Cholesterol and Lipoprotein.
PKGhatak, MD
Cholesterol is a lipid. Lipids are a group of heterogeneous compounds of fatty acids and their derivatives which are not soluble in water and soluble in chloroform, ether and benzene. Oil, fat, wax and steroids belong to this group.
Protein when conjugated with lipids is called a lipoprotein.
Apo-lipoprotein:
Individual protein molecule contains a prosthetic group or a metal that gives its special characteristic. When the prosthetic group or metal part is absent then the protein is designated as Apo-protein. When a lipid molecule conjugates with Apo-protein and then the conjugate combines with lipoprotein the resulting molecule is called Apolipoprotein.
Lipid molecules are wrapped around by proteins in order to make them soluble in the blood, making the transport of cholesterol between tissues possible.
A diagram illustrates the makeup of lipoprotein molecules.
Chemistry of Cholesterol.
Cholesterol is designated as 3-hydroxy-5,6 cholestene.
The cholesterol molecule has a Sterol ring of 19 carbon structure and at position C -17 a side chain is attached, as illustrated in the above diagram.
The rings A, B and C constitute a phenanthrene ring to which a cyclopentene ring D is attached. (this is cycleopenteno- perhydrophenerthrine ring or sterol ring) The double bond between position C5 and C6 gives the molecule its stability.
Source of cholesterol in humans.
Every living cell of the body is able to synthesize cholesterol, however, the liver is the primary organ where cholesterol is synthesized, in addition, the adrenal cortex, testis, ovaries, skin, aorta and intestine also produce cholesterol. Dietary source supply only 15 % of cholesterol. Organ meat, egg yolk, brain and liver are good sources of cholesterol in food. The body recycles cholesterol and excess cholesterol is excreted by the liver in the bile as bile acids and neutral cholesterol. Some bile acids are reabsorbed with fat in the intestine and the rest is excreted in the stool.
The liver synthesizes about 1 gm of cholesterol a day and about 300 mg of cholesterol is obtained from food. Each 100 mg of cholesterol ingested will raise blood cholesterol by 5 mg/dL.
Synthesis of cholesterol.
The cholesterol is synthesized in the Endoplasmic Reticulum of the cytosol of the cell. Mitochondria of the cells generate energy via the Tricarboxylic acid cycle, and Acetyl CoA molecules generated in this process are available for cholesterol synthesis. Fatty acids, ketogenic amino acids and glucose are broken down to 2- carbon, Acetyl CoA molecules, and enter the tricarboxylic acid cycle.
All carbon atoms in a cholesterol molecule are obtained from Acetyl-CoA. Two molecules of Acetyl-CoA condense and form Actoacetyl CoA by the action of the enzyme Theolase. In the next stage, one molecule of acetoacetyl CoA condenses with another molecule of acetyl CoA forming one molecule of Beta-hydoxy-beta-methylglutaryl CoA. This synthesis is catalyzed by a rate-limiting enzyme HMG-CoA synthase ( hydoxy-methylglutaryl Co-A synthase). Beta-hydoxy-beta-methylglutaryl is reduced by HGM-CoA reductase and NADPH acts as an H ion donor. In the next step, mevalonate is Phosphorylated by ATP, and several steps later, condensation of several molecules of Isopente takes place and Farnesyl pyrophosphate is generated.
Further downstream, one molecule of CO2 is lost and 5-C Isoprenoid units are formed. Six molecules of isoprenoid units condense to form Squalene. In the next step, the 19-C squalene assumes a ring form and is called Lanosterol or Steroid ring. There are more steps and at the end, a new cholesterol molecule emerges.
Regulation of cholesterol synthesis:
The rate-limiting HMG-CoA synthetase and HMG-CoA reductase enzymes are the main regulators of cholesterol synthesis. The rate of synthesis of HMG-CoA reductase- messenger- RNA is controlled by the steroid synthesis gene. Various hormones have roles in Cholesterol synthesis.
Cholesterol Esters.
Esters are formed by the conjugation of alcohol with cholesterol by enzyme esterase reacting with the long chain fatty acid of the cholesterol linked to the hydroxyl group. Cholesterol esters are stored in the cytoplasm of the cells as oil drops. When energy is needed esters are hydrolyzed and fatty acids are oxidized for energy production. The freed cholesterol is transported back to the liver by Beta- lipoprotein in the form of HDL.
Cholesterol in the liver:
Cholesterol molecules go to form the cell membrane of liver cells. The rest of the cholesterol is free cholesterol, bile acids and cholesterol esters. Bile acids are Cholic acid, Chinodeoxycholic acid, deoxycholic acid and lithocholic acids. All are derived from cholesterol and each of them can combine with glycine and taurine and produce complex acids and salts.
2 gm of cholesterol is secreted by the liver into the bile. Daily fecal loss of cholesterol is 1.2 gm. Cholesterol does not supply any energy to the body and any excess cholesterol is eliminated from the body in the stool.
In clinical medicine, enzymatic analysis is used in measuring cholesterol. Gas chromatography is the gold standard of cholesterol measurement. Liquid chromatography and mass spectrometry are also used. Lipoproteins term is used for Apolipoproteins for convenience. There are four classes of Apolipoproteins based on their functions.
For the plasma membrane structural integrity: apo-B, E, A-I, A-II.
For Secretion: apo A-1, B-100, B-48.
For cofactors of enzymes: apo A-1, A-V, C-1, C-II, C-III.
For binding with receptors: apo A. apo B.
Apolipoprotein Apo-A: This is a large glycated protein of variable size. Apo-A is a homolog of plasminogen.
Apolipoprotein B: It is perhaps more important that Apo A, is a greater atherogenic risk factor than LDL. The normal blood level of Apo B is less than 100 mg/dL. Apo B can bind with variable amounts of cholesterol. High levels of Apo B are seen in diabetes, pregnancy, and thyroid and kidney diseases. and kidney diseases. Low levels of Apo B can be associated with cirrhosis of the liver, acute hepatic necrosis, and congenital conditions.
Apolipoprotein E: Apo E is a major lipoprotein for cholesterol carriers. Genes controlling the synthesis of Apo E are responsible for the brain lipoprotein content. Alzheimer's disease and Alzheimer's disease carriers are due to carriers of the mutated gene. Apo E is also linked to cerebral angioid-angiopathy and age-related decline of cerebral functions.
Cholesterol- Esters- Transfer- Protein (CETP) facilitates the transfer of cholesterol esters and triglycerides and in between LDL and HDL.
Each lipoprotein molecule is a spherical particle with a hydrophobic nucleus made with triglyceride and cholesterol ester and a peripheral envelope made by polar phospholipids, unesterified cholesterol, and one or more molecule of proteins. Proteins are bonded together with lipids in Non-Covalent bonds that make the molecule exchange its components easily.
It is customary in clinical medicine to classify lipoproteins according to their density and relative sizes. They are classified as chylomicron, very low-density lipoprotein (VLDL). Intermediate-density lipoprotein (IDLP). Low-density lipoprotein (LPL) and high-density lipoprotein (HDL)
LDL: LDL is derived from VLDL and IDL particles and carries 2/3 rd. of cholesterol in the blood. The liver turns out LDL to be transported to muscles for energy generation and to the adipose tissue for storage of excess calories for future use. Because the LDL particles are small, they enter between endothelial cells and are deposited in the subendothelial space. Macrophages phagocytize LDL and turn themselves into ghost cells and become the site of atheroma formation. Atheroma can break and causes coagulation of blood and obstruct circulation and when this happens in coronary arteries and heart attack usually happens.
HDL: HDL is primarily produced in the liver and also produced in the intestine during fat digestion and absorption. In the peripheral tissue, cholesterol is released from cholesterol esters which are transported back to the liver combined with HDL. HDL plays an important role in reverse cholesterol transport from the peripheral tissue back to the liver. This property is considered Anti-atherogenesis. HDL also has anti-inflammatory, anti-oxidant, anti-thrombotic properties and inhibits macrophages from phagocytizing LDL molecules. In the liver, all extra cholesterol is secreted in bile as either free cholesterol and bile salts.
Triglyceride: Triglyceride is an old biochemical term. Structurally, triglyceride is Triacylglyceride. Glycerol is derived from glucose metabolism. It is esterified by fatty acids containing 16 carbon atoms or more. Triglycerides are the medical term for fat. The primary source of triglycerides is food, any extra calorie eaten is turned into triglycerides by the liver.
If the fatty acids have unsaturated bonds, the body can metabolize them rapidly. Most natural fats are mixtures of different triglycerides. The breakdown of glucose takes place in the cytosol and then residue enters the mitochondria.
Looking at the table below, it is evident that triglyceride is a major component of Chylomicron and VLDL and IDL. It is now established that Triglyceride is an independent factor of atherosclerosis besides LDL. People with very high blood triglycerides suffer from Acute Pancreatitis. The normal blood level of triglyceride is 100 mg/dL or below in healthy adults.
Chylomicron: Triglycerides are the major component of chylomicron. After intestinal absorption, the chylomicron travel via lymphatics and then enters portal circulation, and reaches the liver. After a high-fat meal, the plasma becomes milky opaque due to the presence of a high concentration of triglyceride. Lipoprotein lipase enzyme, present in endothelial cells of muscles split triglyceride and uses free fatty acids for energy. In 12 hours of fasting triglyceride returns to the normal level in the blood.
The table below summarizes important differences in various Lipoproteins.
|
|
Chylomicron |
VLDL |
IDL |
LDL |
HDL |
|
Place of synthesis |
Enterocytes of Intestine. |
Liver cells |
Liver |
Endothelial cells of capillaries |
Liver |
|
Particle size |
>75 |
25 -75 |
22-24 |
19 -23 |
10 |
|
Electrophoresis |
None |
Pro -beta |
Slow- beta |
Beta |
Alpha |
|
% of Triglyceride |
90 |
54 |
20 |
4 |
3 |
|
% of Lipid |
>75 |
70 |
24 |
23 |
10 |
|
% of Free cholesterol |
1 |
7 |
9 |
11 |
5 |
|
% of cholesterol ester |
2 |
12 |
35 |
45 |
30 |
|
Protein |
2 |
10 |
12 |
20 |
50 |
|
Apolipoprotein |
A I, II, IV, B 48 C II, III E |
B 100 CII, III E |
B 100 C II, III E |
B 100 |
A I C I, II, III E |
Cholesterol is an essential structural element of the cell wall of all living cells. Cholesterol provides stability to the cell membrane which is primarily formed by phospholipids. All steroid hormones are derived from Cholesterol which is usually synthesized by the endocrine glands themselves. Many co-enzymes have cholesterol molecules in them. Bile salts are primary emulsifying agents for fat digestion in the intestine. The neurons of the brain have the highest concentration of lipids and cholesterol.
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