MBC - Cholesterol Flashcards

1
Q

Why is cholesterol important?

A

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

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2
Q

How many carbon atoms are in cholesterol?

A

27

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3
Q

Describe the structure of cholesterol

A

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

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4
Q

Where is the one hydroxyl molecule on cholesterol found?

A

Position 3

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5
Q

How much of our cholesterol is found in membranes?

A

90%

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6
Q

How does cholesterol affect membrane stiffness?

A

Increases or decreases stiffness depending on temperature and membrane natureq

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7
Q

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

A

500mg

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8
Q

How do we produce cholesterol?

A

De novo synthesis in the liver from acetyl CoA

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9
Q

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

A

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

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10
Q

What is the 1st process in cholesterol synthesis?

A

Synthesis of isopentenyl pyrophosphate in the cytoplasm

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11
Q

What is the 2nd process in cholesterol synthesis?

A

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

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12
Q

What is the 3rd process in cholesterol synthesis?

A

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

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13
Q

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

A

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

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14
Q

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

A

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.

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15
Q

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

A

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

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16
Q

How is HMG-CoA reductase controlled?

A

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

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17
Q

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

A

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

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18
Q

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

A

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

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19
Q

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

A

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

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20
Q

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

A

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

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21
Q

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

A

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

22
Q

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

A

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

23
Q

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

A

Lanesterol is subsequently reduced and demethylated to form cholesterol

24
Q

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

A

19

25
Q

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

A

3

26
Q

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

A

Bile salts
Vitamin D
Steroid hormones

27
Q

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

A

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

28
Q

What is the primary bile salt from cholesterol break down?

A

Glycocholate

29
Q

What is the other bile salt produced for cholesterol breakdown?

A

Taurocholate

30
Q

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

A

They have both hydrophobic and hydrophilic properties.

31
Q

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

A

Pregnenolone

32
Q

What are the 5 classes of steroid hormone?

A
Oestrogens 
Androgens 
Progesterones 
Glucocorticioids 
Mineralocorticoids
33
Q

What converts cholesterol to pregnenolone?

A

Desmolase

34
Q

What is vitamin D?

A

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

35
Q

What are the ions needed for bone development?

A

Calcium
Phosphate
Magnesium

36
Q

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

A

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

37
Q

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

A

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)

38
Q

What is calcitriol?

A

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

39
Q

What does calcitriol bind to?

A

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.

40
Q

What is caused by childhood deficiency of vitamin D3

A

Rickets.

41
Q

What is familial hypercholesterolaemeia (FH)?

A

Monogenic dominant trait that results in cholesterol transport being defective.

42
Q

How are heterozygotes for FH affected?

A

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

43
Q

How are homozygotes for FH affected?

A

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.

44
Q

How was the mechanism for FH discovered?

A

By culturing the fibroblasts of healthy and affected individuals.

45
Q

What was observed in severe FH patients?

A

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

46
Q

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

A

Receptor expression
LDL binding
LDLR endocytosis
Recycling.

47
Q

What are the 2 main strategies for managing hypercholesterolaemia?

A

Inhibition of de novo synthesis in the liver

Reduction of dietary cholesterol absorption in the liver

48
Q

What is cholestyramine?

A

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

49
Q

Are sequestrants or resins effective?

A

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

50
Q

What is lovastatin?

A

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