Cholesterol

Metabolism
ILOs

Classify the different metabolic pathways of

lipids, lipoproteins and ketones bodies and
factors affecting their blood level.
Categorize the related metabolic disorders
and their clinical application on biochemical
and molecular basis.
 1- Structure:

a.Hydrophobic compound, classified as sterols in

animal tissues
b. It consists of four fused hydrocarbons rings
(A, B, C, D), called steroidal nucleus
c. Plasma cholesterol is esterified form which
makes it more hydrophobic than free cholesterol
and transported in association of protein.

2- Sources:

A- Endogenous (de novo synthesis):

Cholesterol is formed in the body almost in
all cells from acetyl-CoA.
B- Exogenous (Diet):
Cholesterol presents only in food of animal
origin such as egg yolk, meat, liver and
brain
3- Functions:
1- Cholesterol enters in the structure of every body cell
(cell membrane).
2- Cholesterol is the precursor of: Vitamin D3, steroid
hormones and bile acids:
a- In skin 7-dehydrocholesterol Vitamin D3.
b- Gonads:
1- Ovaries: Estrogens and progesterone.
2- Testis: Testosterone and androgens.
c- Adrenal cortex:
Glucocorticoids and mineralocorticoids.
d- Liver:
Bile acids.
 4- Synthesis of cholesterol in cytosol mainly in
liver requires acetyl coA &NADPH
1- Formation of acetoacetyl CoA by condensation of two molecules
of acetyl CoA:
O O O O
Thiolase
CH3 - C ~ S - CoA + CH3 - C ~ S - CoA CH3 - C - CH2 - C ~ S - CoA
CoASH
Acetyl CoA Acetyl CoA Acetoacetyl CoA

2- Synthesis of 3-OH-3-methylglutaryl CoA by

HMG CoA synthase:
Liver cells contains two isoenzymes:
a) Cytosolic enzyme for cholesterol synthesis.
b) Mitochondrial enzyme for ketone body synthesis.
 CH3 O
C - CH2 - C ~ S - CoA
O Acetoacetyl - CoA
O
H2O CH3 - C ~ S - CoA
Acetyl - CoA
HMG - CoA synthase
CoASH

CH3 O
HOOC - CH2 - C - CH2 - C ~ S - CoA
OH
-Hydroxy - -Methylglutaryl - CoA

Synthesis of HMG CoA.

3- Synthesis of Mevalonic acid:
Irreversible reduction step by HMG CoA reductase, Rate
limiting step, occurs in cytosol
CH3 O
HOOC - CH2 - C - CH2 - C ~ S - CoA
OH
-Hydroxy - -Methylglutaryl - CoA

2 NADPH+H+
HMG - CoA Reductase
2 NADP+ + CoASH

CH3
HOOC - CH2 - C - CH2 - CH2 - OH
OH
Mevalonate
4- Synthesis of cholesterol from Mevalonic acid:
Mevolanate

Sequaline

Lanosterol

Desmosterol
13 17

10

HO
Regulation of cholesterol synthesis:

HMG CoA reductase is rate limiting step &

major control of cholesterol synthesis.
1- Feed back inhibition:
Cholesterol acts as feed back inhibitor of HMG
CoA reductase enzyme.
2 - hormonal regulation:
insulinupregulates HMGCoA reductase
gene expression &glucagon downregulates it
Statin drugs are analogs of HMG CoA &
reversible inhibitors of HMG CoA reductase.
 Ketone
Metabolism
 Ketone bodies
These are 3 compounds formed by the liver
and include O
O CH3 - C - CH3 OH
CH3 - C - CH2 - COOH 3- Acetone. CH - CH - CH - COOH
3 2
1- Acetoacetate. 2- -Hydroxybutyrate.
Functions (Importance) of ketone bodies:
A- Ketone bodies are used as a source of energy. They are converted
into acetyl-CoA which is oxidized in tricarboxylic acid (TCA) cycle.

B- In prolonged fasting and starvation, ketone bodies can be used as a

source of energy by most of tissues including brain, skeletal muscles,
cardiac muscles and kidneys.

C- Liver does not contain enzymes for ketone bodies oxidation

(Ketolysis). Thus liver cannot oxidize them.
Ketone bodies are important sources
of energy for the peripheral tissues

1) They are soluble in aqueous solution and,

therefore, do not need to be incorporated into
lipoproteins or carried by albumin.
2) They are produced in the liver during periods
when the amount of acetyl CoA present
exceeds the oxidative capacity of the liver.
3) They are used in proportion to their
concentration in the blood by extrahepatic
tissues, such as the skeletal and cardiac muscle
,renal cortex and the brain.
Ketogenesis (Synthesis of ketone bodies)
A- Site: in liver mitochondia
B- Precursor (Acetyl CoA):
1- derived from fatty acids oxidation
2- ketogenic amino acids.
C- Steps:
Acetoacetate is the first ketone body produced.
Then both -hydroxy butyrate and acetone are
derived from it.
1-Formation of acetoacetyl CoA:
a- From condensation of 2 acetyl CoA molecules.
b- It results in the course of -oxidation of fatty acids
(last 4 carbons)
2-Formation of HMG-CoA (-hydroxy methyl
glutaryl CoA)
By condensation of third molecule of acetyl CoA in the
presence of HMG CoA synthase.
3- Formation of acetoacetate by HMG CoA lyase.
4- Acetoacetate is either:
a- Spontaneously decarboxylated into acetone.
b- Reduced into -hydroxybutyrate.
Synthesis of ketone bodies
 Regulation of ketogenesis:

Adipose tissue Blood Liver

Lipolysis Esterificateion
TG FFA FFA Acyl CoA TG
-Oxidation
Insulin Glucagon Acetyl CoA Citric acid cycle
Ketogenesis

Ketone bodies
Ketolysis (oxidation of ketone bodies)
Occurs in mitochondria, in the extra hepatic
tissues because liver dont contain enzymes
needed for ketolysis.
1-Acetone is volatile and removed in the expired air.
2- -hydroxybutyrate is converted into acetoacetate by
hydroxybutyrate dehydrogenase enzyme.
3- Acetoacetate is then converted into acetoacetyl CoA by:
thiophorase enzyme in the presence of succinyl CoA.
4- Acetoacetyl CoA is splitted into 2 molecules of acetyl CoA
which are oxidized in citric acid cycle
Ketogenesis in liver and use by peripheral tissues
Ketone bodies and diabetes:
In type I diabetics, oxaloacetate is low, due to
excess gluconeogenesis, so acetyl-CoA from
fat/protein catabolism does not go to TCA but
rather to ketone body production.
Acetone can be detected on breath of type I
diabetics (ketoacdosis, ketonemia, ketonuria)
due to decrease in insulin &increase in lipolysis
&increase free fatty acids
 Bile acids
Bile salts are synthesized in the liver from cholesterol.
An -hydroxyl group is added to carbon 7 of cholesterol
by 7 -hydroxylase
The double bond is reduced and further hydroxylations
occur resulting in two compounds
-hydroxyl group at position 3,7 (chenocholic acid).
-hydroxyl group at position 3,7,12 (cholic acid).
The side chain is oxidized and converted to a branched
, 5 carbon chain containing a carboxylic acid at the end.
Bile Acids & Salts

Composition of bile: organic & inorganic

compounds
Organic compounds includes: lecithin &
bile salts (conjugated bile acids)
Site of bile synthesis: liver then goes to
duodenum via bile duct for digestion or
stored in gallbladder
Structure of Bile Acids

Amphipathic (has polar & nonpolar face)

Function: emulsifying agents in intestine for dietary TAG &
complex lipids degradation by pancreatic digestive enzymes
Synthesis: in liver by multi-step, multi-organelle pathway of
cholesterol. It includes:
OH insertion
Double bond of B-ring is reduced
Hydrocarbon chain is shortened by three carbon.
Introducing a carboxl group at the end of the
chain.
Structure of Bile Acids

3 carbons COOH cholic acid (triol) or

chenodeoxycholic acid (diol) both are called primary
bile acids
Rate limiting step is introduction of OH at C7 of
cholesterol by cholesterol 7-hydroxylase (ER
cytochrome P450 enzyme in liver which is down-
regulated by cholic acid & up-regulated by cholesterol
 Synthesis of Bile Salts

Bile acids are conjugated to either glycine

(glycochenocholic, glycocholic) or taurine
(taurocholic, taurochenocholic) in liver by
amide bond between COOH & NH2

N.B. taurine is end product of cysteine

metabolism
Synthesis of Bile Salts

They are made in the liver and secreted via the bile
through the gallbladder into the intestine.
Bile salts are more effective detergents than bile
acids (enhanced amphipathic nature)
Bile salts found in bile are important for
cholesterol excretion (as a metabolic product of
cholesterol & solubilizer for cholesterol excretion)
 Fate of the bile salts

Bacteria in intestine remove gly & taurine from

bile salts regenerating bile acids (de-conjugated,
de-carboxylated at position 7).
 Fate of the bile salts

Also bacteria convert primary bile acids into:

Secondary bile acids by removing OH
Deoxycholic acid from cholic acids
Lithocholic from chenodeoxycholic acids
Bile acids are hydrophobic requiring albumin
for portal blood transport
Fate of the bile salts

Bile salts are resorbed in the ileum and

return to the liver, where they can be re-
conjugated with glycine or taurine

The liver recycles about 95 % of the bile

salts each day; 5% are lost in feces
 Cholelithiasis

More cholesterol enters the bile than can be

solubilized by bile salts & lecithin
This lead to cholesterol precipitation in
gallbladder & bile acids in bile due to:
1.Malabsorption of bile acids from intestine
2.Obstruction of biliary tract dysfunction
3.Hepatic dysfunction (synthesis of bile
acids)
References

Mary K. Campbell and Shawn O. Farrell; Biochemistry; 6th edition 2007; Brooks

Cole, ISBN 0495390410.

Walsh, G; Biopharmaceutical: Biochemistry & Biotechnology; Wiley; ISBN

0470843276.