Cholesterol synthesis, transport and excretion

1. Pokhara University
School of Health and Allied Sciences
Cholesterol Synthesis,
Transport and Excretion.
Shailendra Shah
Department of pharmaceutical science
Nobel college, Sinamangal
Pokhara University
July 2, 2018ph Pharmaceutical Seminar 21
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2. Pokhara University
School of Health and Allied Sciences
Overview
Introduction.
Synthesis of cholesterol.
Regulation of cholesterol synthesis.
Transportation of cholesterol
Excretion of cholesterol.
References.
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3. Pokhara University
School of Health and Allied Sciences
Introduction
Cholesterol is –
Amphipatheic lipid.
Hydrophobic compound with single
hydroxy group located at carbon-3 of
ring to which fatty acid can be
attached producing cholesteryl ester.
Essential structural component of
membranes.
Present in tissue and plasma either
free cholesterol or cholesteryl ester.
Precursor of other steroids. July 2, 2018Pharmaceutical Seminar 2
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4. Pokhara University
School of Health and Allied Sciences
Structure of cholesterol
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School of Health and Allied Sciences
Biosynthesis of cholesterol.
 Acetyl-CoA is the precursor.
 More then half of the cholesterol of the body arises by
synthesis and remainder is provided by diet.
 Liver and intestine accounts for approximately 10% of total
synthesis in human.
 Virtually, all tissue nucleated cells are capable of cholesterol
synthesis which occurs in endoplasmic reticulum and cytosolic
compartment.
 Biosynthesis of cholesterol can be studied into five steps ;
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6. Pokhara University
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Contd
1. Synthesis of mevalonate from acetyl coA.
2. Formation of isoprenoid unit from
mevalonate by loss of CO2.
3. Condensation of six isoprenoid unit to
form squalene.
4. Cyclization of squalene to give lanosterol.
5. Formation of cholesterol from lanosterol.
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7. Pokhara University
School of Health and Allied Sciences
Contd…
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School of Health and Allied Sciences
Contd…
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School of Health and Allied Sciences
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School of Health and Allied Sciences
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School of Health and Allied Sciences
Contd…
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12. Pokhara University
School of Health and Allied Sciences
Regulation of cholesterol
synthesis
HMG CoA reductase is the rate limiting enzyme for
biosynthesis of the cholesterol. Regulation of
cholesterol can be discussed under following
processes.
 Sterol dependent regulation of gene
expression.
 Sterol accelerated enzyme degradation.
 Sterol independent
phosphorylation/dephosphorylation.
 Hormonal regulation.
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13. Pokhara University
School of Health and Allied Sciences
1. Sterol dependent regulation of gene
expression.
 Expression of the gene for HMG CoA reductase is
controlled by transcription factor, SREBP-2 (sterol
regulatory element-binding prorotein 2)
 SREBP is an integral protein of the ER membrane
and associates with a second ER membrane protein
SCAP (SREBP cleavage- activating protein).
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14. Pokhara University
School of Health and Allied Sciences
Contd…
When sterol level in the cell is low, SREBP- SCAP
complex is sent out of the ER to the Golgi. In the
Golgi, SREBP is sequentially acted upon by two
proteases, which generate a soluble fragment that
enters the nucleus, binds the SRE and functions as
a transcription factor. This results in increased
synthesis of HMG CoA reductase and therefore
increased cholesterol synthesis.
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15. Pokhara University
School of Health and Allied Sciences
Contd…
If sterols are abundant, they binds SCAP at its sterol-
sensing domain and induced the binding of SCAP
to other ER membrane proteins. This results in the
retention of the SCAP-SREBP complex in the ER
thus, preventing the activation of SREBP and
leading to down regulation of cholesterol synthesis.
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16. Pokhara University
School of Health and Allied Sciences
2. Sterol accelerated enzyme
degradation.
The reductase itself is a sterol-sensing integral protein
of the ER membrane. When sterol levels in the cell
are high, the reductase binds to insig proteins.
Binding leads to ubiquitination and proteasomal
degradation of the reductase.
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17. Pokhara University
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3. Sterol independent
phosphorylation/dephosphorylation.
HMG CoA reductase activity is controlled covalently
through the actions of adenosine monophosphate
-activated protein kinase and a phosphoprotein
phosphatase. The phosphorylated form is active.
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School of Health and Allied Sciences
4. Hormonal regulation.
 The amount of HMG CoA reductase is controlled
hormonally. An increased in insulin and thyrroxine
favors up-regulation of expression of the gene for
HMG CoA reductase. Glucagon and the
glucocorticoids have the opposite effect.
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Transportation of cholesterol
Cholesterol is transported in plasma lipoproteins, with
the greater parts in the form of cholesteryl ester
and in human the highest proportion is found in
LDL.
Cholesteryl ester in diet is hydrolyzed to cholesterol
which is then absorbed by the intestine together
with dietary unesterified cholesterol and other lipid.
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20. Pokhara University
School of Health and Allied Sciences
Contd…
The cholesterol synthesized in the intestine is
incorporated into chylomicrons.
80-90% of absorbed cholesterol is esterified with long
chain fatty acids in the intestinal mucosa.
95% of the chylomicrons cholesterol is delivered to the
liver and most of the cholesterol secreted by the
liver in very low density lipoprotein (VLDL) is
retained during the fomation of intermediate
density lipoprotein (IDL) and LDL, which is taken
up by the LDL receptor in the liver and
extrahepatic tissues.
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21. Pokhara University
School of Health and Allied Sciences
Excretion of cholesterol.
Cholesterol is excreted from the body via the bile
either in the unesterified form or after conversion
into bile acids in the liver. Coprostanol is the
principle sterol in the feces. It is formed from
cholesterol by the bacteria in the lower intestine.
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22. Pokhara University
School of Health and Allied Sciences
References
• Murray RK, Bender DA, Botham KM, Kennelly PJ, Rodwell VW and Weil
PA (2012) Harper's Illustrated Biochemistry (29th
Ed.) McGraw Hill
Medical, New York, pp 251-259.
• Rajagopal G (2006) Coincise Textbook of Biochemistry (2nd
Ed.) Ahuja
Publishing House New Delhi pp 136-142.
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23. Pokhara University
School of Health and Allied Sciences
Thank You
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