In this article we will discuss about:- 1. Distribution of Cholesterol 2. Absorption of Cholesterol 3. Effects 4. Synthesis 5. Storage, Destruction and Control 6. Functions 7. Excretion.
Distribution of Cholesterol:
The broad facts about the distribution of cholesterol are as follows:
i. It is present in all cells – both in the cell membrane and cytoplasm. It is a part of the ‘element constant’.
ii. All body fluids contain cholesterol excepting cerebrospinal fluid (CSF) in which the amount is negligible.
iii. It may exist in the Free State as well as in the form of esters, but these two forms are not equally distributed everywhere. In bile it is present only in the free form.
iv. Brain contains (17%) it and is mainly in free form and suprarenals contain the largest amount.
v. Blood cholesterol. Normal blood cholesterol varies between 150-200 mgm per 100 ml which is equally distributed between plasma and corpuscles. But in the corpuscles it is present chiefly in the free form, while in the plasma the major part remains as esters.
vi. The free cholesterol content of a tissue is characteristic and normally remains very constant but the cholesterol esters may vary in amount.
vii. The distribution of cholesterol in different types of muscles is directly proportional to their degree of activity. The cardiac and smooth muscles have richer cholesterol content than the voluntary muscle. Moreover, the amount of cholesterol in any tissue is roughly proportional to their degree of activity.
viii. Cholesterol and phospholipids always remain together. Moreover, there appears to be a definite ratio between phospholipids and cholesterol for each tissue.
Absorption of Cholesterol:
Absorption of cholesterol from the intestine follows the same principles as other lipids. Ingested cholesterol requires fat for its absorption from the lumen of the intestine into the lymphatics. These are esterified with fatty acids in the intestinal epithelium during their passage into the lymphatics.
It is a complex monohydric secondary alcohol being a very important member of the sterol class. With fatty acids if forms waxes. It is a stable white, crystalline substance, insoluble in water but readily soluble in chloroform, ether, alcohol and other fat-solvents. The crystals have a rhombic or rectangular shape, with one corner broken, off.
Effects of Cholesterol Feeding:
i. Ingestion of cholesterol-rich food, for some length of time, increases the level of cholesterol in blood and such increase is not observed when such sample of diet taken once. The rise of blood cholesterol is accompanied with the rise in bile cholesterol. There is also rise in blood cholesterol when cholesterol-rich diet is not ingested which indicates that this rise is due to increased absorption of cholesterol derived from bile.
ii. Cholesterol feeding is one of the most certain means of producing excess deposition of fats, as well as cholesterol esters in the liver (antilipotropic action).
iii. Arteriosclerosis or atherosclerosis has been observed in animals and man fed with diet containing high cholesterol but it has not been proved in man.
Synthesis of Cholesterol:
That it can synthesised in the body is proved by the following facts:
i. The excretion of cholesterol may exceed the intake over long period of time by as much as 0.3 gm per day.
ii. Experiments with heavy water also suggests that cholesterol is built up from smaller molecules other than sterols.
iii. When rats and mice are fed with acetate labelled with deuterium (D), cholesterol containing D is found in their bodies.
Sequence of Reactions in the path of Cholesterol Synthesis (Figure 10.28):
i. Activation of acetate to acetyl Co A.
ii. Condensation of two acetyl CoA to form acetoacetyl CoA.
iii. Formation of HMG CoA.
iv. Formation of mevalonic acid.
v. Mevalonic acid is phosphorylated by ATP to form ultimately 5-diphosphomevalonic acid.
vi. The diphosphomevalonic acid after losing CO2 and H2O gives rise to isopentenyl pyrophosphate.
vii. The above compound isomerizes to form 3-3-dimethylallyl pyrophosphate which combines with isopentenyl pyrophosphate to give geranyl pyrophosphate.
viii. Another molecule of isopentenyl pyrophosphate combines with geranyl pyrophosphate to form farnesyl pyrophosphate.
ix. Two molecules of farnesyl pyrophosphate combine to form squalene.
x. An oxidocyclase converts squalene to lanosterol.
xi. The conversion of lanosterol to cholesterol involves a number of transformations, some of which are not yet clearly understood.
Storage, Destruction and Control of Cholesterol:
A good deal of cholesterol, derived from the disintegration of blood cells, is stored in the cells of reticulo-endothelial system and retained in the body. Body utilizes cholesterol very economically. The metabolism of cholesterol is under the influence of hormones. Injection of adrenocorticotrophic hormone (ACTH) reduces cholesterol content of adrenal cortex.
In hypothyroidism blood cholesterol rises whereas there is fall of blood cholesterol in hyperthyroidism. A variation in serum cholesterol has also been noted during pregnancy. In diabetes mellitus and atherosclerosis, blood cholesterol is often found to be high. Liver, tissue cells, muscles, organs like heart and brain, etc. play an important part in cholesterol metabolism.
Functions of Cholesterol:
i. Essential Constituent of all Cells:
It is a part of the ‘element constant’ of the cells. Its presence in constant amount in cell indicates that it is intimately concerned with the function of the cells.
ii. Controls Cell Permeability:
Being a constant constituent of cell membrane it is believed to be related to the permeability of the tissue cells.
iii. Prevents Haemolysis:
In some unknown way, it protects the red cells from being easily haemolysed. Low blood cholesterol is associated with haemolysis.
iv. Defensive Action:
Cholesterol is intimately related to the defensive mechanism of the body. During acute infections blood cholesterol falls and tends to rise during recovery.
v. Fat Transport:
A large part of fat is transported through blood as cholesterol esters.
vi. Formation of Cholic Acid (Bile Salts):
It has been shown that cholesterol is the mother substance from which cholic acid is synthesised. Cholic acid is a constituent of bile salts.
vii. Antilipotropic Action:
Cholesterol feeding increases the deposition of fat in the liver. This effect is due to the formation of cholesterol esters and depression of phospholipid formation in the liver.
viii. Controls Cell Division:
Rapidly growing tissues are very rich in cholesterol, such as, the granulation tissues of healing ulcer and rapidly growing tumours, etc.
ix. Antagonistic to Phospholipids:
Its physio-chemical properties are antagonistic to phospholipids; hence, they are always found together.
x. It is a parent substance of all the steroid hormones of sex glands, adrenal cortex.
Interrelation with Other Sterols:
Cholesterol is very closely related to many other sterols of immense physiological importance, for instance:
(a) The active principle of adrenal cortex,
(b) The male sex hormones,
(c) The female sex hormones,
(d) Vitamin D and ergosterol, and
(e) Cholic acid, etc.
Although cholesterol has not been proved to be the mother substance for the formation of other sterols in the body except cholic acid but there are some indications to believe that cholesterol may serve as precursor for the synthesis of other sterols since it has been possible to synthesise sex hormones, both male and female, in the laboratory from cholesterol.
Excretion of Cholesterol:
Excretion takes place in the following ways:
i. In the Bile:
It is found as free cholesterol but a good part of it is reabsorbed from the intestine.
ii. In the Stool:
A part of the bile cholesterol undergoes bacterial putrefaction in the intestine and is excreted as coprosterol. But a small amount of free cholesterol is also found in the stool.
iii. In the Urine:
It appears in the urine only in traces, but appears in larger amounts in different diseases namely in hypercholesteremia where blood cholesterol is high.
iv. In the Skin:
Sebum secretion of the sebaceous glands of the skin contains large quantities of cholesterol and thus drying of the skin is prevented by sebum for its cholesterol constituent.
Blood Cholesterol in Pregnancy:
During pregnancy blood cholesterol rises and rapidly comes back to normal after confinement. It may be that this rise is due to hyperactivity of the adrenal cortex, produced during pregnancy and the exact function is not known. It may also be that this high cholesterol ensures the supply of the mother substance from which large amounts of sex hormones are manufactured during pregnancy.
A very common disease of advanced age, indicated by deposition of cholesterol in the damaged arterial wall. This leads to cerebral thrombosis, myocardial infarctions, etc. It has been established that abnormal lipid metabolism produces atherosclerosis. Several other factors make the system more prone to the disease. One of the principle factors is an injury to arterial wall resulting from any conditions.
A high blood cholesterol level and genetic inheritance might be other contributory factors. Treatment includes administration of thyroid hormones or oestrogen low doses. If dietary saturated fat is substituted by unsaturated one, the blood cholesterol level is lowered and atherosclerosis is prevented.