Cholesterol 2 Import 4

Biochemistry
1
Biochemistry
Cholesterol : is a fat-like substance found
in the blood stream and in all the cells. It is
used in the body in the synthesis of the cell
membranes, protecting nerves, digesting
dietary fats. It produces certain hormones
such as the sexual hormones. Around 75% of
cholesterol of the body needs is made
naturally by the liver and other cells of the
body and can be effected by heredity while the
25% comes from foods such as eggs, meats,
butter, and dairy products (Stein et al., 1994).
2
Biochemistry
 Cholesterol doesn’t contain fatty acids, its
sterol nucleus is synthesized from degradation
products of fatty acid molecules, and thus
giving it different physical and chemical
properties to other lipid
substances .Cholesterol can be obtained from
the diet and it can be synthesized in the body.
The liver is the major site of cholesterol
synthesis in mammals, although the intestine
also forms significant amounts. The rate of
cholesterol formation by these organs is highly
responsive to the cellular level of cholesterol.
3
Biochemistry
 Acetyl-CoA is a building unite of cholesterol,
this unit produced from degradation complex
organic compounds (like carbohydrates, fatty
acids and amino acids) to simple substances .
 Cholesterol and triglycerides are transported
in the body fluids in the form of lipoprotein
particles. Thus, all lipoproteins contain
cholesterol so that an increase in any of them
will elevate the plasma total cholesterol
concentration
4
cholesterol structure
Biochemistry
Lipoprotein:
A lipoprotein is a complex of protein and
lipid with a characteristic density, size
and chemical composition. Lipoproteins
transport lipids in blood between the
sites of their absorption, the liver and
various tissues that utilize lipids. The
major lipoprotein classes are :
6
Biochemistry
A-Chylomicrons:
Which are large lipoprotein of extremely low
density and secreted by the small intestine,
transport dietary triglycerides and cholesterol
esters from the intestine to the tissues.
Chylomicrons may be atherogenic when their
concentrations in plasma is chronically elevated.
Chylomicrons elevations, which are exacerbated by
a high-fat diet, do not appear to be a risk factor for
atherosclerosis.
7
Biochemistry
B-Very low-density lipoprotein (VLDL):
This type of lipoprotein are synthesized in the
liver and are associated with Chylomicrons .
Lipid synthesized by the liver are carried by
VLDL to tissues.VLDL secretion may be
converted by cholesteryl ester availability. It is
important to mention an increase in VLDL
does not consider a serious risk factor for
atherosclerosis
8
Biochemistry
C- Low density lipoprotein (LDL):
people often refer to it as bad cholesterol
This kind of lipoprotein is responsible for carrying
cholesterol from liver to tissues. LDLis engulfed by
cells after binding to LDL receptors. Higher LDL
increases risk factor of heart disease.
The more extreme LDL elevations usually are genetic in
origin, and dietary restriction produces little
improvement . LDL lipoproteins carry cholesterol from
the liver into the body because these cells having LDL-
receptors on their surfaces.
9
Biochemistry:
D-High-density lipoprotein (HDL):
people often refer to it as good cholesterol.
HDL lipoproteins carry cholesterol from liver
and circulate in the blood to pick up excess
cholesterol from the body and carry it back to
the liver to be removed from the body . HDL
are relatively small lipoproteins rich in
cholesteryl esters, phospholipids and
apoprotein A . Two types of HDL can be
isolated from plasma, HDL2 and HDL3
10
Biochemistry
 E-Intermediate-density lipoprotein
(IDL):
 IDL is product of VLDL catabolism in
the bed of capillary, from which a large
share of the triglyceride have been
removed. IDL is converted to LDL and
undetectable in normal plasma
13
Biochemistry
Cholesterol synthesis,
transport and
excretion
Biochemistry
Importance and uses
1- It is a precursors for all steroids, such as, Vit.D,
corticosteroids, sex HS, and bile salts.
2- His an essential structure of cell membranes and outer layer
of LP.
3- Chol ester is a storage form of chol. in tissue.
4- LDL is mediator for chol.
5- It is a major consistituents of gall stone.
6- In the genes of atherosclerosis.
 More than 5% of chol. is synthesized ( 700 mg/day ) and the
remainder is provide from the diet.
 In human 10% synthesis by liver, 10% by small intestine,
and tissue contain nucleated cell are capable to form chol.
Biochemistry
Cholesterol synthesis
 Acetyl CoA is the source of all carbon atom in cholesterol
 The synthesis involve 5 stage:
1- The synthesis of mevalonate 6 carbon compound from
acetyl CoA.
2- Isoprenoid to formed from mevalonate by loss of CO2
3- Six isoprenoid to form squaline
4- Squaline cyclizes to give rise lanosterol.
5- Lanosterol loss 3- methyl group to form cholesterol .
w
Biochemistry
Biochemistry
Biochemistry
The synthesis of cholesterol utilize
1- 18 mole of acetate: each mole of mevalonic acid produce by
3 M of acetate, 6 mole of mevalonat produce cholesterol.
2- 6 mole of CO2 are eliminated from conversion of mevalonic
acid------ 3- isopentyl PP.
3- 3 mole of CO2 are eliminated in conversion of lanosterol to
cholesterol. chol. is 27 C atom.
4- Required 18 mole of ATP.
5- Required 13 mole of NADPH.
 HMG CoA reductase: this inhibited by elevated level of
cholesterol, blocking the excessive synthesis when high
cholesterol is taken in diet.
Biochemistry
Regulation of cholesterol synthesis

 Regulation of chol. is near the beginning of pathway at
HMGCoA reductase.
1- Mark decrease in the activity of enzyme in fasting.
2- There is feed bake mechanism, the enzyme inhibited by
mevaloante, and cholesterol., cholesterol ester it is metabolite
may act either:
a- Repression‫ قمع‬the synthesis of new reductase.
b- Inducing the enzyme degrade the existing reductase.
3- Inhibited by cholesterol taken up via LDL receptor (apo
B100, E receptors) which effect on chol. synthesis and on
reductase activity.
Biochemistry
4- Insulin, thyroid HS increase HMG CoA reductase

activity, whereas glucagon and glucocorticoids
decrease activity of the enzyme.
5- Variation of cholesterol in diet, when there is only
0.05%. in the diet, 70-80% of chol. synthesis in
liver, adrenal gland, in the body. When dietary
intake reside up to 2%. The endogenous production
decrease and the hepatic synthesis is inhibited by
cholesterol-rich chylomicrons remnants, taken by
liver inhibited sterol synthesis.
Biochemistry
Disorder of lipid metabolism
 Serum cholesterol and its relation to atherosclerosis
 Atherosclerosis characterize the presentation of chol. Ester of
LP containing apo B100 i.e. VLDL, TDL and LDL. Any
disease cause high amount or elevated in these lipoprotein
cause atherosclerosis. Such diseases are:
1- lipid nephrosis 2- hypothyroidism 3- another condition
of hyperlipemia
Factors affect serum cholesterol level
1- Hereditary factors, which is the greatest factor affected blood
chol. Conce.
2- Diet and envirment factor also affected.
Biochemistry
 The substance of poly unsaturated, Mono unsat. F.A is good and leads to
reduce serum cholesterol levels. These acids present in sunflower, cotton
seeds, soybean oil, but butter, beef fat, contain high amount of saturated
F.A.
 The reason for poly unsaturated F.A lower S. chol. Is not clear , however
several hypothesis as:
1- Stimulation chol. Excretion 2- stimulation chol. Oxidation to bile
acid.
 It is possible that chol. Ester of poly unsat. F.A are more rapidly
metabolize by the liver and other tissue and enhance their excretion or
oxidation. The important thing is by increase distribution of cholesterol
from plasma to tissue due to increase catabolic rate of LDL due to the
regulation of LDL receptor by poly unsat. F.A and reduce regulation in
presence of sat. F.A, because of formation small VLDL that contain more
chol. Which is metabolize at slower rate than large partical.
 Sucrose, fructose have greater effect in raising blood lipid than other
carbohydrate.
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Biochemistry

Regulation of cholesterol synthesis

4- Insulin, thyroid HS increase HMG CoA reductase

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