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

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 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:


       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

Post a Comment