m Cholesterol is present in tissues and in plasma either as free

cholesterol or as a storage form, combined with a long-chain

fatty acid as cholesteryl ester.

m Cholesterol is an amphipathic lipid and as such is an essential

structural component of membranes and of the outer layer of
plasma lipoproteins.

m It is synthesized in many tissues from acetyl-CoA and

m Is the precursor of all other steroids in the body such as

„
„ 
 

   „  
 .
m As a typical product of animal metabolism,
cholesterol occurs in foods of animal origin such
as egg yolk, meat, liver, and brain.

m Plasma low-density lipoprotein (LDL) is the

vehicle of uptake of cholesterol and cholesteryl
ester into many tissues.

m Free cholesterol is removed from tissues by

plasma high-density lipoprotein (HDL) and
transported to the liver, where it is eliminated
from the body either in unchanged form or after
conversion to bile acids in the process known as
reverse cholesterol transport.
m Cholesterol is a major constituent of ›allstones.

m Pathologically is a main causing factor in the

genesis of atherosclerosis of vital arteries,
causing cerebrovascular, coronary, and
peripheral vascular disease.

m 2therosclerosis is due to deposition of

cholesterol in the lumen of arteries
m A little more than half the cholesterol of the body arises
by synthesis (about 700 mg/d), and the rest is provided
by the average diet.

m The liver and intestine account for approximately 10%

each of total synthesis in humans.

m Virtually all tissues containing nucleated cells are

capable of cholesterol synthesis, which occurs in the
endoplasmic reticulum and the cytosol.

m 2cetyl-Co2
s the ource of 2ll Carbon 2toms in

Cholesterol
¦ynthesis of cholesterol occurs in the cytoplasm of most tissues, but
the liver, intestine, adrenal cortex, and steroidogenic reproductive
tissues are the most active. ¦ynthesis of cholesterol involve
followin› steps:-
1. Acetate, via acetyl CoA, is the initial precursor for cholesterol
synthesis, leading in two steps to  Co2.
2. Conversion of  Co2 to mevalonic acid is catalyzed by the key
regulatory enzyme,  Co2 reductase.
m a. This is the rate-limitin› step of cholesterol synthesis.
m b. HMG CoA reductase is heavily re›ulated by several
mechanisms.
m M
0xpression of the HMG CoA reductase gene is controlled by a
steroldependent transcription factor, which increases enzyme
synthesis in response to low cholesterol levels.
m M

nsulin up-regulates the gene and ›luca›on down-regulates it
m M
0nzyme activity is controlled by reversible phosphorylation
/dephosphorylation in response to 2, ie, cholesterol synthesis is
suppressed when energy levels are low.
. evalonic acid is then modified by phosphorylation and
decarboxylation, and several molecules of it are condensed to form
cholesterol in a complex series of eight reactions.
m The biosynthesis of cholesterol may be divided into five
steps:

(1) ¦ynthesis of mevalonate occurs from acetyl- CoA

(Figure 1).

(2) Isoprenoid units are formed from mevalonate by loss of

CO2 (Figure 2).

(3) ¦ix isoprenoid units condense to form squalene.

(4) ¦qualene cyclizes to give rise to the parent steroid,

lanosterol.

(5) Cholesterol is formed from lanosterol (Figure 3).

tep 1²Biosynthesis of evalonate:
m HMG-CoA (3-hydroxy-3-methylglutaryl-CoA) is formed by the
reactions used in mitochondria to synthesize ketone bodies .

m Initially, two molecules of acetyl-CoA condense to form acetoacetyl-

CoA catalyzed by cytosolic thiolase.

m Acetoacetyl-CoA condenses with a further molecule of acetyl-CoA

catalyzed by -Co2 synthase to form HMG-CoA, which is
reduced to mevalonate by NADPH catalyzed by -Co2
reductase.

m This is the principal regulatory or rate limiting step in the pathway of

cholesterol synthesis and is the site of action of the most effective
class of cholesterol-lowering drugs, the HMG-CoA reductase
inhibitors (statins) (Figure below).
m tep 2²Formation of
soprenoid nits:

m Mevalonate is phosphorylated sequentially by ATP

by three kinases, and after decarboxylation the
active isoprenoid unit, isopentenyl diphosphate,
is formed. Figure (2)
m tep ²ynthesis of ix
soprenoid nits Form  ualene:

m Isopentenyl diphosphate is isomerized by a shift of the double bond

to form dimethylallyl diphosphate, then condensed with another
molecule of isopentenyl diphosphate to form the ten-carbon
intermediate ›eranyl diphosphate (Figure 2).

m A further condensation with isopentenyl diphosphate forms farnesyl

diphosphate.

m Two molecules of farnesyl diphosphate condense at the

diphosphate end to form s ualene.

m Initially, inorganic pyrophosphate is eliminated, forming presqualene

diphosphate, which is then reduced by NADPH with elimination of a
further inorganic pyrophosphate molecule.
m tep
²Formation of anosterol from
s ualene
m ¦qualene can fold into a structure that closely
resembles the steroid nucleus (Figure 3).
m Before ring closure occurs, squalene is
converted to squalene 2,3-epoxide by s ualene
epoxidas in the endoplasmic reticulum.
m The methyl group on C14 is transferred to C13
and that on C8 to C14 as cyclization occurs,
catalyzed by oxidos ualene is a lanosterol
cyclase.
m tep ²Formation of Cholesterol:

m The formation of cholesterol from lanosterol takes place

in the membranes of the endoplasmic reticulum and
involves changes in the steroid nucleus and side chain
(Figure below).
m The methyl groups on C14 and C4 are removed to form
14-desmethyl lanosterol and then zymosterol.

m The double bond at C8±C9 is subsequently moved to

C5±C6 in two steps, forming desmosterol.

m Finally, the double bond of the side chain is reduced,

producing cholesterol.
m The above figure explain - Biosynthesis of
cholesterol. The numbered positions are those of
the steroid nucleus and the open and solid circles
indicate the fate of each of the carbons in the
acetyl moiety of acetyl-CoA.
m Asterisks: Refer to labeling of squalene in above
Figure