocorticoids (e.g. cortisol)
2. Mineralocorticoids (e.g. aldosterone)
3. Progestins (e.g. progesterone)
4. Androgens (e.g. testosterone)
5. Estrogens (e.g. estradiol)
Synthesis
of vitamin D
Cholesterol converts to 7-dehydrocholesterol & is converted to
cholecalciferol (vit- D3) by ultraviolet rays in the skin
Disorders –
Hypercholesteroleima
•
Hypercholesterolemia - Increase in plasma cholesterol (> 200
mg/dl) concentration. It is observed in many disorders
1.
Diabetes mellitus: Due to increased cholesterol synthesis since the
availability of acetyl CoA is increased
2.
Hypothyroidism (myxoedema): Due to decrease in the HDL receptors on
hepatocytes
3.
Obstructive jaundice: Due to an obstruction in the excretion of
cholesterol through bile
4.
Nephrotic syndrome: Increase in plasma globulin
concentration is the characteristic feature of nephrotic syndrome
5.
Associated with atherosclerosis and coronary heart disease
Causes of hypercholesterolemia
•
Heredity: High levels of cholesterol may be inherited because genes may influence
the metabolism of LDL (bad) cholesterol
•
Foods high in saturated fats and Cholesterol: This is the most common cause of
hypercholesterolemia as excess of saturated fats may modestly increase LDL
(bad) cholesterol level
•
Other diseases: Some people suffering from diabetes may have high levels of
cholesterol
•
Lifestyle Changes: Changes in lifestyle has lead to decrease in exercise which may
lead to increase in fat and cholesterol levels
Risk factors of hypercholesterolemia
Some important risk
factors for high cholesterol are:
•
Obesity
•
Eating a
diet high in saturated fat and trans fatty acids
•
Nephrotic
syndrome
•
Diabetes
mellitus
•
Hypothyroidism
•
High blood
pressure
•
Drinking
alcohol
•
Smoking
Control of
hypercholesterolemia
Several measures are to lower the plasma cholesterol level are
1.
Consumption of PUFA: Dietary intake of polyunsaturated fatty acids (PUFA)
reduces the plasma cholesterol level. Oils with rich PUFA content are cotton seed oil,
soyabean oil, sunflower oil, corn oil, fish oils etc. Ghee & coconut oil are
poor sources of PUFA
2.
Dietary cholesterol: Avoidance of cholesterol-rich foods
3. Plant
sterols: Certain plant sterols ( e.g. Sitostanoel esters) reduce plasma
cholesterol levels by inhibiting the intestinal absorption of dietary
cholesterol
4.
Dietary fiber: Intake of dietary fibers like beans decreases the
cholesterol absorption from the intestine
5. Avoiding high carbohydrate diet
6.
lmpact of lifestyles: Elevation in plasma cholesterol is observed in
people with smoking, abdominal obesity, Iack of exercise, stress, high blood
pressure, consumption of soft water etc
7.
Moderate alcohol consumption: 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
8. Use
of drugs: Drugs such as lovastatin which inhibit HMG CoA reductase and decrease
cholesterol synthesis are used.
•
Statins currently in use include atorvastatin,
simvastatin and pravastatin
•
Certain drugs-cholestyramine and colestipol-bind
with bile acids and decrease their intestinal absorption
•
Clofibrate increases the activity of lipoprotein
lipase and reduces the plasma cholesterol and triacylglycerol
Hypocholesterolemia
•
Hypocholesterolemia: A decrease in the plasma cholesterol, although
less common, is also observed.
•
Hyperthyroidism, pernicious anemia, malabsorption
syndrome, hemolytic jaundice etc., are some of the disorders associated with
hypocholesterolemia
Summary
•
Cholesterol biosynthesis is controlled by the rate
limiting enzyme HMG CoA reductase
•
HMG-CoA is
the precursor for cholesterol synthesis
•
Cholesterol is converted to bile acids, steroid
hormones & vitamin D
•
Increase in plasma cholesterol (> 200 mg/dl)
concentration is known as hypercholesterolemia
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