BIOCHEMISTRY MD 3208 CARDIOVASCULAR SYSTEM

Cholesterol Metabolism and

Hypercholesterolemia

07.10.2015
SRUDENTS IN THE LECTURE ROOM
AFTER LUNCH
 CLINIC K
OPENING HOURS-6-9pm

What are
causes of
chest pain?
 Learning Outcomes
List the sources and functions of
cholesterol(4*)
Outline the cholesterol synthesis and its
regulation.(3*)
State factors affecting cholesterol level(4*)
Describe how cholesterol is transported and
removed in the body.(5*)
Discuss the hypercholesterolemia and its
clinical importance.(5*)
 INTRODUCTION
Understanding the cholesterol metabolism is very helpful
for the physician in the management of
hypercholesterolemia.
 Cholesterol Structure
Free cholesterol

Cholesterol Ester

R-COO

Major steroid in the body

Present in tissues & plasma lipoproteins
as free cholesterol 30% or as cholestrol ester 70%.
 MILESTONES

It was isolated from gallstone in 1784.

Cholesterol was first found to be associated with

atherosclerosis in 1912-1913 by Nikolai Anichkov.

Cholesterol synthesis pathway was elucidated in

1950s

Thirteen Nobel Prizes have been awarded to

scientists whose careers in cholesterol.

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 Sources
(1) Endogenous source
-synthesized about 500-700 mg/day
-all nucleated cells can synthesize
cholesterol
(2) Exogenous source
-average diet contains 300-500 mg/Day
-food of animal origin such as meat, liver,
brain, egg yolk, lard

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 Cholesterol Synthesis
De novo synthesis is occurred in all
nucleated cells.
Site- cytosol and endoplasmic
reticulum
Greatest in liver(50%, intestine(10-
20%),skin, adrenal cortex ,
reproductive tissue and placenta.
Acetyl CoA is a precursor.

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Regulation of Cholesterol
Synthesis

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 Regulation of Cholesterol
Synthesis
Regulatory enzyme is HMG CoA
reductase.
Its activity is decreased in fasting.
(1) Allosteric effectors
- cholesterol & mevalonate exert
negative feed-back inhibition on the
enzyme.
- Acetyl CoA-positive feed-back
activation on the enzyme.
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 (2) Hormonal Control
Glucagon- inactive form of HMG-CoA
reductase by phosphorylation (fasting)

Insulin- active form of HMG-CoA

reductase by dephosphorylation (fed)

Thyroid hormone increases and

glucocorticoid decreases the enzyme
activity.
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(3) Sterol-mediated regulation of
transcription

An increase in the intracellular

cholesterol inhibits transcription of
the HMG-CoA reductase gene, leading
to a decrease in de novo cholesterol
synthesis.

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 Blood Cholesterol Level &
Its Transport
Blood Cholesterol level= 3.8-6.7 mmol/L
(150 250 mg/dl)
Dietary cholesterol (Exogenous)
- transported by chylomicron from
intestine to liver.
Endogenous cholesterol
- transported by VLDL & LDL from liver
to tissue.
- transported by HDL from tissue to
liver.
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 Functions of Cholesterol
Formation of Bile acids & Bile salts
Synthesis of Adrenal cortical hormones
Synthesis of Sex hormones
Precipitated in corneum & protect the skin
Prevent evaporation of water from skin
Precursor of Vitamin D
Component of cell membranes

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 Factors Influencing Blood Cholesterol
Level
(1) Hereditary Factors
(2) Dietary Factor
(3) Hormone
(4) Life Style

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 Factors control concentration of blood
cholesterol

1. Hereditory factors

Hyperlipidemia
Type --IIa .Defective LDL receptor
Type --IIb. Overproduction of Apo B 100
Type-- III .Abnormality in Apo E

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 (2) Dietary Factors
i) Dietary Cholesterol
Reduce 100 mg of dietary cholesterol can decrease 0.13 mmol/L in
blood
ii) PUFA - lowers blood cholesterol by :
Stimulation of cholesterol excretion into intestine
Stimulation of cholesterol oxidation to bile acids.
Upregulation of LDL Receptors.

iii) SFA - Eg. Butter fat, beef fat, coconut oil, palm oil.
increases blood cholesterol
Inhibiting conversion of cholesterol to bile acids
Decreasing cellular uptake of LDL
iv) Dietary Fiber
5% decrease in serum cholesterol is observed by adding a
reasonable amount of fiber (30 gm) to the diet.
v) Dietary content of garlic------decrease blood lipids
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 (3) Hormones
1. Estrogens
-increase HDL & decrease LDL
-increase catabolism of LDL by increasing number of
LDL receptor

2. Thyroid Hormones
-lowers blood cholesterol
-by increasing number of LDL receptors in liver

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 (4) Life Style

Increasing Factors Decreasing Factors

- Smoking, Coffee Drinking, - Moderate drinking of Red
Drinking Soft Water
wine
- Male Gender

- Obesity

- Lack of exercise

- Emotional Stress

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 The ring structure of cholesterol can not be
metabolized to CO2 & H2O.
About 1 gm of cholesterol is eliminated from
the body per day.
0.5 gm 0.5 gm
Bile acids (P&S) Neutral sterol
Coprostanol
Cholestanol

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 Hypercholesterolemia
is the presence of high levels of cholesterol in
the blood.
CAUSES
Primary causes
Genetic defect--- familial hypercholesterolaemia
Secondary causessecondary to metabolic
derangement
DM, obesity, alcohol, nephrotic
syndrome, hypothyroidism, Cushings syndrome
 Familial Hypercholesterolemia

is a genetic disorder characterized by high

cholesterol levels, specifically very high levels
of low-density lipoprotein (LDL, "bad
cholesterol"), in the blood and
early cardiovascular disease.
mutations in gene that encodes the LDL
receptor protein, which normally removes LDL
from the circulation, or apolipoprotein B (Apo
B)
Clinical signs of hypercholesterolemia
xanthelasma = Yellow deposits of cholesterol-
rich fat around the eyelids
arcus senilis =white or gray discoloration of
the peripheral cornea
tendon xanthoma
 Hypercholesterolemia and
atherosclerosis
chronically elevated serum cholesterol
contributes to formation of atheromatous
plaques in the arteries.
This can lead to
progressive stenosis (narrowing) or
complete occlusion (blockage) of arteries.
Alternatively smaller plaques may rupture and
cause a clot to form and obstruct blood flow
Sudden occlusion of
Coronary artery --- myocardial infarction or
heart attack.
Cerebral artery --- stroke.
Lower limb arteries--- Peripheral arterial
disease (calf pain when walking)
Confirmation ----Lipid profile
Interpretation of cholesterol levels
cholesterol type mg/dl mmol/l interpretation
<200 <5.2 desirable
Total cholesterol 200-239 5.2-6.2 borderline
>240 >6.2 high
<100 <2.6 most desirable
100-129 2.6-3.3 good
130-159 3.4-4.1 borderline high
LDL cholesterol
high and
160-189 4.1-4.9
undesirable
>190 >4.9 very high
undesirable; risk
<40 <1.0
increased
okay, but not
HDL cholesterol 41-59 1.0-1.5
optimal
good; risk
>60 >1.55
lowered
 Cholesterol Lowering Drugs
Statin drugs
- are the reversible competitive inhibitors of
HMG-CoA reductase.
e.g., lovastatin, simvastatin, atovastatin
Cholestyramine bile-acid binding resin (blocks bile
acid reabsorption in the intestine)
Ezetimibe block cholesterol absorption in jejunum

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 REFERENCES
HERPERS Biochemistry
Lippincotts Biochemistry textbook
Devlins textbook of biochemistry.
Davidsons textbook of medicine.