Cholestrol

Question 1

What is cholesterol?

Answer 1

Steroid 
27 carbon atoms 
Cyclic rings and a hydrophobic tail 
Planet apart from the hydroxyl group at position 3
Very hydrophobic

Question 2

What file does cholesterol play in cell membranes?

Answer 2

90% of all out body cholesterol is found in cell membranes

Increases and decreases membrane stiffness depending on temperature and nature of the membrane

Question 3

How and why must cholesterol be synthesised in the liver?

Answer 3

Dietary uptake is limited to 500 mg a day
But there is a great need for it in our bodies
All physiological requirements are supplied by de novo synthesis in the liver
From acetyl CoA

Question 4

The synthesis of cholesterol is split into 3 parts?

Answer 4

1. Synthesis of isopentyl pyrophosphate
   (Cytoplasm)
2. Condensation of 6 molecules of isopentyl pyrophosphate to form squalene
   (Cytoplasm)
3. Cyclisation and demethylation of squalene by monooxygenases to give cholesterol
   (ER)

Question 5

What is the first reaction in the first step of cholesterol synthesis?

Answer 5

2 Acetyl CoA
—>
Acetoacetyl CoA

Using beta ketothiolase and release in one CoA

Question 6

What is the Second reaction in the first step of cholesterol synthesis?

Answer 6

Acetoacetyl CoA + acetyl CoA
—>
HMG-CoA

Using HMG-CoA synthase and
Water —> CoA

Question 7

What is the Third reaction in the first step of cholesterol synthesis?

Answer 7

Reduction of HMG CoA
—>
Mevalonate

Using HMG CoA reductase
And the reducing power comes from 2 NADPH
And 2 H+
CoA is released along with two NADP+

Question 8

Why is the step involving the formation of mevalonate so important?

Answer 8

Runs on a negative feedback loop

Increased levels of mevalonate, cholesterol and bile salts all inhibit the action of HMG CoA reductase

Control

Question 9

What is the Fourth reaction in the first step of cholesterol synthesis?

Answer 9

Mevalonate undergoes sequential phosphorylation at hydroxyl groups at points 3 and 5
Then decarboxylation
This forms 3-isopentyl pyrophosphate

Uses 3 ATP and releases one Pi and one CO2

Question 10

Isoprene units (like isopentyl pyrophosphate) confer lipophilicity to biomolecules, what does this mean?

Answer 10

It helps molecules to be able to sit in the lipid bilayer

Post translational modification

Question 11

What is the fifth reaction in the first step of cholesterol synthesis?

Answer 11

Dimethylallyl pyrophosphate is formed from isopentyl PP in an isomerisation reaction

This condenses with another isopentyl PP to for a 10C molecule geranyl PP

A third isopentyl PP is added to form a 15C
Farnesyl PP

Question 12

What is the sixth reaction in the first step of cholesterol synthesis?

Answer 12

Two farnesyl PP molecules condense to form a C30 squalene
As well as two molecules of PP
Reducing power comes from one NADPH

Question 13

What is the seventh reaction in the first step of cholesterol synthesis?

Answer 13

Squalene cyclised you cholesterol in three steps

1. Squlalene is reduced in the presence of oxygen and NADPH to form squalene epoxide which has a different carbon carbon double bond distribution, priming the molecule for ring fusion
2. Squalene epoxide is then turned into lanesterol that has four rings characteristic of cholesterol
3. Lanesterol is reduced and demethylated to give cholesterol

Question 14

What are some of the uses of cholesterol?

Answer 14

Bile salts
Steroid hormones
Vitamin d metabolites

Question 15

What are bile salts?

Answer 15

They have hydrophobic and hydrophilic areas allowing them to emulsify dietary fats
They are a major breakdown product of cholesterol
Cholesterol undergoes a series of reactions to become primary bile salt, glycholate and taurocholate

Question 16

What are steroid hormones?

Answer 16

Synthesised from cholesterol
The precursor pregnenolone is synthesised from cholesterol by the enzyme desmolase

All 5 classes of steroid hormones come from pregnenolone:
Prostagens
Glucocorticoids
Mineralocorticoids 
Androgens 
Oestrogens

Question 17

What are vitamin d metabolites?

Answer 17

Vitamin D is a collective term for steroids that are vital for intestinal absorption of important ions needed for bone development
The western diet is low in vitamin D so our main source is from the activity of UV light upon 7-dehydrcholesterol on the skin

Calcitriol is the most active vitamin D
Derived from cholesterol
Acts as promoter of key genes involved in bone metabolism

A vitamin D deficiency causes rickets

Question 18

What is familial hypercholesterolaemia?

Answer 18

Monogenic dominant trait
Cholesterol transportation is defective

Individuals who have one copy of a mutant gene have cholesterol level 2-3 times higher than usual
Susceptible to atherosclerosis
Individuals who have two copies of this gene are severely effected
5 times normal levels
Suffer atherosclerosis and coronary infarction in adolescence

Question 19

What are the mechanisms underlying familial hypercholesterolaemia?

Answer 19

Cholesterol in the form of LDL is taken up by the LDL receptor (LDLR)
Fibroblasts from patients with FH lack function LDLRs
There are many mutations in domains of the LDLR that all lead to FH
These can effect receptor expression, LDL binding, LDLR endocytosis and recycling

Question 20

How is FH controlled?

Answer 20

Inhibition of de novo cholesterol synthesis
Achieved by HMG CoA reductase inhibitors
Also known as statins and act as competitive inhibitors

Reduction of dietary cholesterol absorption
Achieved by resins
These bind or sequester bile acid-cholesterol complexes preventing their reabsorbtion by the intestine