Cholesterol biosynthesis

CHOLESTEROL
BIOSYNTHESIS
Department of Biochemistry, KMC, DuwakotThursday, April
09, 2015

Cholesterol
Thursday, April 09, 2015
 Chole: bile; Stereos: solid
 Principal sterol synthesized by animals.
 In vertebrates, hepatic cells typically produce more
cholesterol than other cells.
 Absent among prokaryotes.

Biomedical importance of
cholesterol
 One of the most publicized lipids since it has got correlation with
cardiovascular disease.
 And, less advertised as a component of cell membrane
 Cholesterol occurs in food of animal origin such as egg yolk, liver, meat,
brain etc.
 Vehicle for cholesterol uptake in tissues: LDL
 Vehicle for transport: HDL
 Cholesterol is the major constituent of gall stone. Thursday, April 09, 2015

Cholesterol | Introduction
 Amphipathic lipid, found in two forms:
 Free form
 Esterified form
 Component of outer layer of plasma membrane,
synthesized from Acetyl-CoA
 Precursor for:
Corticosteroids
Bile acids
Sex hormones
Vitamin D

Cholesterol biosynthesis
 Almost equal amount of cholesterol is derived from diet and
synthesis in body.
 700 mg/day is synthesized. Liver and Intestine accounts for
10% each.
 NOTE: Virtually all cells containing nucleated cells are
capable of synthesizing cholesterol which occurs in
endoplasmic reticulum (ER) and nucleus.
 Acetyl-CoA is the source of all carbon atoms in cholesterol.
Coronary atherosclerosis correlates with high plasma LDL/HDL cholesterol ratio.

Cholesterol biosynthesis
 Divided into 5 steps:
 1. Synthesis of mevalonate occurs from Acetyl-CoA
 2. Isoprenoid units are formed from MEVALONATE by loss of
CO2
 3. Six isoprenoid units condense to form SQUALENE
 4. SQUALENE is cyclizes to give rise to parent steroid
LANOSTEROL
 5. Cholesterol is formed from LANOSTEROL

Step 1. Biosynthesis of MEVALONATE
Provastatin, Lovastatin,
Mevastatin
Alternative pathways: through
cytosolic acetoacetyl-CoA
synthetase

Formation of Isoprenoid units

3. Six Isoprenoid units forms
Squalene

4. Formation of LANOSTEROL

5. Formation of Cholesterol

Regulation of Cholesterol synthesis
is controlled by HMG-CoA reductase

Regulation of Cholesterol synthesis
is controlled by HMG-CoA reductase
1. Decreased synthesis of cholesterol in starving animals is accompanied by
reduced activity of the enzyme.
2. Hepatic synthesis is inhibited by dietary cholesterol.
3. HMG-CoA reductase in liver is inhibited by Cholesterol.
4. Cholesterol and metabolites represses transcription of HMG-CoA
reductase transcription by Sterol Regulatory Element Binding Protein
(SREBP).
5. Insulin or thyroid hormone  increases HMG-CoA reductase activity
1. While, Glucagon or glucocorticoids decrease it.

Increase and Decrease in Cholesterol
 Increased by
 1. Uptake of cholesterol-containing lipoproteins by
receptors.
 2. Uptake of free cholesterol from cholesterol-rich
lipoproteins to the cell membrane
 3. Cholesterol synthesis
 4. Hydrolysis of cholesterol ester by the enzyme
cholesterylester hydrolase.

Increase and Decrease in Cholesterol
 Decreased by
 1. Efflux of cholesterol from the membrane to
lipoproteins of low cholesterol potential
 2. Esterification of cholesterol by ACAT (acyl-CoA:
cholesterol acyltransferase)
 3. Utilization of cholesterol for synthesis of other
steroids such as hormones or bile acids in liver

What are the factors that influence
cholesterol balance in tissues?
LDL receptor is highly regulated.

Transport of Cholesterol between
tissues in plasma lipoproteins
What is reverse cholesterol transport?

Transport of Cholesterol between
tissues in plasma lipoproteins
Cholesterol that is synthesized in extrahepatic tissues or acquired from
lipoproteins is returned to the liver for excretion in a process called
“reverse cholesterol transport”.

Uptake of cholesterol by receptor-
mediated endocytosis

Conversion of cholesterol to bile

Excretion of Cholesterol from body
 Excreted from the body via the bile either in the
unesterified form or after conversion into bile acids
in the liver.
 Coprostanol is the principal sterol in the feces; it is
formed from cholesterol by the bacteria in the lower
intestine.

Cholesterol balance in tissues
 Increase of cholesterol in cells
 Increased synthesis of cholesterol
 Hydrolysis of cholesterol ester by the enzyme
“cholesterol ester hydrolyase”.
 Uptake and delivery of cholesterol in cells by
circulating LDL
 Uptake of cholesterol-containing lipoproteins by ‘non-
receptor’
 Uptake of free cholesterol by cell membranes

Cholesterol balance in tissue
(contd…)
 Decrease of cholesterol in cells
 Efflux of cholesterol from cells to HDL
 Esterification of cholesterol by the enzyme “Acyl-CoA-
cholesterol acyl transferase” (ACAT).
 Utilization of cholesterol for synthesis of steroid
hormones, viz. glucocorticoids, mineralo-corticoids,
gonadal hormones
 In liver cells: formation of cholic acid
 Formation of Vitamin D3

Consideration of other factors that
influence cholesterol level in blood
 Dietary fats (saturated FA vs Unsaturated FA)
 Dietary cholesterol
 Dietary carbohydrates
 Heredity
 Blood groups
 Calorie Intake
 Vitamin B-complex
 Minerals
 Dietary fibers
 Physical exercise
 Life style of an individual

Clinical aspects
 Plasma cholesterol level >5.2 mmol/L is one of the
major factors in promoting atherosclerosis.
 Prolonged elevation of levels of VLDL, IDL,
chylomicron remnants, or LDL in blood (e.g.,
diabetes mellitus, lipid nephrosis, hypothyroidism)
 LDL/HDL cholesterol ratio is a good predictive
parameter.

Drugs help to reduce serum
cholesterol and triacylglycerol
 Statin acts by inhibiting HMG-CoA reductase and
upregulating LDL receptor activity
 Example: atrovastatin, simvastatin, fluvastatin,
pravastatin.
 Ezetimibe reduces blood cholesterol levels by
inhibiting the absorption of cholesterol by the intestine
by blocking uptake via the Neimann-Pick C-like 1
protein.

1. Harper’s Biochemistry, 25th. Edition.
2. Lippincott’s Illustrated Review, 5th.
Edition
3. Lehninger, Principles of Biochemistry,
5th. Edition.
References

Cholesterol biosynthesis

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