Introduction

Cholesterol is an extremely important biological molecule that has roles

in membrane structure as well as being a precursor for the synthesis of the steroid
hormones, the bile acids, and vitamin D. Both dietary cholesterol, and that
synthesized de novo, are transported through the circulation in lipoprotein
particles. The same is true of cholesteryl esters, the form in which cholesterol is
stored in cells. Due to its important role in membrane function, all cells express the
enzymes of cholesterol biosynthesis.

The synthesis and utilization of cholesterol must be tightly regulated in order to

prevent over-accumulation and abnormal deposition within the body. Of particular
clinical importance is the abnormal deposition of cholesterol and cholesterol-
rich lipoproteins in the coronary arteries. Such deposition, eventually leading to
atherosclerosis, is the leading contributory factor in diseases of the coronary
arteries.

Biosynthesis of Cholesterol

Slightly less than half of the cholesterol in the body derives from biosynthesis de
novo. Biosynthesis in the liver accounts for approximately 10%, and in the
intestines approximately 15%, of the amount produced each day. The cholesterol
biosynthesis pathway involves enzymes that are in the cytoplasm, microsomes
(ER), and peroxisomes. Synthesis of cholesterol, like that of most biological lipids,
begins from the two-carbon acetate group of acetyl-CoA. The initial steps in the
pathway of cholesterol biosynthesis are collectively called the mevalonate pathway
which itself culminates with the synthesis of the isoprenoid molecule, isopentenyl
pyrophosphate (IPP).
The acetyl-CoA utilized for cholesterol biosynthesis is derived from an oxidation
reaction (e.g., fatty acids or pyruvate) in the mitochondria and is transported to the
cytoplasm by the same process as that described for fatty acid synthesis (see the
Figure below). Acetyl-CoA can also be synthesized from cytosolic acetate derived
from cytoplasmic oxidation of ethanol which is initiated by cytoplasmic alcohol
dehydrogenase (ADH). All the reduction reactions of cholesterol biosynthesis use
NADPH as a cofactor. The isoprenoid intermediates of cholesterol biosynthesis
can be diverted to other synthesis reactions, such as those for dolichol (used in the
synthesis of N-linked glycoproteins, coenzyme Q (of the oxidative
phosphorylation pathway) or the side chain of heme-a. Additionally, these
intermediates are used in the lipid modification of some proteins.

Process of cholesterol synthesis

The process of cholesterol synthesis can be considered to be composed of

five major steps where the reactions that culminate in the synthesis of
isopentenyl pyrophosphate, and its isomeric form dimethylallyl pyrophosphate,
are commonly referred to as the mevlonate pathway:

1. Acetyl-CoAs are converted to 3-hydroxy-3-methylglutaryl-CoA (HMG-

CoA)

2. HMG-CoA is converted to mevalonate

3. Mevalonate is converted to the isoprene based molecule, isopentenyl

pyrophosphate (IPP)

4. IPP molecules are converted to squalene

5. Squalene is converted to cholesterol.

FOUR STATES OF CHOLESTEROL SYNTHESIS

1.   Acetate ® Mevalonate  (by three cytosolic enzymes)

 
·        Thiolase
 

 
·        

Hydroxymethylglutaryl-CoA synthase
                                                                                 b-Hydroxymethylglutaryl-CoA (
HMG-CoA)
 
·        HMG-CoA reductase  (Fig. 19-38)

·        The first two enzymes in cytosol are involved in cholesterol synthesis,

whereas the corresponding mitochondrial enzymes are involved in ketone body
(acetoacetate) synthesis.
·        The synthesis of mevalonate is irreversible, and is the rate-determining
step in cholesterol synthesis.
·        HMG-CoA reductase can be inhibited by cholesterol.
 
2.   a.  Mevalonate ®® Isopentenyl pyrophosphate (IPP)       
b.  IPP ⇌ Dimethylallyl pyrophosphate (DMP) by isopentenyl pyrophosphate
isomerase
  
3.   (IPP +  DMP) ®®® Squalene  
 
4.   Squalene ®®® Cholesterol
·        squalene ® 2,3-oxidosqualene (Fig. 19-40) catalyzed by squalene epoxidase,
requires NADPH.
·        2,3-oxidosqualene ® lanosterol (Fig. 19-41)
·        lanosterol ® cholesterol by 19 steps
(Need to know structures of 2,3-oxidosqualene and lanosterol.)
 
 
Complex lipids  
 
1. Phosphatidic Acid, Diacylglycerol, Triacylglycerol.  (Fig. 19-30)
·        Phosphatidic acid, diacylglycerol, and triacylglycerol are all synthesized
from fatty acyl-CoA and glycerol-3-phosphate or dihydroxyacetone phosphate.
·        The acyltransferases are not completely specific for any particular acyl-
CoA with respect to either chain length or degree of unsaturation.  However, in
human adipose tissue triacylglycerols, 1-acyl group is mostly saturated
(especially the C-16 palmitoyl) and the 2-acyl group is mostly unsaturated
(especially the C-18, cis-D9 oleyl).
 
2. Phosphatidylethanolamine, Phosphatidylcholine, and Phosphatidylserine
·        Both ATP and CTP are required to activate ethanolamine and choline.  The
activated metabolites subsequently react with 1,2-diacylglycerol to
generate phosphatidylethanolamine and phosphatidylcholine.  (Fig. 19-34)
·        Phosphatidylserine can be obtained
from phosphatidylethanolamine and serine by an exchange reaction.  (p. 664)
 
3. Phosphatidylinositol and Phosphatidylglycerol
·        Both Phosphatidylinositol and Phosphatidylglycerol are
from Phosphatidic Acid (Fig. 19-35).
·        CTP is required to activate phosphatidic acid to form CDP-diacylglycerol.

Biosynthesis

All animal cells manufacture cholesterol, for both membrane structure and other
uses, with relative production rates varying by cell type and organ function. About
80% of total daily cholesterol production occurs in the liver and the intestines;
other sites of higher synthesis rates include adrenal glands, and reproductive
organs.

Synthesis within the body starts with the mevalonate pathway where two

molecules of acetyl CoA condense to form acetoacetyl-CoA. This is followed by a
second condensation between acetyl CoA and acetoacetyl-CoA to form 3-hydroxy-
3-methylglutaryl CoA (HMG-CoA).[26]

This molecule is then reduced to mevalonate by the enzyme HMG-CoA reductase.

Production of mevalonate is the rate-limiting and irreversible step in cholesterol
synthesis and is the site of action for statins (a class of cholesterol lowering drugs).
Mevalonate is finally converted to isopentenyl pyrophosphate (IPP) through two
phosphorylation steps and one decarboxylation step that requires ATP.
Three molecules of isopentenyl pyrophosphate condense to form farnesyl
pyrophosphate through the action of geranyl transferase.

Two molecules of farnesyl pyrophosphate then condense to form squalene by the

action of squalene synthase in the endoplasmic reticulum.[26]
Oxidosqualene cyclase then cyclizes squalene to form lanosterol. Finally,
lanosterol is converted to cholesterol through a 19-step process.[27][28]
The final 19 steps to cholesterol contain NADPH and oxygen to help
oxidize methyl groups for removal of carbons, mutases to move alkene groups,
and NADH to help reduce ketones.

Konrad Bloch and Feodor Lynen shared the Nobel Prize in Physiology or

Medicine in 1964 for their discoveries concerning some of the mechanisms and
methods of regulation of cholesterol and fatty acid metabolism.
BENEFITS OF CHOLESTEROL TO MAN WITH ITS LIMITATIONS/
HEALTH HAZARD

Cholesterol is often described as a waxy substance. Approximately 80% of the

cholesterol that is needed by the body is made in the liver. The rest to acquired
through eating substances with cholesterol in them or by eating sugars, fats and
proteins that can be converted to cholesterol. Most products with cholesterol in
them are animal products like dairy goods and meat. Sugars, fats and proteins are
fairly obvious. The fats to watch out for are saturated and trans fats. Processed
foods often contain these types of fats, especially things like cakes, biscuits and
potato chips.

Benefits of cholesterol

1. Cholesterol is a hard substance that is used in the membranes of each cell in

the body. It gives the cell strength and rigidity.
2. Increase vitamin D. Vitamin D is used in the immune system and can help to
regulate blood pressure. If a person is in the sun, the sunlight will convert
cholesterol to vitamin D.
3. Cholesterol acts as a transport for various antioxidant vitamins and enzymes,
particularly vitamin A and E.
4. Skin Protection. The waxy substance acts as a protective layer against sun
and wind damage. It has been found in higher than normal levels in scar
tissue suggesting that it is involved in the healing process.

Limitation / health hazard of cholesterol

1. Cholesterol is not soluble in the blood so it has to be transported by
attaching to lipoproteins in the blood. The two important types of
lipoproteins are known as low density and high density lipoproteins.
2. Low density lipoproteins (LDL) transport cholesterol away from the liver for
use in the functions described above. However, when there is too much LDL
cholesterol it tends to stick to the artery walls. This is know as thickening
arteries or athersclerosis. Atherosclerosis can cause high blood pressure as
the volume of the arteries is decreased. It can lead to blood clots if there are
blockages in the arteries. This can lead to a stroke. Ultimately, too much
cholesterol leads to heart disease.
3. High density lipoproteins (HDL) are responsible for transporting cholesterol
back to the liver where it is excreted.
4. LDL cholesterol is known as bad cholesterol. HDL cholesterol is known as
good cholesterol. The aim of anyone with a high cholesterol reading is to
reduce LDL and increase HDL.
5. This can be done be modifying eating habits so that more fiber is eaten. Eat
less carbohydrates and the right type of fats. Saturated and trans fats are out.
Take on regular exercise to utilize excess calories consumed and to work the
body.
w-density lipoprotein (LDL) is the “bad,” unhealthy kind of cholesterol. LDL
cholesterol can build up in your arteries and form fatty, waxy deposits called
plaques.

High-density lipoprotein (HDL) is the “good,” healthy kind of cholesterol. It

transports excess cholesterol out of your arteries to your liver, which removes
it from your body.
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Cholesterol itself isn’t bad. Your body needs some cholesterol to make
hormones, vitamin D, and digestive fluids. Cholesterol also helps your organs
function properly.