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What is Cholesterol ?
Cholesterol is a soft waxy
substance, belongs to the class of lipids called sterols,
structural lipids present in membranes of eukaryotic cells.
Cholesterol is the major sterol in animal tissues. It is
amphipathic, with a polar head group and a non-polar hydrocarbon
body.
Cholesterol has a chemical formula of C27H45OH and molecular
mass of 386.65 g/mol. It is present in tissues and in plasma
either as free cholesterol, or as a storage form, combined with
long chain fatty acid as cholesteryl ester. The name cholesterol
originates from the Greek chole- (bile) and stereos (solid), and
the chemical suffix -ol for an alcohol. Researchers first
identified cholesterol in solid form in gallstones in 1784. Most
cholesterol is not dietary in origin; it is synthesized
internally. Similar sterols are found in other eukaryotes:
stigmasterols in plants and ergosterol in fungi, for e.g..
Bacteria cannot synthesize sterols, a few bacterial species,
however can incorporate exogenous sterols into their membranes.
The characteristic structure of cholesterol is the steroid
nucleus consisting of four fused rings, three with six carbons
and one with five. The steroid nucleus is almost planer and is
relatively rigid; the fused rings do not allow rotation about
c-c bond.
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What are
the functions of Cholesterol ?
Cholesterol is found in every cell of the body. It is especially
abundant in the membranes of cells where it plays a structural
role. It helps to maintain the integrity of the membranes.
Molecule for molecule, can make up nearly half of the cell
membrane. Cholesterol is also present in the membranes of
organelles present inside the cell e.g. in the mitochondria,
endoplasmic reticulum.
Plasma membrane of each cell is composed of a continuous double
layer of phospholipid interweaved with cholesterol and proteins.
Phospholipid is also an amphipathic molecule with polar
phosphate group and non-polar fatty acid chain. Cholesterol’s
hydroxyl group aligns with the phosphate head group of
phospholipid. The remaining portion of it tucks into the fatty
acid portion of the membrane. Because the way cholesterol is
shaped part of the steroid ring is closely attracted to part of
fatty acid chain on the nearest phospholipid chain. Thus
cholesterol confers firmness and integrity to plasma membrane.
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Cholesterol also helps maintain
fluidity of the membranes. Membranes are dynamic structures such
that membranes are capable of changing shape without losing
their integrity. This change in shape is due to the non-covalent
interactions among lipids in the bilayer. This fluidity is also
largely dependent on the lipid composition of the membrane. The
hydrophobic chains of fatty acids can be highly ordered to
provide a stiff structure. With an increase in the temperature,
hydrophobic side chains undergo a transition from ordered state
to a disordered one taking one a liquid-like or fluid
arrangement, this occurs at a definite temperature called
transition temperature(Tm). Cholesterol modifies fluidity of
membranes. At temperatures below Tm, it keeps the membrane in a
fluid state by preventing interactions between the hydrocarbon
fatty acyl chains.At temperatures above Tm, it limits disorder
thus limiting fluidity.
Cholesterol helps secure important proteins in the membrane that
performs important functions like channeling or pumping
substances into and out of the cells, attaching to and
communicating with nearby cells or responding to hormones.
Cholesterol is abundant in the tissues of the brain, and nervous
system. Myelin that covers nerve axons and help conduct
electrical impulses is over one-fifth cholesterol by weight.
Studies have indicated that cholesterol is an important factor
in the formation of synapses that forms the basis of learning
and memory. Availability of cholesterol can directly limit the
ability to form synapse, which in turn has a direct impact on
mental functioning and health.
Human body uses cholesterol to synthesize bile acids, which are
important for the digestion of fats. Cholesterol acts as a
precursor to vitamin D which functions in calcium metabolism,
and bone health. Cholesterol is the precursor to all steroid
hormones eg, glucocorticoids, mineralocoticoids, and sex
hormones. Studies have indicated that cholesterol also functions
in protecting the body against various gastrointestinal and
respiratory infections.
What are sources of Cholesterol
?
Cholesterol can be obtained from animal food such as egg yolk,
meat, animal fat(lard), poultry, fish, sea food, and whole milk
diary products.
How is Cholesterol Synthesized ?
A little more than half the cholesterol of the body arises by
synthesis and the remainder is provided by average diet.
Virtually all tissues containing nucleated cells are capable of
cholesterol synthesis. . Within the cells, synthesis takes place
in the endoplasmic reticulum and cytosol. Cholesterol is
synthesized from acetyl CoA. Synthesis involves the
isomerization of 5 carbon isoprene units.
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Biosynthesis of cholesterol may be divided into 4 steps
• Condensation of three acetate units to form 6 carbon
intermediate, mevalonate.
• Conversion of mevalonate to activated isoprene units.
• Polymerization of six 5 carbon isoprene units to from a 30-
carbon intermediate, squalene.
• Cyclisation of squalene to form the four rings of the steroid
nucleus with a further series of changes(oxidations, removal of
methyl groups) to produce cholesterol.
Much of cholesterol synthesis in vertebrates takes place in the
liver a small fraction of which is incorporated into hepatocyte
membrane, but most of it is exported in one of the three forms:
biliary cholesterol, bile acids or cholesteryl esters.
Cholesterol and cholesteryl esters are insoluble in water and
are transported from tissue of origin to the tissue in which
they will be stored or consumed. They are carried in the blood
plasma as plasma lipoproteins, which |
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are macromolecular complexes of
specific carrier proteins called apolipoproteins with various
combinations of cholesterol and cholesteryl esters. Cholesterol is
transported to the extrahepatic tissues via Low Density lipoprotein
(LDL) involving specific receptors for LDL. The binding of LDL to
LDL receptors initiates endocytosis which conveys LDL and its
receptor into the cell. Eventually, cholesterol is released into the
cytosol via hydrolysis brought about by lysosome.
Cholesterol synthesis is a complex
and energy expensive process, so it is highly regulated to
complement dietary intake. In mammals cholesterol production is
regulated by intracellular cholesterol concentration and by hormones
insulin and glucagon. Intracellular cholesterol concentration
regulates the rate limiting step in the synthetic pathway, which is
the formation of mevalonate catalyzed by enzyme HMG coA reductase.
It also regulates the storage of cholesterol by regulating the
enzyme that esterifies cholesterol to cholesteryl ester and the
uptake of LDL- cholesterol.via LDL receptor. Hormonal control is
mediated by covalent modification of HMG CoA reductase. Glucagon
stimulates phosphorylation (inactivation) and insulin promotes
dephosphorylation, activating the enzyme and favouring cholesterol
synthesis. High Density Lipoprotein is another class of plasma
lipoprotein that originates in the liver and small intestine . About
one-third to one-fourth of blood cholesterol is carried by
HDL.However HDL tends to carry cholesterol to the liver where it is
converted to bile salts.
Unregulated cholesterol production can lead to serious human
disease. When the sum of cholesterol synthesized and those obtained
in the diet exceeds the amount required for the synthesis of
membranes, bile salts, and steroids, there occurs pathogical
accumulations of cholesterol in the blood vessels called
atherosclerotic plaques resulting in the obstruction of blood
vessels, a disease known as atherosclerosis. It is the leading cause
of death in western industrialized countries.
Which is the Bad Cholesterol ?
The risk of developing it is directly related to the plasma
concentration of LDL cholesterol, and inversely related to that of
HDL cholesterol. Therefore, LDL cholesterol is frequently referred
to as “bad cholesterol” whereas HDL cholesterol is called “good
cholesterol”. Atherosclerosis is a disorder of the arterial wall,
characterized by the accumulation of cholesteryl esters. LDL is the
major carrier of cholesterol in the blood. If too much cholesterol
circulates in the blood, it can slowly build up in the walls of the
arteries feeding the heart. Together with other substances it can
form a plaque, a thick, hard deposit that can clog the arteries.A
clot or thrombus that forms near the plaque blocks flow of blood to
the heart muscle, goes on to precipitate myocardial infarction(heart
attack). HDL cholesterol removes excess cholesterol from the plaques
and slows their growth. Hence HDL levels seems to protect against
heart attack.
Familial Hypercholesterolemia is a human genetic disease,
characterized by high blood cholesterol levels thereby leading to
development of severe atherosclerosis in childhood. These
individuals have defective LDL receptor and lack receptor mediated
uptake of cholesterol carried by LDL. Consequently, there occurs
accumulation of blood cholesterol, and formation of atherosclerotic
plaques. In this disorder HDL levels are very low. Tobacco smoke is
a major risk factor of heart disease since it lowers HDL levels and
increases the tendency for blood to clot. Regular physical activity
increases HDL cholesterol and therefore lower the risk of heart
disease.
What are some drugs that are used to
lower Cholesterol ?
Cholesterol lowering drugs are used to treat individuals who have
higher than normal levels of cholesterol in their blood. Such drugs
may reduce the risk of cardiovascular diseases or death associated
with atheroscelosis, when diet restriction, lifestyle changes, and
weight reduction are insufficient. The drugs for first choice are
the HMG CoA reductase inhibitors eg, lovastatin, pravaststin,
simvastatin. These statin drugs are very effective. Other classes of
drugs includes bile acid sequestrants. Both classes of drugs appear
to be free of serious side effects.
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