L36. Cholesterol Synthesis and Lipoprotein Transport

Question 1

What is the definition of dyslipidaemia? What can it predispose to?

Answer 1

An abnormal Lipid Profile

To atherosclerosis, increased risk of MI and stroke

Question 2

What is a lipid profile? What are four major types of abnormal lipid profiles?

Answer 2

The levels of LDL, HDL, and triaglycerides in the body. Particularly the ratio of these to one another.

Hypercholestrolaemia (total cholesterol increased >5mM)
Hyperticlyceridaemia (increased blood TAG)
Mixed hyperlipiademia
Low HDL cholesterol

Question 3

What is the relationship between LDLs and the risk of developing coronary diseases and between HDLs and this risk?

Answer 3

The higher the LDLs the the higher the risk

The lower the HDLs the higher the risk

Question 4

What kind of correlation exists between the total cholesterol: HDL ratio and the risk of developing coronary disease?

Answer 4

A very strong positive correlation: the higher the ratio (defined as > 5mM) the higher the risk of developing coronary disease

Question 5

What is cholesterol?

What is it an important component of

Answer 5

Roughly translates to solid alcohol in bile
A 3-hydroxy-5-6-cholestene (a C27 polymer)

It is an important component of Lipoproteins (Chylomicrons, LDL, VLDL and HDL)

Question 6

Cholesterol is a precursor to a number of important biological molecule, what are three of them?

Answer 6

1. Vitamin D
2. Steroid Hormones
3. Bile salts

Question 7

Free cholesterol is an amphiphatic molecule. What is meant by this?

Answer 7

It has a hydrophobic part and a hydrophilic part

Question 8

What is the main endogenous source of cholesterol production in the body?

Answer 8

Cholesterol is synthesised in the liver (de novo synthesis)

Question 9

What are the four main fates of cholesterol (both endogenous and exogenous)?

Answer 9

1. Most is transported to the tissues for storage and use as energy: free cholesterol that is esterified in VLDL and chylomicrons and then taken up by the tissues
2. Storage in the gall bladder as bile salts
3. Used in the production of steroid hormones and vitamin D in the adrenal and gonad glands and the skin
4. Makes up membrane lipids providing steric hinderance

Question 10

What are bile salts?

Answer 10

Detergent like molecules that are secreted on demand by the body to emulsify fats, taking up lipid from the diet

Question 11

How does cholesterol provide the steric hinderance to the membranes?

Answer 11

The cholesterol intercalates in the lipid bilayer: within the kinks made by the fatty acyl chains and this reduces their fluidity.

There are membrane rafts that have high concentrations of cholesterol and are thus more rigid.

Question 12

Describe the process of cholesterol synthesis in the liver

Answer 12

Acetyl CoA is made in the mitochondria
It is then converted into Hydromethyglutaryl-CoA (HMG-CoA)
HMG-CoA is converted into Mevalonic Acid by HMG-CoA reductase (an important enzyme)
Mevalonic Acid undergoes several sequences of metabolism into intermediates –> Squalene –> Cholesterol
Cholesterol negatively feeds back onto the enzyme HMG-CoA

Question 13

What is the significance of the enzyme HMG-CoA for the cholesterol synthesis pathway?

Answer 13

It is the rate limiting step of the synthesis of the pathway
The activity of the reductase governs the relative amounts of cholesterol made in the liver
(Thus it is an important drug target)

Question 14

What is important to note about the intermediate products made in the pathway?

Answer 14

Drug interference with the aim of altering cholesterol synthesis may have severe consequences as the intermediary components are also affected (this may lead to pathology)

Question 15

Why is there a need for a specific mechanism for the body to transport cholesterol?

Answer 15

Cholesterol is a non-soluble, largely hydrophobic molecule which means that its ability to dissolve in the plasma is very low. (0.1mM compared to the 5mM present).

Free cholesterol is also able to alter the properties of membranes (problematic if delivered to the wrong site)

Question 16

What is the mechanism of cholesterol transport?

Answer 16

Cholesterol (and triaglycerides) is esterified to make it more hydrophobic and then incorporated into small protein-lipid composits called CHYLOMICRONS

Question 17

What are chylomicrons?

Answer 17

Small Protein-Lipid (amphiphatic) molecules with a core of cholestyl ester that carry cholesterol around in the plasma

Chylmicrons, LDL, VLDL and HDL

Question 18

How is cholesterol obtained from the diet?

Answer 18

Triaglycerides (TAGs) and Cholesterol from the diet is absorbed in the small intestine and packaged into chylomicrons in the lymphatic system. This drains them into the blood stream towards the tissues. The tissues contain LIPOPROTEIN LIPASE which allows them to take up cholsterol from the chylomicrons

Question 19

What is a triaglycerole?

Answer 19

An important form of dietary cholesterol: the main constituents of natural fats and oils.

Question 20

Draw the synthesis, transport and use of cholesterol around the body

Answer 20

• TAG is packed into chylomicrons while cholesterol into VLDL
• These are taken to capillaries and tissues where Lipoprotein Lipases take out free fatty acids from it leaving VLDL remnants or Chylomicron remnants taken back to the liver
• VLDLs can be turned into LDLs which either go back to the liver or accumulate in extrahepatic tissues (like blood vessels)
• HDL precursors from the liver go through the plasma and enter extrahepatic tissue and take up cholesterol, becoming HDL going back to the liver.

Question 21

What process if HDL important for?

Answer 21

Reverse Cholesterol Transport: Called the “Good” Cholesterol as it sequesters extra cholesterol from the tissues and takes it back to the liver.

Question 22

What is Apolipoprotein?

Answer 22

A protein without its co-factors (without the lipid)

Question 23

What is the significance of ApoE?

Answer 23

It is very important in taking up the cholesterol for carrying it around the body.

It is the major difference between VLDL and LDL is the loss of ApoE leading to LDL formation (when cholesterol > TAG it is LDL)

Question 24

Compare and contrast the different lipoproteins from each other in descending size

Answer 24

Chylomicrons:
Formed in the intestinal mucosa and carry TAG
Have apolipoproteins: ApoE (take up), B48 (structural) and APCII (activation of lipoprotein lipase)

VLDL:
Formed in the liver and carry cholesterol from there
ApoB100 (binds to SR-B1 receptor on the liver) - efficient take up by the liver
ApoE

LDL:
Derived from VLDL
Circulates to deliver cholesterol to the tissues
ApoB100 (binding to the liver)

HDL:
Made in the liver and intestine
ApoA-1 (HDL formation and binding to the liver)

Question 25

What are 3 important enzymes in the process of cholesterol transport and uptake in the body?

Answer 25

1. Lipoprotein Lipase into the tissue
2. ACAT in the liver helps the formation of VLDL
3. LCAT in the plasma helps HDLs scavenge cholesterol from membranes

Question 26

What is the mechanism by which high LDL levels leads to an increased risk of cardiovascular disease?

Answer 26

LDL accumulation in the tissues gets oxidated and this oxLDL accumulates in the arterial walls leading increased expression of adhesion molecules by endothelial cells
Increase macrophages and increased inflammation = formation of FOAM cells
oxLDLs are toxic to the tissues
Formation of a fibrous tissue cap and a necrotic core: fibrous cap in atherosclerosis

Question 27

What is controversial about dietary recommendations in terms of plasma cholesterol levels?

Answer 27

Dietary consumption may not be significant in determining blood level of cholesterol (the de novo liver synthesis may be the major contributor)

Question 28

What is a statin?

Answer 28

A drug that are competitive inhibitors of the HMG-CoA reductase enzyme (by mimicking Mevalonic acid) - in attempt to reduce serum cholesterol levels

Question 29

What is an adverse effect of statin use?

Answer 29

Q10 depletion (important to mitochondrial bioenergy transfer) and causes skeletal muscle and cardiac muscle complications. 
How? Q10 is synthesised by activated isoprene - an intermediate of the cholesterol synthesis pathway. Statins reduce the production of isoprene.