Metabolism 7 - Cholesterol

Question 1

What proportion of cholesterol in the body is found in cell membranes?

Answer 1

More than 90% of cholesterol.

Question 2

Summarise the three main parts of cholesterol biosynthesis.

Answer 2

1) Synthesis of isopentenyl pyrophosphate - an activated isoprene unit which acts as a building block
2) Condesnation of 6 molecules of ispoentyl pyrophosphate to form squalene
3) Cyclisisation and demethylation of squalene to give cholesterol

Question 3

How are physiological requirements of cholesterol in the body met?

Answer 3

They are met by de novo synthesis in the liver.

Question 4

Where do the three parts of cholesterol synthesis occur?

Answer 4

Synthesis of isopentenyl pyrophosphate occurs in the cytoplasm, as does formation of squalene. Cyclisation and demethylation of squalene occurs in the endoplasmic reticulum.

Question 5

How is HMG-CoA reductase controlled?

Answer 5

It is controlled by end product inhibition from cholesterol. This is a negative fedback mechanism.

Question 6

How is cholesterol used to make steroid hormones?

Answer 6

Cholesterol acts as the basis of steroid hormones - forming the precursor pregnenolome by the action of the enzyme desmolase. Pregnenolone forms all 5 classes of steroid hormones.

Question 7

What vitamin is synthesised from cholesterol?

Answer 7

• Vitamin D. This requires the exposure of the skin to sunlight.
• Calcitrol is formed from vitamin D3. It is important in calcium metabolism.

Question 8

How are bile salts synthesised from cholesterol?

Answer 8

Cholesterol is converted to the primary bile salt glycocholate, as well as taurocholate.

Question 9

What are lipid rafts?

Answer 9

Lipid rafts are assemblies of cholesterol and sphingolipids in the cell membrane. These organise cell signalling by localising key proteins such as cell surface receptors.

Question 10

How does cholesterol bind to and affect the function of the hedgehog signalling protein?

Answer 10

Cholesterol is covalently attached to the N terminal of he hedgehog signalling protein during processing. This limits diffusion into tissues so successful limb formation during embryogenesis can occur.

Question 11

What are lipoproteins?

Answer 11

Lipoproteins are made of a phospholipid monolayer which contains cholesterol and apoproteins. In the core of the lipoprotein there are cholesterol esters and triaglycerols.

Question 12

Why are cholesterol esters not cholesterol present in the core of lipoproteins?

Answer 12

They are more hydrophobic than cholesterol allowing them to pack tightly in the lipoprotein core.

Question 13

How can cholesterol esterd be synthesised?

Answer 13

• Cholesterol esters are made from cholesterol and lecithin.
• They can be generated from long chain fatty acyl coA species using acyl coA-acyltransferase. This ensyme acts on cholesterol taken up by endocytosis.

Question 14

How are lipoproteins classified?

Answer 14

According to their density.

Question 15

What are the forms of lipoproteins?

Answer 15

• Chylomicrons
• Very low density lipoproteins
• Intermediate density lipoproteins
• Low dendity lipoproteins
• High density lipoproteins

Question 16

How are different lipoproteins recognised by different cell types?

Answer 16

They are recognised by a varying apoprotein component.

Question 17

Describe the process of fat digestion and absorption

Answer 17

• Lipid digestion results in formation of mixed micelles, containing cholesterol, fat-soluble vitamins, monoacylglycerol, diacylglycerol and free fatty acids alongside bile salts.
• Mixed micelles are absorbed by enterocytes at the brush border of the SI. Triaglycerols are reformed before being incorporated into chylomicrons and transported through the lymphatics to the bloodstream.

Question 18

Describe the pathway of chylomicrons.

Answer 18

• Chylomicrons travel from the lacteals to the thoracic duct and the left subclavian vien where they enter the bloodstream.
• They encounter lipoprotein lipase, which catalyses the hydrolysis of triaglycerols to glycerol and fatty acids.
• Fatty acids undergo B-oxidation, and glycerol is used in gluconeogenesis in the liver.

Question 19

What is left over following the encounter of chylomicrons with lipoprotein lipase?

Answer 19

Chylomicronremnants, which are taken up by the liver.

Question 20

What are HDLs?

Answer 20

HDLs are goos cholesterols which take cholesterol from peripheral tissues to the liver for use of disposal, which lowers the total blood cholesterol.

Question 21

What are LDLs?

Answer 21

LDLs are bad cholesterol, as they lead to atherosclerosis - taking cholesterol from the liver to the peripheral tissues. More than 40% of their weight is made from cholesterol esters.

Question 22

What is the role of HDLs?

Answer 22

They pick up cholesterol released into the plasma from the dying cells, and deliver this to the liver.

Question 23

What is th role of LDLs?

Answer 23

Regulate de novo synthesis of cholesterol at the peripheral tissues.

Question 24

What is a healthy HDL:LDL ratio?

Answer 24

3:1

Question 25

What is familial hypercholesterolaemia?

Answer 25

A monogenic dominant trait. A single copy results in high risk of atherosclerosis. Two copies of a mutant gene results in severe atherosclerosis and coronary infarction in adolescence.

Question 26

Describe the structure and function of the LDL receptor.

Answer 26

The LDL receptor has a ligand binding domain, which causes cholestrol to be taken up in the form of LDL.

Question 27

How is hypercholesterolaemia controlled?

Answer 27

Controlled using resins, and HMG-CoA inhibitors.

Question 28

What is another name for HMG-CoA Reductase inhibitors?

Answer 28

Statins