56 - Cholesterol Synthesis and Lipoprotein Transport

Question 1

Chemical type of cholesterol

Answer 1

Sterol (modified steroid)

Question 2

Function of cholesterol in cell membranes

Answer 2

Required for membrane permeability and fluidity

Question 3

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

Answer 3

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

Question 4

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

Answer 4

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

Question 5

Function of lipoproteins

Answer 5

Carry cholesterol in the blood

Question 6

Statin mechanism

Answer 6

HMG-CoA reductase inhibitors

Question 7

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

Answer 7

5mM

Question 8

Is cholesterol found in plants?

Answer 8

No.

Question 9

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

Answer 9

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)

Question 10

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

Answer 10

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.

Question 11

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

Answer 11

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.

Question 12

Effect of esterifying cholesterol

Answer 12

Makes it more hydrophobic. Easier to incorporate into lipoprotein structures

Question 13

What is activated isoprene?

Answer 13

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

Question 14

Derivatives of activated isoprene
1)
2)

Answer 14

1) Carotenoids

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

Question 15

Why is cholesterol transported in lipoproteins?
1)
2)

Answer 15

1) Hydrophobic.

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

Question 16

Chylomicron role

Answer 16

Package TAGs and esterified cholesterol from GIT

Question 17

VLDL role

Answer 17

Package TAG and cholesterol esters stored and generated in the liver

Question 18

Lipoprotein lipase

Answer 18

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

TAGS enter muscle and adipocytes

Question 19

LDL role

Answer 19

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

Question 20

HDL role

Answer 20

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

Question 21

Where are chylomicrons formed?

Answer 21

Intestinal mucosa

Question 22

Via which structures do chylomicrons transport TAGS?

Answer 22

Blood vessels and lymphatics

Question 23

Apolipoproteins associated with chylomicrons
1)
2)
3)

Answer 23

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

Question 24

VLDL site of synthesis

Answer 24

Liver

Question 25

``` Apolipoproteins associated with VLDL 1) 2) 3) 4) ```

Answer 25

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

Question 26

LDL precursor

Answer 26

VLDL

Question 27

LDL role vs VLDL role

Answer 27

VLDL delivers TAGs to tissues. | LDL delivers cholesterol to tissues

Question 28

Apolipoproteins associated with LDL 1) 2)

Answer 28

1) ApoA-V | 2) ApoB-100

Question 29

HDL site of synthesis

Answer 29

Liver and intestine

Question 30

HDL synthesis 1) 2)

Answer 30

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

Question 31

Liver receptor that HDL binds to

Answer 31

SR-B1. | For transfer of cholesterol cargo to liver

Question 32

Enzyme in liver that helps VLDL form

Answer 32

ACAT (acyl-CoA-cholesterol acyl transferase)

Question 33

Enzyme in plasma that helps HDL scavenge cholesterol from membranes

Answer 33

LCAT (lecithin-cholesterol acyl transferase)

Question 34

Examples of dyslipidaemias 1) 2) 3)

Answer 34

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

Question 35

``` Atherosclerosis formation 1) 2) 3) 4) 5) 6) 7) ```

Answer 35

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.

Question 36

Rate-limiting step in cholesterol synthesis

Answer 36

HMG-CoA reductase conversion of HMG-CoA to mevalonate

Question 37

Drugs that are competitive inhibitors of HMG-CoA

Answer 37

Statins

Question 38

Possible serious side effect of statin medication

Answer 38

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