Cholesterol and Lipoprotein

Metabolism

Ricardo R. Santos, MD
Structure of Cholesterol
An alicyclic compound whose structure
include:

• Cyclopentanoperhydrophenanthrene nucleus
• Single hydroxyl group at C-3
• Double bond between C-5 and C-6

• Eight-membered branched hydrocarbon chain

attached to ring D at C-17

• Two angular methyl groups: a) one designated C-18

attached to C-13; b) second designated C-19
attached to C-10
Two forms of cholesterol
1. Free cholesterol
- unesterified to fatty acid; amphipathic
- found in membranes and outer layer
of lipoproteins
- 30% of total cholesterol in the blood
- biologically active form

2. Cholesterol ester
- fatty acid is esterifed to OH grp at C-3
- found in lipid core of lipoproteins
- 70% of total cholesterol in the blood
- storage form of cholesterol in the tissue
Cholesterol Values

• Plasma: 150 – 200 mg/100 ml

(mostly as cholesterol ester)

• Bile: 390 mg/100 ml

(mostly as free cholesterol; 96% of total)

• Total cholesterol is estimated by

Liebermann-Burchard reaction
Importance of Cholesterol
• Important component of membranes and
outer layer of lipoproteins

• Precursor of:
- vitamin D3 (skin)
- bile acids (liver)
- steroid hormones (adrenals and gonads)

• Protects gallbladder membrane from

irritating and harmful effects of bile salts
 Foods rich in cholesterol

• Cholesterol is primarily of animal origin

- skin, liver, intestines, adrenal gland,
gonads, brain

• Egg yolk, meat

Medical importance of cholesterol

• Atherosclerosis
• Gallstones
• Hyperlipoproteinemias
Biosynthesis of Cholesterol
General considerations
- Liver, intestine, adrenal cortex, gonads, placenta
have the greatest capacity to synthesize chol.

- All carbon atoms of cholesterol are derived from

acetyl CoA.

- Cholesterol synthesis takes place in the cytosol

and endoplasmic reticulum; 700 mg/day

- Synthesis is expensive (18 ATPs/cholesterol)

- Reducing power in the form of NADPH is

provided by HMP shunt
Five Steps in the Synthesis of Cholesterol

1. Biosynthesis of mevalonate

2. Formation of isoprenoid units

3. Formation of squalene

4. Cyclization of squalene to lanosterol

5. Conversion of lanosterol to cholesterol

 Step 1 – Formation of Mevalonate
(Rate-limiting Step)

Acetyl CoA
Thiolase
CoA

Acetoacetyl CoA
HMG-CoA synthase Acetyl CoA
(cytosolic)
CoA

3-Hydroxy-3-methylglutaryl CoA
(HMG-CoA)
 From HMG-CoA to Mevalonic Acid

HMG-CoA

HMG-CoA reductase NADPH

(committed enzyme)

NADP

Mevalonate
 Regulation of HMG-CoA Reductase
HMG-CoA reductase is an intrinsic membrane protein
of the endoplasmic reticulum and its active site
extends into the cytosol.

1. Feedback inhibition by cholesterol

2. Hormonal regulation
* Insulin stimulates (favor dephosphorylated
active form of enzyme)
* Glucagon inhibits (favor phosphorylated
inactive form of enzyme)
3. Cholesterol-mediated inhibition of gene
transcription
4. Inhibition by drugs: “statins” – e.g., simvastatin,
lovastatin, pravastatin, atorvastatin, etc.
Regulation of Cholesterol Synthesis
Step 2. Formation of isopentenyl
pyrophosphate
• Sequential phosphorylation of mevalonate
by kinases utilizing ATP

• Take place several times

• Need six isoprenoid units to form one
cholesterol

• Most expensive stage

• 1 mevalonate to 1 isoprenoid unit = 3 ATPs
• 6 isoprenoid units to 1 cholesterol = 18 ATPs
 Step 3. Formation of Squalene

• Involves initial isomerization of isopentenyl

pyrophosphate.
• Followed by a series of condensation reactions
forming geranyl pyrophosphate and
farnesylpyrophosphate.
• Condensation of two farnesylpyrophosphates
forming the 30-carbon atom squalene.
• Pyrophosphate is released in each
condensation step.
• Isopentenyl-PP is a precursor of important
compounds like ubiquinone and dolichol.
Synthesis of Cholesterol
Step 4. Formation of Lanosterol

• Involves cyclization of squalene to form

lanosterol by endoplasmic reticulum-bound
squalene oxidocyclase

• Squalene oxidocyclase has two enzymatic

activities: epoxidase (monooxygenase) and
cyclase (oxidosqualene:lanosterol cyclase)

• Lanosterol has also 30 carbon atoms

Synthesis of Cholesterol
 Step 5. From Lanosterol to Cholesterol
• Takes place in the membrane of endoplasmic
reticulum

• The major pathway in mammals proceeds

through 7-dehydrocholesterol involving a
series of double bond reductions and
demethylations.

• Alternative pathway involves:

1. three demethylations to give zymosterol
2. isomerization of double bond to form desmosterol
3. reduction of double bond to form cholesterol
Major and alternative routes from lanosterol
to cholesterol
Lanosterol

Major route Alternative route

7-dehydrocholesterol Zymosterol

Desmosterol

Cholesterol
Metabolism of Cholesterol
Mutations on LDL Receptor
Fate of Endogenous Cholesterol
Plaque Formation in Atherosclerosis
Oxidized LDL and plaque formation
Fatty Streak of Atherosclerosis
Fibrofatty plaque of Atherosclerosis
Intraluminal Thrombus