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
 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
 Cholesterol plays major role in the genesis of
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
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
 Regulation of HMG-CoA reductase:
 Reduced activity in fasting animals
(reduced synthesis of cholesterol during
 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
 It is commonly known that a high level
of cholesterol in the blood –
hypercholesterolemia – poses a risk for
coronary heart disease (CHD) & heart
 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
 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
 Carries about one-third to one-fourth of blood
 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)
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)
Vit. C
Bile acids
Vit. C defic.
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.