MBC - Cholesterol

Question 1

Why is cholesterol important?

Answer 1

It is a vital molecule of cell membranes, if signalling pathways, and acts as a precursor for many important biomolecules

Question 2

How many carbon atoms are in cholesterol?

Answer 2

27

Question 3

Describe the structure of cholesterol

Answer 3

4 cyclic rings fused together. Steroidal ring in planar structure and is very hydrophobic: consisting of mainly carbon and hydrogen atoms.

Question 4

Where is the one hydroxyl molecule on cholesterol found?

Answer 4

Position 3

Question 5

How much of our cholesterol is found in membranes?

Answer 5

90%

Question 6

How does cholesterol affect membrane stiffness?

Answer 6

Increases or decreases stiffness depending on temperature and membrane natureq

Question 7

How much dietary cholesterol do we take in a day roughly?

Answer 7

500mg

Question 8

How do we produce cholesterol?

Answer 8

De novo synthesis in the liver from acetyl CoA

Question 9

How much of our vital cholesterol is accounted for by diet?

Answer 9

none - we produce all the cholesterol we need in the liver.

Question 10

What is the 1st process in cholesterol synthesis?

Answer 10

Synthesis of isopentenyl pyrophosphate in the cytoplasm

Question 11

What is the 2nd process in cholesterol synthesis?

Answer 11

Condensation of the 6 isopentenyl pyrophosphate molecules to form squalene in the cytoplasm

Question 12

What is the 3rd process in cholesterol synthesis?

Answer 12

Cyclisation and demethylation of squalene by monoxygenases to form cholesterol in the endoplasmic reticulum.

Question 13

What is the 1st step in part 1 of synthesis?

Answer 13

Acetyl CoA is joined with another acetyl CoA to form Acetoacetyl CoA via B-ketothiolase, losing a CoA.

Question 14

What is the 2nd step in part 1 of synthesis?

Answer 14

Acetoacetyl CoA is joined with another acetyl CoA to form 3-hydroxy 3-methylglutaryl CoA (HMG-CoA) via HMG-CoA synthase, with the addition of water and loss of CoA.

Question 15

What is the 3rd step in part 1 of synthesis?

Answer 15

HMG-CoA is reduced via HMG-CoA reductase to form mevalonate, with the oxidation of NADPH to NADP+ +CoA.

Question 16

How is HMG-CoA reductase controlled?

Answer 16

Mevalonate, cholesterol and bile salts can all inhibit the enzyme therefore act to negatively inhibit the enzyme and avoid overproduction of cholesterol.

Question 17

What is the 4th (final) step in part 1 of synthesis?

Answer 17

Mevalonate undergoes sequential phosphorylation at positions 3 and 5 followed by decarboxylation to form 3-isopentenyl pyrophosphate.

Question 18

What is the 1st step of part 2 in synthesis?

Answer 18

pentenyl pyrophosphate is converted to dimethylallyl pyrophosphate in an isomerisation reaction.

Question 19

What is the 2nd step of part 2 in synthesis?

Answer 19

dimethylallyl pyrophosphate undergoes 2 sequential condensation reaction in which 2 pentenyl pyrophosphate molecules are added to give farsenyl pyrophosphate.

Question 20

What is the 3rd (final) step of part 2 in synthesis?

Answer 20

Farsenyl pyrophosphate condenses with another farsenyl pyrophosphate molecule to form squalene and two pyrophosphate molecules, under squalene synthetase.

Question 21

What is the 1st step of part 3 in synthesis?

Answer 21

Squalene is reduced to squalene epoxide using NADPH which is oxidised to NADP+ and H2O, via squalene monoxygenase.

Question 22

What is the 2nd step of part 3 in synthesis?

Answer 22

Squalene epoxide is catalysed into lanesterol via squalene epoxide lanesterol cyclase.

Question 23

What is the 3rd (final) step of part 3 in synthesis?

Answer 23

Lanesterol is subsequently reduced and demethylated to form cholesterol

Question 24

How many discrete steps does it take to convert lanesterol to cholesterol?

Answer 24

19

Question 25

How many methyl groups are removed from lanesterol to convert it to cholesterol?

Answer 25

3

Question 26

Give three examples of how cholesterol's versatility is shown.

Answer 26

Bile salts Vitamin D Steroid hormones

Question 27

Bile salts are a major product of cholesterol, how much of synthesised cholesterol contributes to bile salts?

Answer 27

About half of the 800mg of cholesterol produced by the liver.

Question 28

What is the primary bile salt from cholesterol break down?

Answer 28

Glycocholate

Question 29

What is the other bile salt produced for cholesterol breakdown?

Answer 29

Taurocholate

Question 30

What is the main feature of bile salts that allows them to emulsify fats?

Answer 30

They have both hydrophobic and hydrophilic properties.

Question 31

What is the main precursor for all 5 steroidal hormone classes?

Answer 31

Pregnenolone

Question 32

What are the 5 classes of steroid hormone?

Answer 32

``` Oestrogens Androgens Progesterones Glucocorticioids Mineralocorticoids ```

Question 33

What converts cholesterol to pregnenolone?

Answer 33

Desmolase

Question 34

What is vitamin D?

Answer 34

Collective term of hormones that are required for the intestinal absorption of ions needed for bone regulation

Question 35

What are the ions needed for bone development?

Answer 35

Calcium Phosphate Magnesium

Question 36

How do people with a Western diet get most of their vitamin D?

Answer 36

Sunlight, as the Western diet typically contains low vitamin D levels

Question 37

How does UV light causes the synthesis of vitamin D from cholesterol?

Answer 37

UV light facilitates the conversion of 7-dehydrocholesterol to previtamin D3. Previtamin D3 is then converted to vitamin D3 (cholecalciferol) which is ultimately converted to calcitriol (1,25-dihydroxycholecalciferol)

Question 38

What is calcitriol?

Answer 38

The most active vitamin D metabolite and plays a key role in calcium metabolism

Question 39

What does calcitriol bind to?

Answer 39

It acts as a steroid hormone so binds to Vitamin D responsive elements (VDREs) in the promoter region of the target gene to influence bone metabolism.

Question 40

What is caused by childhood deficiency of vitamin D3

Answer 40

Rickets.

Question 41

What is familial hypercholesterolaemeia (FH)?

Answer 41

Monogenic dominant trait that results in cholesterol transport being defective.

Question 42

How are heterozygotes for FH affected?

Answer 42

They have serum cholesterol 2-3 times higher than a normal person. They are at risk to atherosclerosis in middle age.

Question 43

How are homozygotes for FH affected?

Answer 43

This is sever FH, serum cholesterol may be around 5 times higher than normal They are at risk to atherosclerosis or myocardial infarction during adolescence.

Question 44

How was the mechanism for FH discovered?

Answer 44

By culturing the fibroblasts of healthy and affected individuals.

Question 45

What was observed in severe FH patients?

Answer 45

Patients lacked functional LDL receptors (LDLRs), due to mutations in several domains of LDLRs.

Question 46

What else has been reported due to mutations in LDLR domains?

Answer 46

Receptor expression LDL binding LDLR endocytosis Recycling.

Question 47

What are the 2 main strategies for managing hypercholesterolaemia?

Answer 47

Inhibition of de novo synthesis in the liver | Reduction of dietary cholesterol absorption in the liver

Question 48

What is cholestyramine?

Answer 48

Resin/sequestrant that binds to bile acid-cholesterol complex to prevent its absorption into the liver.

Question 49

Are sequestrants or resins effective?

Answer 49

Yes - they can lower LDLs by 15-30% and raise HDLs by 3-5%.

Question 50

What is lovastatin?

Answer 50

Statin or HMG-CoA reductase inhibitor. Competitively inhibits the enzyme to prevent the formation of cholesterol early on.