CHOLESTEROL SYNTHESIS,

TRANSPORT, AND EXCRETION

AT THE END OF THIS LECTURE

YOU ARE EXPECTED TO:
Give the biological importance of
cholesterol
Identify the characteristics of cholesterol
structure
Name the essential steps towards the
synthesis of cholesterol
Discuss how cholesterol synthesis is
regulated

AT THE END OF THIS LECTURE

YOU ARE EXPECTED TO:
Identify factors that influence cholesterol
balance in the body
Discuss how cholesterol is transported to
different body tissues
Discuss how cholesterol is excreted from
the body
Define some clinical conditions related to
abnormal cholesterol metabolism

BIOLOGIC IMPORTANCE OF
CHOLESTEROL
Structural component
of all cell membranes
Modulates membrane
fluidity
At temperatures
below melting
temperature, it
increases membrane
fluidity

BIOLOGIC IMPORTANCE OF
CHOLESTEROL
Cholesterol is a precursor of bile acids,
steroid hormones, and Vitamin D
Cholesterol is a component of plasma
lipoproteins sent to the peripheral tissues
When produced in excess, cholesterol
causes atherosclerotic plaque formation
and leads to an increased risk for
coronary artery disease

CHOLESTEROL STRUCTURE
Highly hydrophobic
Has 4 fused hydrophobic rings
(steroid nucleus) with 8-carbon
branched hydrocarbon chain
attached to C-17 of the D ring
Ring A has a hydroxyl group at
C3
Ring B has a double bond
between C5 and C6
Steroids with 8 to 10 carbon
atoms in the side chain at C17
and a hydroxyl group at C3 are
called sterols
Cholesterol is the major sterol in
animal tissues

CHOLESTERYL ESTERS (CE)

Most plasma cholesterol is
in an esterified form with a
fatty acid attached at C3
This makes the structure
even more hydrophobic
than free cholesterol
Not normally found in
membranes
Must be transported in
association with a protein
(lipoprotein), or be
solubilized by phospholipids
and bile salts in bile

SYNTHESIS OF
CHOLESTEROL

OVERVIEW
Cholesterol is synthesized by virtually all
tissues, but is largely contributed by the
liver, intestine, adrenal cortex, and
reproductive tissues
All C atoms are from acetate
NADPH provides reducing equivalents
Synthesis occurs in the cytoplasm, with
enzymes in both cytosol and ER
membrane

SYNTHESIS OF 3-HYDROXY-3METHYGLUTARYL CoA (HMG CoA)

Similar to the pathway
that produces ketone
bodies
In the liver, the
cytosolic HMG CoA
synthase participates
in cholesterol
synthesis, while the
mitochondrial enzyme
synthesizes ketone
bodies

SYNTHESIS OF MEVALONIC
ACID (MEVALONATE)
Rate-limiting step in
cholesterol synthesis
Irreversible
Occurs in the cytosol
HMG CoA reductase is
an intrinsic membrane
protein of the ER with the
catalytic domain
projecting into the cytosol
This step is inhibited by
statins (Simvastatin,
Atorvasatin, etc.)

HO
H2C
C

CH2

SCoA

HMG-CoA

HMG-CoA
Reductase

2NADP+
+ HSCoA
HO

C
O

2NADPH

H2C

CH3

CH3
CH2

H2
C

OH

mevalonate

CHOLESTEROL SYNTHESIS
1. Mevalonate (6C) is converted to Mevalonate 5
phosphate in 2 steps requiring ATP
2. IPP (5C) is synthesized by decarboxylation. It
is the precursor of the isoprenoids
3. IPP is isomerized to DPP
4. IPP and DPP condense to form the 10-carbon
GPP
5. A second molecule of IPP condenses with GPP
to form a 15-C FPP

CHOLESTEROL SYNTHESIS
6. Two molecules of FPP combine, releasing
pyrophosphate, and are reduced to form Squalene
(30C)
7. Squalene is converted to lanosterol in a series of steps.
Squalene hydroxylation triggers cyclization to
lanosterol
8. A multistep process converts lanosterol to cholesterol.
This involves:
a. Shortening of C chain from 30 to 27
b. Removal of 2 methyl groups at C4
c. Migration of double bond form C8 to C5
d. Reduction of the double bond between C24 and C25

 Many of the reactions involved in

converting lanosterol to cholesterol and
other steroids are catalyzed by members
of the cytochrome P450 enzyme
superfamily

Farnesyl pyrophosphate, an intermediate

on the pathway for cholesterol synthesis,
also serves also as precursor for synthesis
of various non-steroidal isoprenoids.

FARNESYL PYROPHOSPHATE/DIPHOSPHATE
GIVES RISE TO:

DOLICHOL for the synthesis

of N-glycosides

UBIQUINONE or coenzyme Q for the

Electron Transport Chain

REGULATION OF CHOLESTEROL
SYNTHESIS
Major control point is the reaction
catalyzed by HMG CoA reductase, which
is inhibited by mevalonate, cholesterol,
and statin drugs
It is only hepatic synthesis that is inhibited
by dietary cholesterol
Insulin or thyroid hormone increases HMG
CoA reductase activity, while glucagon or
glucocorticoids decrease it

FACTORS THAT INFLUENCE

CHOLESTEROL BALANCE IN
TISSUES

CELL CHOLESTEROL 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
Hydrolysis of cholesteryl esters by the
enzyme cholesteryl ester hydrolase

CELL CHOLESTEROL
DECREASE IS DUE TO:
Efflux of cholesterol from the cell
membrane to HDL promoted by LCAT
(lecithin:cholesterol acyltransferase).
LCAT is also known as PCAT
Esterification of cholesterol by ACAT (AcylCoA:cholesterol acyltransferase)
Utilization of cholesterol for synthesis of
other steroids, such as hormones, or bile
acids in the liver

ROLE OF CHOLESTERYL ESTER TRANSFER

PROTEIN (CETP) IN PLASMA LIPID TRANSPORT
CETP facilitates
the transfer of CE
from HDL to
VLDL, IDL, and
LDL in exchange
for TAG.
This allows LCAT
conversion of free
cholesterol to CE,
facilitating reverse
cholesterol
transport

METABOLISM OF LDL AND THE

ROLE OF THE LDL RECEPTOR
VLDL is produced from the liver and is
composed mostly of TAG
VLDL transfers TAG from liver to tissues.
When TAG synthesis exceeds VLDL
synthesis, it results in fatty liver
VLDL is the precursor of LDL
LDL contains less TAG than VLDL
LDL has a high concentration of
cholesterol and cholesteryl esters

METABOLISM OF LDL AND THE

ROLE OF THE LDL RECEPTOR
The primary function of LDL is to provide
cholesterol to the peripheral tissues, or
return cholesterol to the liver
LDL binds to cell surface receptors that
recognize apolipoprotein B-100

DEGRADATION OF
CHOLESTEROL

 The ring structure of cholesterol cannot be

metabolized to carbon dioxide and water
in humans
The intact sterol nucleus is eliminated by
conversion to bile acids and bile salts
Bile acids and bile salts are excreted in
the feces
Some cholesterol is also secreted into the
bile

 Synthesis of bile acids is one of the

predominant mechanisms for the
excretion of excess cholesterol
However, the excretion of cholesterol in
the form of bile acids is insufficient to
compensate for an excess dietary intake
of cholesterol.

 Some of the
cholesterol in the
intestine is modified
by bacteria before
excretion
The primary
compound made is
coprostanol, a
reduced derivative of
cholesterol

BILE
Consists of a watery mixture of organic
and inorganic compounds
Lecithin and bile salts (conjugated bile
acids) are quantitatively the most
important organic components of bile
Can pass directly from the liver where it is
synthesized to the duodenum through the
common bile duct, or be stored in the
gallbladder

STRUCTURE OF BILE ACIDS

Contains 24 carbons with 2 or 3
hydroxyl groups and a side chain
that terminates in a carboxyl
group
Has a pKa of 6 and is not fully
ionized at physiologic pH
Amphipathic, with the hydroxyl
groups above the plane of the
steroid ring and the methyl
groups below the plane
Act as emulsifying agents to
prepare fats for degradation

PRIMARY BILE ACIDS

 The reaction catalyzed by the 7-hydroxylase is

the rate limiting step in bile acid synthesis
This step is down-regulated by cholic acid and upregulated by cholesterol

SYNTHESIS OF BILE SALTS

Before the bile acids leave
the liver, they are conjugated
to a molecule of either
glycine or taurine by an
amide bond between the
carboxyl group of the bile
acid and the amino group of
the added compound
Conjugation takes place in
peroxisomes

 The ratio of glycine to taurine forms in the

bile is 3:1
The salt forms are fully ionized (negatively
charged) at physiologic pH
Because of their enhanced amphipathic
nature, bile salts are more effective
solubilizers

ACTION OF INTESTINAL FLORA

ON BILE SALTS
Bacteria in the
intestine can remove
glycine and taurine
and regenerate bile
acids
They can also form
secondary bile acids
through
deconjugation and
dehydroxylation

OH

DEOXYCHOLIC ACID FROM

GLYCOCHOLIC ACID

OH

LITHOCHOLIC ACID FROM

CHENODEOXYCHOLIC ACID

ENTEROHEPATIC CIRCULATION
OF BILE ACIDS AND BILE SALTS
Of the 15 to 30 grams of bile salts
secreted from the liver, more than 95% are
reabsorbed through the ileum, pass
through the portal vein, and are reused
Only 0.5 g are lost in the feces
Because bile acids are hydrophobic, they
are carried by albumin noncovalently
through the circulation

 Bile acid sequestrants like cholestyramine

bind bile acids in the gut and prevent their
reabsorption, promoting cholesterol
excretion
Dietary fiber also binds bile acids and
promotes their excretion

CLINICAL ASPECTS

ATHEROSCLEROSIS AND
CORONARY HEART DISEASE
Atherosclerosis is due to the deposition of
cholesterol and cholesteryl ester from the
plasma lipoproteins to the artery walls
A high HDL and low LDL protects a person
from this complication. This is one of the
benefits provided by exercise

DYSLIPOPROTEINEMIAS
Due to various defects in lipoprotein
formation, transport, or destruction
Not all are harmful
Diseases such as Diabetes Mellitus,
Hypothyroidism, Kidney disease, and
atherosclerosis exhibit abnormal
lipoprotein patterns that resemble
dyslipoproteinemias

CHOLELITHIASIS (GALLSTONES)
Occurs when more cholesterol enters the
bile than can be solubilized by the bile
salts and lecithin present
Surgery is the treatment of choice, but
administration of chenodeoxycholic acid
may help to supplement the bodys supply
of bile acids