Abdul Salam M Sofro

Faculty of Medicine
YARSI University
Learning objectives
By the end of lectures, students are
expected to understand:
The process of cholesterol synthesis
and excretion
Cholesterol transport in blood
circulation
Introduction
Cholesterol present in tissue & in plasma
lipoproteins either as free cholesterol or, combined
with a long chain FA as cholesteryl ester
It is synthesized in many tissues from acetyl-CoA
and is ultimately eliminated from the body in the
bile as cholesterol or bile salts
Cholesterol is precursor of all other steroids in the
body (corticosteroids, sex hormones, bile acids &
vitamin D)
It is typically a product of animal metabolism
occurs in food of animal origin (egg yolk, meat,
liver, brain)
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.
Cholesterol synthesis occurs in the cytoplasm
and microsomes from the two-carbon acetate
group of acetyl-CoA.
Biomedical importance
Cholesteryl ester is a storage form of cholesterol
found in most tissues
It is transported as cargo in the hydrophobic core
of lipoprotein
LDL is the mediator of cholesterol & cholesteryl
ester uptake into many tissues
Free cholesterol is removed from tissues by HDL
and transported to liver for conversion to bile
acids (cholesterol is major constituent of
gallstones)
Cholesterol plays major role in the genesis of
atherosclerosis
Acetyl-CoA is the source of all carbon atom
in cholesterol
Five stages in biosynthesis of cholesterol:
Synthesis of Mevalonate, a six-carbon compound,
from acetyl-CoA
Isoprenoid units are formed from mevalonate by
loss of CO2
Six isoprenoid units condense to form the
intermediate squalene
Squalene cyclisized to parent steroid, lanosterol
Cholesterol is formed from lanosterol after several
further steps including the loss of three methyl
groups
Pathway of cholesterol biosynthesis. Synthesis begins with the transport of acetyl-CoA ffrom
the mitochondrion to the cytosol. The rate limiting step occurs at the 3-hydroxy-3-
methylglutaryl-CoA (HMG-CoA) reducatase, HMGR catalyzed step. The phosphorylation
reactions are required to solubilize the isoprenoid intermediates in the pathway.
Regulating Cholesterol Synthesis
Normal healthy adults synthesize cholesterol
at a rate of approximately 1g/day and
consume approximately 0.3g/day. A relatively
constant level of cholesterol in the body (150
- 200 mg/dL) is maintained primarily by
controlling the level of de novo synthesis.
The level of cholesterol synthesis is
regulated in part by the dietary intake of
cholesterol.
Regulation of HMG-CoA reductase:
Reduced activity in fasting animals
(reduced synthesis of cholesterol during
fasting)
Feedback mechanism whereby HMG-
CoA reductase in liver in inhibited by
mevalonate, the immediate product &
cholesterol, the main product of the
pathway (cholesterol metabolite, eg.
oxygenated sterol is considered to
repress transcription of the HMG-CoA
reductase gene
Many factors influence the cholesterol balance
in tissues:
Increase is due to uptake of cholesterol-
containing lipoproteins by receptors;
uptake of free cholesterol from
cholesterol-rich lipoproteins to the cell
membrane; cholesterol synthesis; and
hydrolysis of cholesteryl-ester by the
enzyme cholesteryl ester hydrolase
Decrease is due to efflux of cholesterol
from the membrane to lipoproteins of low
cholesterol potential; esterification of
cholesterol by acyl-CoA:cholesterol
acyltransferase (ACAT); and utilization of
cholesterol for synthesis of other steroids,
such as hormones or bile acids in liver

The cellular supply of cholesterol is maintained
at a steady level by three distinct mechanisms:

1. Regulation of HMGR activity and levels
2. Regulation of excess intracellular free
cholesterol through the activity of acyl-
CoA:cholesterol acyltransferase, ACAT
3. Regulation of plasma cholesterol levels via
LDL receptor-mediated uptake and HDL-
mediated reverse transport.

Cholesterol is transported between
tissues in plasma lipoproteins
In human on westernized diets, the total plasma
cholesterol is about 5.2 mmol/L (rising with age
& wide variations between individuals)
Mostly in esterified form & transported in plasma
lipoproteins being the highest in the LDL (or in
VLDL if VLDL is quantitatively more prominent)
Dietary cholesterol takes several days to
equilibrate with cholesterol in the plasma &
several weeks to equilibrate with cholesterol of
the tissues


Good & bad Cholesterol and their effect on
health
It is commonly known that a high level
of cholesterol in the blood
hypercholesterolemia poses a risk for
coronary heart disease (CHD) & heart
attack.
Cholesterol is insoluble in the blood, it is
transported to and from the cells by
carriers known as lipoproteins
Low-density lipoprotein (LDL) or Bad
Cholesterol
Is the major cholesterol carrier in the
blood if too much LDL cholesterol
circulates in the blood.
It can slowly build up in the walls of the
arteries feeding the heart and brain.
Together with other substances it can
form plaque, a thick, hard deposit that
can clog those arteries (a condition
known as atherosclerosis)
High-density lipoprotein (HDL) or Good
Cholesterol
Carries about one-third to one-fourth of blood
cholesterol
Experts think HDL tends to carry cholesterol
away from the arteries and back to the liver,
where it is metabolized and removed.
It is believed that HDL can remove excess
cholesterol from plaques and therefore slow
their growth. However, while a high level of HDL
decreases the associated risks, a low level of
HDL cholesterol level may increase the
possibility of stroke or heart attack.
Cholesterol excretion
Cholesterol must enter the liver & be excreted in
the bile as cholesterol or bile acids (salts)
About 1 g of cholesterol is eliminated from the
body per day. Approx. half is excreted in the
feces after conversion to bile acids, the
remainder is excreted as cholesterol.
Much of the cholesterol excreted in the bile is
reabsorbed & at least some of the cholesterol
that serves as precursor for the fecal sterols is
derived from the intestinal mucosa.
Coprostanol is the principal sterol in the
feces (formed from cholesterol by the
bacteria in lower intestine)
Cholesterol
7-OH-Cholesterol
Cholyl-CoA
Chenodeoxy-
cholyl-CoA
Taurocholic acid
Glycocholic acid
Deoxycholic acid
Lithocholic acid
Tauro- & glyco-
Chenodeoxycholic acid
(primary bile acid)
(primary bile acid)
(primary bile acid)
(secondary bile acid)
(secondary bile acid)
7-hydroxylase
Vit. C
(-)
Bile acids
Vit. C defic.
Cholesterol
(+)
Most bile acids return to the liver in
the enterohepatic circulation
Product of fat digestion including
cholesterol are absorbed in the first 100
cm of small intestinum
Primary & secondary bile acids are
absorbed almost exclusively on the
ileum, returning to the liver by way of
portal circulation about 98-99% of the
bile acids secreted into the intestine
(called enterohepatic circulation)
Perhaps only as little as 400 mg/d escapes
absorption & eliminated in the feces
(represent a major pathway for the
elimination of cholesterol)
About 3-5 g bile salts can be cycled through
the intestine 6-10 times with only a small
amount lost in the feces each day an
amount of bile acid equivalent to that lost in
the feces is synthesized from cholesterol by
the liver.