56 - Cholesterol Synthesis and Lipoprotein Transport Flashcards

1
Q

Chemical type of cholesterol

A

Sterol (modified steroid)

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2
Q

Function of cholesterol in cell membranes

A

Required for membrane permeability and fluidity

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3
Q

What is cholesterol an important component of?
1)
2)
3)

A

1) Bile acids
2) Steroid hormones
3) Vitamin D
Is a precursor to these

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4
Q

Critical intermediates in cholesterol synthesis pathway
1)
2)
3)

A

1) HMG-CoA (hydroxymethylglutaryl)
2) Isoprene
3) Squalene

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5
Q

Function of lipoproteins

A

Carry cholesterol in the blood

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6
Q

Statin mechanism

A

HMG-CoA reductase inhibitors

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7
Q

Above what level of total blood cholesterol does risk of heart disease significantly increase?

A

5mM

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8
Q

Is cholesterol found in plants?

A

No.

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9
Q
Fates of cholesterol synthesised in the liver
1)
2)
3)
4)
A

1) Transport (esterified, assembled into VLDL)
2) Bile acid synthesis (stored in gall bladder, used to emulsify dietary fats)
3) Vitamin D, steroid hormone synthesis (in gonads, adrenal glands, skin)
4) Membranes (10-50% of membrane lipid)

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10
Q

What does cholesterol do in a cell membrane?
1)
2)
3)

A

1) Provides adjustment to mammalian membrane fluidity at 37 degrees.
2) Rigid cholesterol ring fits in between unsaturated fatty acyl chains, makes membrane less fluid.
3) Membrane rafts have higher concentrations of cholesterol, glycolipids, sphingolipids.

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11
Q
Steps of cholesterol synthesis
1)
2)
3)
4)
5)
6)
7)
A

1) Acetyl-CoA generated in mitochondria
2) Acetyl-CoA converted to HMG-CoA
3) HMG-CoA converted to mevalonic acid by HMG-CoA reductase
4) Mevalonic acid converted to activated isoprene
5) Activated isoprene converted to squalene
6) Squalene converted to cholesterol
7) Cholesterol negatively feeds back on HMG-CoA reductase.

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12
Q

Effect of esterifying cholesterol

A

Makes it more hydrophobic. Easier to incorporate into lipoprotein structures

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13
Q

What is activated isoprene?

A

An intermediate in cholesterol synthesis.
Made from mevalonic acid.
Converted to squalene

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14
Q

Derivatives of activated isoprene
1)
2)

A

1) Carotenoids

2) Quinone electron carriers (EG: ubiquinone in e- transport chain)

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15
Q

Why is cholesterol transported in lipoproteins?
1)
2)

A

1) Hydrophobic.

2) Would alter properties of membranes and cause problems if delivered to wrong site

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16
Q

Chylomicron role

A

Package TAGs and esterified cholesterol from GIT

17
Q

VLDL role

A

Package TAG and cholesterol esters stored and generated in the liver

18
Q

Lipoprotein lipase

A

Enzyme on vascular wall that removes TAGs from LDL, VLDL.

TAGS enter muscle and adipocytes

19
Q

LDL role

A

When VLDL is exposed to lipoprotein lipase, can either become IDL fragments or LDL, which delivers remaining cholesterol esters from VLDL to tissues

20
Q

HDL role

A

Scavenges free cholesterol in blood, transports to liver for bile salt formation
Prevents macrophages from becoming foam cells

21
Q

Where are chylomicrons formed?

A

Intestinal mucosa

22
Q

Via which structures do chylomicrons transport TAGS?

A

Blood vessels and lymphatics

23
Q

Apolipoproteins associated with chylomicrons
1)
2)
3)

A

1) ApoA-I to V
2) ApoB 48
3) ApoC-I to III

24
Q

VLDL site of synthesis

A

Liver

25
Q
Apolipoproteins associated with VLDL
1)
2)
3)
4)
A

1) ApoA-V (involved in uptake of LDL remnants)
2) ApoB-100
3) ApoC-I to III
4) ApoE

26
Q

LDL precursor

A

VLDL

27
Q

LDL role vs VLDL role

A

VLDL delivers TAGs to tissues.

LDL delivers cholesterol to tissues

28
Q

Apolipoproteins associated with LDL
1)
2)

A

1) ApoA-V

2) ApoB-100

29
Q

HDL site of synthesis

A

Liver and intestine

30
Q

HDL synthesis
1)
2)

A

1) ApoA-I starts process of HDL synthesis
2) Two ApoA-I proteins make a hydrophobic ring that rounds up cholesterol esters and phospholipids. This forms mature HDL

31
Q

Liver receptor that HDL binds to

A

SR-B1.

For transfer of cholesterol cargo to liver

32
Q

Enzyme in liver that helps VLDL form

A

ACAT (acyl-CoA-cholesterol acyl transferase)

33
Q

Enzyme in plasma that helps HDL scavenge cholesterol from membranes

A

LCAT (lecithin-cholesterol acyl transferase)

34
Q

Examples of dyslipidaemias
1)
2)
3)

A

1) Hypercholesterolaemia
2) Hypertriglyceridaemia
3) Decrease in HDL cholesterol

35
Q
Atherosclerosis formation 
1)
2)
3)
4)
5)
6)
7)
A

1) Modified (oxidised) LDL accumulates in an artery wall (favoured by high LDL).
2) Endothelial cells in the artery react by displaying adhesion molecules.
3) White cells (monocytes and T-cells) invade the tissue and secrete inflammatory
mediators (cytokines).
4) Macrophages appear, take up the modified LDLs using scavenger receptors.
5) Macrophages become engorged with cholesterol. At this stage they are called
foam cells.
6) Fibrous tissue develops to trap the foam cells.
7) Foam cells produce “tissue factor” that can lead to a blood clot in the artery upon
rupture of the plaque.

36
Q

Rate-limiting step in cholesterol synthesis

A

HMG-CoA reductase conversion of HMG-CoA to mevalonate

37
Q

Drugs that are competitive inhibitors of HMG-CoA

A

Statins

38
Q

Possible serious side effect of statin medication

A

Depletion of Q10. This is an electron carrier in mitochondrial e- transport chain.
This can have deleterious effects on cardiac and skeletal muscle.