CHOLESTEROL AND THE HUMAN BODY

INTRODUCTION: Almost all nucleated cells including arterial walls can synthesise cholesterol. It is widely distributed in the body. In a 70 kg man, a total of about 140g of cholesterol is available; which is roughly distributed as 30g in brain and nerves, 30g in muscles, 30 g in adipose tissue, 20g in skin, 10g in blood, 10g in liver and spleen, 5g in bone marrow, 3g in alimentary tract, and 2g in adrenal gland. Cholesterol is a light yellow crystalline solid. When the crystals are examined under the microscope, they show a notched appearance. Cholesterol is soluble in chloroform and other fat solvents. It is the most important animal steroid from which other steroid compounds are formed. Cholesterol is widely distributed in animal tissues. It is absent in prokaryotes. In plants, cholesterol is absent, but other plant sterols are present. In bacteria and plants, compounds similar to steroids exist, known as hopanoids.

CLINICAL SIGNIFICANCE OF CHOLESTEROL: The level of cholesterol in blood is related to the development of atherosclerosis and myocardial infarction.

FUNCTIONS OF CHOLESTEROL

1. Cell membranes: Cholesterol is a component of membranes and has a modulating effect on the fluid state of the membrane. Theplasma membrane

2. Nerve conduction: Cholesterol has an insulating effect on nerve fibers.

3. Bile acids and bile salts are derived from cholesterol. Bile salts are important for fat absorption.

4. Steroid hormones: Glucocorticoids, androgens and estrogens are from cholesterol.

5. Vitamin D3 is from 7-dehydro-cholesterol.

6. Esterification: The OH group of cholesterol is esterified to fatty acids to form cholesterol esters.

ABSORPTION OF CHOLESTEROL: Cholesterol ester present in the diet is hydrolysed by cholesterol-esterase. The free cholesterol is incorporated into bile salt micelle and absorbed into the mucosal cell. Absorption needs micellar formation. There is a specific protein which facilitates the transport of cholesterol into the mucosal cell from the micelle. Inside the mucosal cell, cholesterol is re-esterified and incorporated into chylomicrons. The chylomicrons reach the bloodstream through lymphatics. This dietary cholesterol reaches the liver through chylomicron remnants.

BIOSYNTHESIS OF CHOLESTEROL: All carbon atoms of cholesterol are derived from acetyl CoA. The major sites of synthesis of cholesterol are liver, adrenal cortex, testes, ovaries and intestine. All nucleated cells can synthesise cholesterol, including arterial walls. The enzymes involved in the synthesis of cholesterol are partly located in the endoplasmic reticulum and partly in the cytoplasm.

REGULATION OF CHOLESTEROL SYNTHESIS

1. Regulation at transcription: The regulatory enzyme is HMG CoA reductase. Long-term regulation involves regulation of transcription of the gene for HMG CoA reductase. When sufficient cholesterol is present in the cell, transcription of the gene for HMG CoA reductase is suppressed, and cellular synthesis of cholesterol is decreased. When cholesterol in diet is low, synthesis is increased.  

2. Cholesterol regulates the expression of HMG CoA reductase gene and LDLR (LDL receptor) gene. A specific recognition sequence known as the sterol regulatory element (SRE) is present in DNA. SRE binding by sterol regulatory element binding protein (SREBP) is essential for the transcription of these genes. When cholesterol levels are sufficiently high, the SREBP remains as an inactive precursor. The SREBP cleavage activator protein (SCAP), is an intracellular cholesterol sensor. When cholesterol is less, SCAP escorts SREBP to Golgi bodies. Two Golgi proteases (S1P and S2P) sequentially cleave the SREBP to a protein which binds to SRE and activates transcription of HMG CoA reductase gene.  

3. Covalent modification: Short-term regulation is by covalent modification of the enzyme. Cyclic AMP mediated cascade phosphorylates the enzyme which is inactive. Dephosphorylated form is active. Further, the activity of HMG CoA reductase is also regulated by the rate of degradation of enzyme protein.  

4. Insulin and thyroxine increase the activity of HMG CoA reductase.  

5. Cortisol and glucagon decrease its activity.  

6. Drugs: Lovastatin and other "statin" group of drugs are competitive inhibitors of HMG CoA reductase. So, they are used in clinical practice to reduce cholesterol level in blood.

CHOLESTEROL POOL AND CHOLESTEROL METABOLISM: The total body cholesterol content varies from 130-150 grams. LDL (low density lipoprotein) transports cholesterol from the liver to the peripheral tissues and HDL (high density lipoprotein) transports cholesterol from tissues to liver. Cells of extrahepatic tissues take up cholesterol from LDL. The free cholesterol released within the cell has the following fates:  

1. Incorporated into cell membranes.  

2. Metabolised to steroid hormones, especially in adrenal cortex and gonads. 

3. Esterified with saturated fatty acids and stored in the cell. The enzyme ACAT (acyl cholesterol acyl transferase) helps in this reaction. 

4. Esterified with poly-unsaturated fatty acids (PUFA) by the action of LCAT (lecithin cholesterol acyl transferase) and incorporated into HDL, transported and finally excreted through liver.

EXCRETION OF CHOLESTEROL: Average diet contains about 300 mg of cholesterol per day. Body synthesizes about 700 mg of cholesterol per day. Out of this total 1000 mg, about 500 mg of cholesterol is excreted through bile. This cholesterol is partly reabsorbed from intestines. Vegetables contain plant sterols which inhibit the re-absorption of cholesterol. The unabsorbed portion is acted upon by intestinal bacteria to form cholestanol and coprostanol. These are excreted (fecal sterols). Another 500 mg of cholesterol is converted to bile acids, which are excreted in the bile as bile salts.

LIVER AND CHOLESTEROL: The liver has a major role in controlling the plasma levels of LDL cholesterol.  

1. Liver synthesises cholesterol  

2. Liver removes cholesterol from Lp remnants.  

3. Liver is the only organ that can excrete cholesterol through bile.  

4. Liver converts cholesterol to bile acids.

RELATED;

1.  THE PLASMA MEMBRANE

REFERENCES