Biosynthesis of Cholesterol

Biosynthesis of Cholesterol  

Cholesterol is synthesized in the cell cytosol and endoplasmic reticulum from acetylCoA. Liver and intestine account each for 10% of the total cholesterol synthesized in the body. Almost all tissues containing nucleated cells can synthesize cholesterol. The synthesis follows five major steps which include:
  • Acetyl CoA is converted to HMG CoA.
  • HMG CoA is reduced to Mevalonate by a reductase. 
  • Mevalonate undergoes three times Phosphorylation, in the presence of 3 ATPs and various kinases.The product is 3- phosphor-5 pyrophospho mevalonate. 
  • Dephosphorylation, decarboxylation converts it to Isopentenyl pyrophosphate. 
  • It is isomerised to dimethyl allyl pyrophosphate by isomeras. 
  • Isopentenyl pyrophosphate and dimethyl allyl pyrophosphate form Geranyl PP(10C). 
  • Geranyl PP and one more molecule of Isopentenyl PP→ Farnesyl PP(15C). 
  • Two of Farnesyl PP join to form Squalene (30C). 
1. Squalene undergoes cyclization, loses three carbon atoms,aquire a double bond,forms cholesterol

Regulation of Cholesterol Synthesis: 

Acetyl CoA is converted to Mevalonate. It is the committed step in the synthesis of cholesterol. Almost 800 mg of cholesterol is synthesized in our body .HMG CoA reductase is the regulatory enzyme. 
1. Dietary cholesterol inhibits endogenous synthesis. 
2. Fasting leads to low levels of the key enzyme. 
3. Insulin activates protein phosphatase which converts it to active enzyme. Glucagon decreases its activity through c AMP dependent protein kinase. 
4. Whenever ATP levels are low, the enzyme is switched off by AMP activated protein kinase. 
5. m RNA for HMG CoA reductase is under the control of sterols . High concentration of sterols inhibits the synthesis of m RNA, there by the synthesis of enzyme. 
6. High levels of degradation products lead to rapid degradation of HMG CoA reductase.  

Catabolism of Cholesterol: 

Intestinal Bacteria converts cholesterol to coprostanol which is excreted in feces. Cholesterol breaks down to cholic acid and chenodeoxycholic acid.Both are bile acids.They combine with sodium, Potassium to form bile salts. The key enzyme α-hydroxylase is inhibited by high concentration of bile acids. 
Functions of Bile Salts 
  • They lower surface tension ,emulsify fats ,a pre requisite for the action of pancreatic lipase 
  • They activate Lipase. 
  • They shift the pH from 9 to 6 
  • They form micelles with fatty acid,a mono,di,triglyceride and help in absorption 
  • Promote absorption of fat soluble vitamins 
  • Bile salts keep cholesterol in soluble form in gall bladder.
  • They regulate the breakdown of cholesterol 

Cholelitiasis (Gall stones): 

Absence of bile salts precipitate cholesterol as gall stones.Solublity of cholesterol depends on the ratio of phospholipids, bile salts to cholesterol.Due to infections bile acids are destroyed which leads to decreases solubility of cholesterol. 

Decrease of bile salts can be due to: 
A. Failure in enterohepatic circulation 
B. Cirrhosis of Liver 
C. Disease of ileum. 

The patients are treated with chenodeoxycholic acid to solublize the cholesterol or the stones are removed by surgical intervention. 

Hypercholesterolemia : 

Normal cholesterol level is 150-250mg% in blood. High concentration leads to hyper cholesterolemia. Excess cholesterol gets deposited under the skin, tendons as Xanthomas. In some cases the regulatory enzyme HMG-CoA reductase is not sensitive to feed back regulation. Such people suffer from familial hypercholesterolemia. 

Atherosclerosis: 

Deposition of lipids in the connective tissues of intima of arteries is called atherosclerosis. It causes obstruction to blood flow, leading coronary heart disease, stroke, myocardial infarction etc. The process is initiated when there is injury to endothelial cells of blood vessels. A number of factors are responsible for injury .The condition is compounded by hyper lipidemia. Atherogenesis is the process by which atherosclerotic plaques form, a critical step in the disease, atherosclerosis. Low-density lipoprotein complexes (LDLs), which are the primary means of transporting cholesterol in the blood, are readily oxidized. A class of white blood cells recognizes the oxidation and absorbs the LDL through its scavenger receptor. They becomes engorged and is referred to as a foam cell. Foam cells attract other white blood cells, which leads to accumulation of more cholesterol. Ultimately, this accumulation of cholesterol becomes one of the chief chemical constituents of the atherosclerotic plaque that forms at the site. Circulating monocytes accumulate at the site of injury, ingest excess of lipids. If the damage to the intima continues, there is infiltration of platelets at the site. Foam cells and platelets aggregate, and release substances resulting in atheromatic plaque. 

Hypercholesterolemic Drugs 

• Compactin inhibits HMG CoA reductase.Cholesterol synthesis decreases. 
• Mevinolin Competes for Mevalonate ,Cholesterol synthesis decreases 
• Cholsetepol, cholesteyramine (Resins) combine with bile salts and inhibit their reabsorption. Here Bile salts are lost in feces. As a result more cholesterol breaks down to bile salts. 
• Diatery fiber is not a drug, better than a drug because 
  •  Bile salts gets trapped in fiber and lost in feces. 
  •  More cholesterol breaks down 
  •  Cholesterol absorption is decreased because of indigestible fiber 
  •  All other lipids are absorbed less.