Metabolism of Cholesterol

Metabolism of Cholesterol

Metabolism of Cholesterol


     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

HMG CoA reductase activity is inhibited by bile acids

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

Synthesis of bile acids

     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 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

Synthesis of vitamin D

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:


     Eating a diet high in saturated fat and trans fatty acids

     Nephrotic syndrome

     Diabetes mellitus


     High blood pressure

     Drinking alcohol


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: 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


     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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