Lipids 4

Question 1

What makes cholesterol useful?

Answer 1

That it’s Janus-faced and has insolubility in water

Question 2

Sources of cholesterol?

Answer 2

1. Diet eg eggs, liver, fish
2. De novo synthesis (adults on low cholesterol diet synthesis around 800mg cholesterol per day), cells can’t degrade steroid nucleus, excreted by the liver (in bile), consume it biochemically

Question 3

What’s the major site of cholesterol synthesis?

Answer 3

Liver (needs to be tightly regulated)

Question 4

Where are all 27 carbons of cholesterol derived from?

Answer 4

Acetyl CoA in 3 stages

Question 5

3 stages synthetic process that cholesterol gains 27 carbons?

Answer 5

1. Synthesis of isopentenyl pyrophosphate, an inactivated isoprene that is the key building block of cholesterol
2. Condensation of 6 molecules of isopentyl pyrophosphate to form squalene
3. The cyclisation of squalene in an “outstanding reaction” and the tetracyclic product is subsequently converted into cholesterol

Question 6

Where do the three stages of cholesterol synthesis located?

Answer 6

1= cytoplasm
2,3= endoplasmic reticulum

Question 7

What’s the committed step of cholesterol formation?

Answer 7

Synthesis of mevalonate

Question 8

What catalyses the synthesis of mevalonate?

Answer 8

HMG-CoA reductase

Question 9

What is the intermediate in the first step of cholesterol synthesis?

Answer 9

HMG-CoA (from acetyl CoA and acetoacetyl CoA)

Question 10

Four ways HMG COA reductase controlled?

Answer 10

1. Rate of synthesis
2. Rate of translation
3. Rate of degradation
   (1-3 alter the amount of enzyme more than 200 fold)
4. Phosphorylation of the reductase reduces its activity

Question 11

What are potent competitive inhibitors of HMG-CoA reductase?

Answer 11

Lovostatin and related compound

Question 12

What is another method on inhibiting cholesterol levels?

Answer 12

Inhibiting intestinal reabsorption of bile salts (bile salts ate cholesterol derivatives that promote the absorption of dietary cholesterol and dietary fats)- this is the oral administration of positively charged polymers (eg cholestyramine) that bind negatively charged bile salts

Question 13

What transports cholesterol throughout the organism?

Answer 13

Lipoproteins

Question 14

What are lipoproteins comprised of?

Answer 14

A core of hydrophobic lipids surrounded by a shell of more polar lipids and proteins

Question 15

What can lipoprotein particles shift between?

Answer 15

Classes as they release or pickup cargo, thereby changing their density

Question 16

What is the purpose of low- density lipoprotein?

Answer 16

B100, cholesterol transport

Question 17

What’s the purpose of high-density lipoprotein?

Answer 17

Reverse cholesterol transport

Question 18

What are the two roles of the apoproteins (protein components of macro molecular aggregates)?

Answer 18

Solubilise hydrophobic lipids

Contain cell-targeting signals

Question 19

What plays a central role in cholesterol metabolism?

Answer 19

Low-density lipoproteins

Question 20

What’s a primary source of cholesterol from cells outside the liver and intestine that don’t make a lot of it?

Answer 20

Plasma (not de novo synthesis)

Question 21

Primary source of cholesterol transport?

Answer 21

LDL

Question 22

Steps of receptor mediated endocytosis?

Answer 22

1. B100 (apolipoprotein) binds to LDL receptor
2. LDL particle complex is internalised by endocytosis
3. Endosome is acidified (proton pump)
   Causes receptor to release LDL cargo- some receptor returns to cell surface, some is degraded
4. Endosome fuses to lysosomes, protein components hydrolysed to free amino acids. Cholesterol esterols hydrolysed to release free cholesterol (membrane biosynthesis, re-esterified, stored inside cell- must be ester)

Question 23

How does the LDL receptor relinquish its cargo on entering the cell?

Answer 23

In its extended or open state it binds LDL

In its closed state it releases the LDL in endosome and decreases pH of endinsmbe

Question 24

What does the absence of the LDL receptor lead to?

Answer 24

Hypercholesterolaemia and atherosclerosis

Question 25

What is familial hyoercholesterolaemia?

Answer 25

When cholesterol is deposited in various tissue because the high concentration of LDL cholesterol in the plasma- molecular effect in most cases is an absence or a deficiency of functional receptors for LDL

Question 26

What is homozygote in familial hypercholesterolaemia?

Answer 26

No functional LDL receptors | Most die of severe coronary heart disease in childhood

Question 27

What is heterozygote form of familial hypercholesterolaemia??

Answer 27

Half the normal number of LDL receptors | Premature cardiovascular disease in 30s or 40s

Question 28

What does one class of mutations that results in familial hypercholesterolaemia do?

Answer 28

Generates receptors that are reluctant to give up LDL cargo

Question 29

What do 50% of FH mutations do?

Answer 29

Disrupts the open/closed state conversion

Question 30

What does the FH mutation of failure to disrupt the open/closed state interconversion do?

Answer 30

Results in failure of the receptor to release the LDL particle and loss of the receptor by degradation

Question 31

What are some important derivatives of cholesterol?

Answer 31

Vitamin D, bile salts, steroid hormones

Question 32

What are bile salts?

Answer 32

- polar derivatives of cholesterol - highly effective detergents - are released into the small intestine and solubilise dietary lipids

Question 33

What is a precursor to the 5 major classes of steroid hormones?

Answer 33

Cholesterol