Cholesterol

Question 1

What is cholesterol used for?

Answer 1

A component of cell membranes
Signalling pathways
Precursor for other biomolecules

Question 2

What is the basic structure of cholesterol?

Answer 2

Composed of 27 carbons, 4 cyclic rings and a hydrophobic tail
Steroid ring structure is planar
Apart from the hydroxyl group at position 3, the molecule is very hydrophobic, consisting only of carbon and hydrogen atoms

Question 3

Why is cholesterol important in cell membranes?

Answer 3

It can increase or decrease the stiffness of the membrane depending on the temperature and other factors of the membrane

Question 4

Where is the cholesterol synthesised from and using which mechanism?

Answer 4

Liver

Cholesterol Synthesis from Acetyl CoA

Question 5

Overview of the cholesterol synthesis pathway in 3 steps:

Answer 5

1. Synthesis of isopentenyl pyrophosphate, an activated isoprene unit which serves as a key building block (cytoplasm).
2. Condensation of six molecules of isopentenyl pyrophosphate to form squalene (cytoplasmic reactions).
3. Cyclisation and demethylation of squalene by monooxygenases to give cholesterol (ER reactions)

Question 6

What is the first step of cholesterol synthesis?

Answer 6

Take place in the cytoplasm:
- Two molecules of acetyl CoA condense
2 AcetylCoA —-beta-ketothiolase—-> AcetoacetylCoA
- Condensation of another Acetyl-CoA molecule to form HMG-CoA (3-hydroxy-3-methylglutarine CoA)
AcetoacetylCoA + AcetylCoA —-HMG-CoA synthase—-> HMG-CoA
- HMG-CoA is reduced to generate Mevalonate
HMG-CoA —-HMG-CoA reductase—-> Mevalonate
Mevalonate regulates this enzyme via end-product inhibition
- Mevalonate then undergoes sequential phosphorylation at the hydroxyl groups at position 3 and 5, followed by decarboxylation to form 3-Isopentenyl pyrophosphate (isopentyl PP)

Question 7

What is the second step of cholesterol synthesis?

Answer 7

Take place in the cytoplasm:

• Firstly an isomerisation reaction using Isopentenyl Pyrophosphate Isomerase converts 3-Isopentenyl pyrophosphate to Dimethylallyl pyrophosphate
• Two condensation reactions where isopentyl PP is sequentially added to the Dimethylallyl pyrophosphate forms Farnesyl pyrophosphate (15C)
• Two farnesyl-PP molecules then condense to form squalene (30C) plus 2 molecules of pyrophosphate

Question 8

What is the third and final step of cholesterol synthesis?

Answer 8

Take place in the cytoplasm:

• Squalene is reduced in the presence of oxygen and NADPH to form squalene epoxide which has a different C=C bond distribution, priming the molecule for carbon ring fusion
• Squalene epoxide lanosterol-cyclase catalyses the formation of Lanosterol. A series of 1,2-methyl group and hybride shifts along the chain of the squalene molecule result in the formation of four rings
• Lanosterol is subsequently reduced and three methyl units removed (demethylated) to generate cholesterol

Question 9

What is required for this pathway?

Answer 9

ATP for the phosphorylations

NADPH as the reducing agents

Question 10

What can cholesterol be used to synthesise?

Answer 10

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

Question 11

What is the process of bile salt synthesis?

Answer 11

A series of reactions convert cholestrol into the primary bile salts - glycocholate and taurocholate

Question 12

What is the process of steroid hormone synthesis?

Answer 12

The enzyme desmolase converts cholesterol to form the precursor, pregnenolone
All five classes of steroid hormones come from pregnenolone: Progestagens, glucocorticoids, mineralocorticoids, androgens and oestrogens

Question 13

What is vitamin D?

Answer 13

Collective term for a group of steroids necessary for the absorption of calcium, phosphate and magnesium (required for bone development)

Question 14

What is the process of Vitamin D synthesis?

Answer 14

The 7-dehydrocholesterol is located in the epdermis of the skin
UV light activity converts 7-dehydrocholesterol to Vitamin D

Question 15

What plays an important role i calcium metabolism?

Answer 15

Calcitrol

Question 16

What does vitamin D3 deficiency in children lead to?

Answer 16

Rickets - a defect of bone development in children

Question 17

What is Familial Hypercholesterolaemia and what are some symptoms?

Answer 17

FH is a monogenic dominant trait in which cholesterol transportation is defective
Heterozygotes - cholesterol levels approximately 2-3 times higher than in normal people and are susceptible to atherosclerosis (hardening of the arteries) in middle age
Homozygotes - cholesterol levels are five times higher than in healthy individuals and severe atherosclerosis (due to deposition of LDL-derived cholesterol in the coronary arteries) and coronary infarction may be observed in adolescence, and xanthomas

Question 18

What is the disease mechanism underlying FH?

Answer 18

Normally, LDL is taken up by LDL receptors on cell surfaces, but in those suffering from FH, they lack functional LDL receptors
Can be due to receptor expression, LDL binding or LDLR endocytosis and recycling

Question 19

What are the 2 strategies to control FH?

Answer 19

1. Inhibition of de novo cholesterol synthesis - using HMG-CoA reductase inhibitors (AKA statins), e.g. lovastatin acts as a competitive inhibitor of HMG-CoA Reductase (by having a similar structure to the substrate HMG-CoA)
2. Reduction of dietary cholesterol absorption - using resins e.g. Cholestyramine which bind or sequester bile acid-cholesterol complexes preventing their reabsorption by the intestine, can lower LDL by 15 -30% and raise HDL by 3 - 5%