Cholesterol Flashcards

1
Q

What is cholesterol?

A

a steroid composed of 27 carbon atoms

- composed of cyclic rings (planar) with a hydrophobic tail

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2
Q

Is cholesterol hydrophobic?

A

Apart from the hydroxyl group at position 3

- consisting only of carbon and hydrogen atoms

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3
Q

What is the role of cholesterol?

A

vital component of cell membranes (90 % of cholesterol in body is found there)

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4
Q

What is a key property of cholesterol?

A

it can increase and decrease membrane stiffness, depending on the temperature and the nature of the membrane

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5
Q

How is cholesterol obtained?

A

dietary uptake v. small: 500mg/day

- most supplied by the liver through de novo synthesis of cholesterol from acetyl-CoA

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6
Q

What are the main 3 steps in cholesterol synthesis?

A
  1. Synthesis of isopentenyl pyrophosphate
  2. Condensation
  3. Cyclisation and demethylation
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7
Q

What is isopentenyl pyrophosphate?

A

an activated isoprene which is a key building block (cytoplasmic reactions).

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8
Q

What happens in the condensation step of cholesterol synthesis?

A

Condensation of six molecules of isopentenyl pyrophosphate to form squalene (cytoplasmic reactions)

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9
Q

What happens in the Cyclisation and demethylation step of cholesterol synthesis?

A

Cyclisation and demethylation of squalene by monooxygenases to give cholesterol (ER reactions)

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10
Q

What is step 1 of cholesterol biosynthesis?

A

2 x acteyl-CoA condense to form acetoacetyl CoA
enzyme: β-KETOTHIOLASE
and one CoA is lost

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11
Q

What is step 2 of cholesterol biosynthesis?

A

acetoacetyl CoA + acetyl CoA –(H2O –> CoA)–> 3-hydroxy-3-methylglutaryl CoA (HMG-CoA)
enzyme: HMG-CoA SYNTHASE

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12
Q

What is step 3 of cholesterol biosynthesis?

A

HMG-CoA is reduced to generate mevalonate
enzyme: HMG- CoA REDUCTASE
in the process: 2 NADPH + 2 H+ –> 2 NADP+ + CoA

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13
Q

What controls HMG-CoA?

A

under the control of negative feedback by:
end product- cholesterol
intermediate mevalonate
bile salts

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14
Q

What is step 4 of cholesterol biosynthesis?

A

3 phosphorylations from mevalonate to 5-pyrophospho-mevalonate (3 ATP converted to ADP)
one carboxylation from 5-pyrophospho-mevalonate to 3-isopentenyl pyrophosphate (loosing CO2 and Pi)

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15
Q

What is the activated isoprene unit useful for?

A

building block for further synthesis

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16
Q

What is the role of isoprene?

A

confers lipophilicity to molecules

17
Q

How do molecules get affinity for lipid bilayers?

A

lipid modifications: prenylation

18
Q

What is step 5 of cholesterol biosynthesis?

A
  • dimethylallyl is produced by isomerization from isopentyl PP
  • this condenses with a unit of isopentenyl-PP to produce geranyl-PP (10C)
  • a third isopentenyl-PP is added to form farnesyl-PP (15C)
19
Q

What is step 6 of cholesterol biosynthesis?

A

2 x farnesyl-PP molecules condense to form squalene (30C) + 2 pyrophosphate + NADP+ + H+

20
Q

What is step 7 of cholesterol biosynthesis?

A
  • squalene reduced to squalene epoxide in the presence of O2(–> H2O) and NADPH [primes molecule for ring fusion]
  • formation of lanosterol (4 rings)
21
Q

What is step 8 of cholesterol biosynthesis?

A

lanosterol is reduced and 3 methyl units removed to generate cholesterol

22
Q

What are bile salts ?

A

the major breakdown products of cholesterol

converted into glycocholate and taurocholate

23
Q

what is the role of bile salts?

A

key in emulsifying dietary fats due to their hydrophobic and hydrophillic faces

24
Q

What are streriods?

A

The precursor pregnenolone is generated from cholesterol by the action of the enzyme desmolase. All five classes of steroid hormones come from pregnenolone

25
Q

What are the 5 classes of steroids?

A

Progestagens, glucocorticoids, mineralocorticoids, androgens and oestrogens

26
Q

What is vitamin D?

A

a collective term for a group of steroids which are vital for the intestinal absorption of important ions needed for bone development, namely calcium, phosphate and magnesium

27
Q

What is our main source of vitamin D?

A

activity of UV light upon 7-dehydrocholesterol in the epidermis of the skin

28
Q

What is calcitriol?

A

the most active vitamin D metabolite and plays a key role in calcium metabolism
- It functions as a steroid hormone, binding to vitamin D response elements (VDREs) in the promoter of target genes and inducing key genes involved in bone metabolism

29
Q

What does a deficiency in vitamin D3 lead to?

A

rickets, a defect of bone development in children.

30
Q

What is Familial hypercholesterolaemia (FH)?

A

monogenic dominant trait in which cholesterol transportation is defective
– more susceptible to atherosclerosis

31
Q

What happens when a person has Familial hypercholesterolaemia (FH)?

A
    • xanthomas lying superficially over the knees, the wrists, and hands arise from the scavenging of plasma LDL-derived cholesterol by macrophages of the skin
    • Deposition of LDL-derived cholesterol in the coronary arteries. This can lead to their occlusion and myocardial infarction
32
Q

What is cholesterol taken up by on the cell surface ?

A

specific receptor molecules- the LDL receptor (LDLR)

33
Q

What do FH patients lack?

A

functional LDLRs

34
Q

A variety of mutations in the low density lipoprotein receptor (LDLR) give rise to the condition known as familial hypocholesterolaemia. Which functions do LDLR mutations affect directly ?

A

Mutations in the LDLR gene can affect LDLR expression, LDL binding, LDLR expression and LDLR recycling

35
Q

How can FH be controlled?

A

Inhibition of de novo cholesterol synthesis by the liver,
or the reduction of dietary cholesterol absorption by the intestines
[HMG-CoA reductase inhibitors-liver and resins- intestine]

36
Q

What do resins do?

A

bind or sequester bile acid-cholesterol complexes preventing their reabsorption by the intestine
- lower LDL by 15 -30% and – - raise HDL by 3 - 5%.

37
Q

Examples of resins?

A

Cholestyramine (brand names: Questran, Prevalite)

38
Q

Examples of HMG-CoA-Reductase inhibitors ?

A

Lipitor (Pfizer), Crestor (Astra Zeneca), lovastatin