Metabolism 8

Question 1

Cholesterol can change interactions with the cytoskeleeton

Answer 1

T

Question 2

What are the 3 parts of biosynthesis of cholesterol?

Answer 2

1. Synthesis of isopentyl pyrophosphate.
2. Condensation of 6 molecules of isopentyl pyrophosphate, forming squalene.
3. Squalene cyclisation and demethylation by monooxygenases, giving cholesterol.

Question 3

Explain the biosynthesis of cholesterol (upto squalene).

Answer 3

1. 2 acetyl-CoA molecules condensed, forming acetoacetyl CoA
2. Another acetyl-CoA molecule condensed with acetoacetyl CoA. Forms HMG-CoA.
3. HMG-CoA reduced, generating mevalonate.
4. Hydroxyl groups at position 3 and 5 are then sequentially phosphorylated and decarboxylated. Forms 3-isopentenyl pyrophosphate.
5. Isopentenyl pyrophosphate is isomerised to dimethylallyl pyrophosphate by isopentenyl pyrophosphate isomerase.
6. Dimethylallyl pyrophosphate is then condensed with a unit of isopentenyl pyrophosphate, forming geranyl pyrophosphate.
7. 3rd isopentenyl pyrophosphate molecule condenses with geranyl pyrophosphate, forming 15C Farnesyl pyrophosphate.
8. 2 farnesyl pyrophosphate molecules condense to form 30C squalene and 2 molecules of pyrophosphate.

Question 4

How is squalene cyclised to cholesterol?

Answer 4

3 steps.

1. Squalene reduced in presence of oxygen and NADPH to form squalene epoxide.
2. Squalene epoxide lanosterol-cyclase catalyses lanosterol formation. 4 rings formed.
3. Lanosterol reduced and 3 methyl units removed, generating cholesterol.

Question 5

What do all 5 classes of steroid hormones come from?

Answer 5

Pregnenolone (desmolase catalyses cholesterol conversion)

Question 6

Vitamin D is synthesised from cholesterol. How?

Answer 6

Through UV light

Question 7

Talk to me about bile salts

Answer 7

1. Have hydrophobic and hydrophilic face.
2. Form micelles, where hydrophilic faces face away from triacylglycerols (TAGS) and hydrophobic faces point towards TAGS.
3. Emulsification of fats in intestine.

Question 8

Describe lipoproteins

Answer 8

Lipids are insoluble in aqueous solutions, posing transportation problems.

Lipids are packaged within lipoproteins (consist of phospholipid monolayer containing cholesterol and apoproteins).

In the core of a lipoprotein there is a cholesterol ester and TAGs.

Question 9

What does apoprotein do?

Answer 9

Allow particle to be recognised by the tissue

Question 10

How is cholesterol ester synthesised (for the lipoprotein core)?

Answer 10

1. In the plasma, from cholesterol and the acyl chain of phosphatidylcholine.

Catalyst: lecithin cholesterol acyltransferase (LCAT)

2. Alternatively, Acyl CoA acyltransferase (ACAT) could be used. It can generate cholesterol esters from long chain fatty acyl CoA species.

ACAT is an intracellular enzyme acting on cholesterol taken in by endocytosis.

Question 11

Why is cholesterol made into cholesterol esters?

Answer 11

Makes cholesterol esters more hydrophobic than cholesterol, and can pack more tightly in lipoprotein core.

Question 12

What are the classifications of Lipoproteins?

Answer 12

BASED ON DENSITY

1. Chylomicrons (CM)
2. Very Low Density Lipoproteins (VLDL)
3. Intermediate Density (IDL)
4. Low density Lipoproteins (LDL)
5. High density Lipoproteins (HDL)

Each lipoprotein has varying apoprotein content so is recognised by different cell types

Question 13

What happens to fats when they are absorbed and packaged into chylomicrons?

Answer 13

The chylomicrons travel in the lymphatic duct from the intestines to the thoracic duct and subclavian vein

Question 14

What are the points of entry of chylomicrons entering the bloodstream?

Answer 14

Thoracic duct and subclavian vein

Question 15

Where is lipoprotein lipase located?

Answer 15

Capillary endothelial cells, lining a variety of tissues

Question 16

What do lipoprotein lipases do?

Answer 16

Catalyse hydrolysis of TAGs (in chylomicrons) to glycerol and fatty acids.

Question 17

How is lipoprotein activated?

Answer 17

Apoprotein C-2 helps

Question 18

What happens to the glycerol produced from lipoprotein lipase?

Answer 18

Goes to liver for use in gluconeogenesis

Question 19

Familial hypercholesterolaemia. Describe.

Answer 19

1. Inherited as a monogenic dominant trait
2. Homozygotes severely affected, have a serum level 5x higher than normals
3. Homozygotes can have severe atherosclerosis / coronary infection in adolescence.

Question 20

What do HDLs do?

Answer 20

Take cholesterol from peripheral tissues back to liver for use/disposal. Lower total serum cholesterol

Question 21

What do LDLs do?

Answer 21

Transport cholesterol from liver to peripheral tissues.

Question 22

Describe receptor mediated endocytosis of LDLs

Answer 22

1. LDLRs receive LDLs and send them into early end-some.
2. Here the LDLRs are recycled back to the plasma membrane.
3. LDLs transferred to lysosomes where they are degraded to give free cholesterol.

Question 23

Mutations in which gene result in familial hypercholesterolaemia?

Answer 23

LDLR gene

Question 24

What are the 5 classes of mutations of the LDLR gene?

Answer 24

1. Class 1. Mutation in LDLR promoter/frameshift/deletion. LDLR not synthesised.
2. Class 2. Mutation throughout coding region. LDLR not transported properly from ER to golgi, so low cell surface expression.
3. Class 3. Mutation in region encoding n terminus. LDLR doesn’t bind effectively to LDL.
4. Class 4. Mutation in cytoplasmic domain. LDLR-LDL complex doesn’t cluster in Clathrin coated pits for receptor mediated endocytosis.
5. Class 5. Mutation in EGFP domain. LDL not released from receptor in endosome and LDLR not recycled back to cell surface.

Question 25

How can hypercholesterolaemia be controlled?

Answer 25

1. HMG-CoA reductase inhibitors.
   - AKA statins
   - Lovastatin is a competitive inhibitor of HMG-CoA reductase
2. Resins/Sequestrants
   - Bind / sequester bile acid-cholesterol complexes, so they cannot be reabsorbed by the intestine. Lowers LDL levels, raises HDL levels.