Introduction
Cholesterol is widely distributed in animal tissues. It is absent in plants, but other plant sterols are present. In a 70 kg man, a total of about 140 g of cholesterol is available. It is soluble in chloroform and other fat solvents. It is the most important animal steroid from which other steroid compounds are formed.
Structure Of Cholesterol
It contains a 27 carbon ring system called cyclopentanoperhydrophenathrene with four rings labelled A-D:
- A, B and C are cyclohexane rings, D is a cyclopentane ring
- The six-membered rings are in a phenanthrene arrangement
- One hydroxyl group at carbon 3
- A double bond between carbon atoms 5 and 6
- An eight carbon side chain attached to the 17th carbon
Absorption Of Cholesterol
Before being absorbed, cholesterol is first solubilized through a process called emulsification. Emulsification occurs by the formation of mixed micelles that contain:
- Unesterified cholesterol
- Fatty acids
- Monoglycerides
- Phospholipids
- Conjugated bile acids
Bile acids, by acting as detergents, are the most critical factor in micelles formation. In their absence, digestion and absorption of both cholesterol and triglycerides is severely impaired. The ability of cholesterol to form micelles is also influenced by the quantity of dietary fats and thus, increase in amount of fats in diets results in increase in mixed micelles which in turn allows for more cholesterol absorption. Typically, cholesterol absorption occurs in the terminal ileum and jejunum. About 30 – 60% of dietary cholesterol is absorbed per day. Once cholesterol enters the intestinal mucosal cell, it is packaged with triglycerides, phospholipids and a large protein called apolipoprotein into a large protein particle called chylomicrons. Chylomicrons are secreted into the liver and eventually enters the systemic circulation.
Cholesterol Biosynthesis
Introduction
Although cholesterol enters the body from diet, it is also synthesized endogenously by all tissues from acetyl-CoA. Knowledge of this endogenous cholesterol synthesis pathway has assumed great significance because drug agents for the treatment for coronary heart disease have been sought after to suppress or decrease cholesterol synthesis.
SITE
All nucleated cells can synthesize cholesterol, including arterial walls. The major sites of cholesterol biosynthesis are:
- Testes
- Adrenal cortex
- Intestine
- Liver
- Ovaries
- Skin
- Neural tissue
- Aorta
[Mnemonic – TAILO SAN]
The enzymes involved in the synthesis of cholesterol are partly located in the endoplasmic reticulum and partly in the cytoplasm.
Pathway
REGULATION
Regulation at Transcription
The regulatory enzyme is HMG-CoA reductase. Long term regulation involves regulation of gene transcription for HMG-CoA reductase.
Covalent Modification
Short term regulation is by covalent modification. HMG-CoA reductase is active in dephosphorylated state.
Hormonal Effects On Hmg-Coa Reductase
- Insulin – Increases Its Activity
- Thyroxine – Increases Its Activity
- Cortisol – Reduces Its Activity
- Glucagon – Reduces Its Activity
Drugs
Lovastatin and other statin group of drugs are competitive inhibitors of HMG-CoA reductase. They are used clinically to treat hypercholesterolaemia.
Biomedical Importance/Functions Of Cholesterol
- For the synthesis of bile salts which are important in lipid digestion and absorption
- For the synthesis of steroid hormones
- For the synthesis of vitamin D3 (from 7-dehydrocholesterol)
- As a structural component of biological membranes
- Nerve conduction – cholesterol is used to insulate nerve fibres
- Esterification – the –OH group of cholesterol is esterified by lecithin cholesterol acyl transferase to form cholesterol esters
Cholesterol Catabolism
Except for specialized endocrine cells that use cholesterol for the synthesis of steroid hormones, most peripheral cells have limited ability to further catabolize cholesterol. Cholesterol esters are hydrolysed to free cholesterol by various lipases in all cells. After that, cholesterol has to be returned to the liver to undergo further catabolism. Approximately one third of the daily production of cholesterol (≈ 400 mg/day) is converted into bile acid. About 90% of the bile acids are reabsorbed and returned to the liver by enterohepatic circulation. Not all cholesterol delivered to the liver is converted to bile salt. Much of it is resecreted into the circulation on lipoprotein and the remainder is directly excreted into the bile where it is solubilized into mixed micelles by bile acids and phospholipids. When the amount of cholesterol in bile exceeds the amount of these solubilizing agent, it is possible for cholesterol to precipitate and form cholesterol gall stones. Bile acids that enter the large intestine are partially deconjugated by bacterial enzymes into secondary bile acids. Cholic acid is converted to deoxycholic acid. Chenocholic acid is converted to lithocholic acid.
