Cholesterol

Question 1

What is cholesterol?

Answer 1

A steroid which is able to increase or decrease membrane stiffness depending on temperature and the nature of the membrane. It changes interactions with the cytoskeleton

Question 2

How are physiological requirements for cholesterol fulfilled?

Answer 2

By the liver through the de novo synthesis of cholesterol from Acetyl-Co A

Question 3

3 main parts of cholesterol biosynthesis

Answer 3

1) Synthesis of isopentenyl pyrophosphate, an activated isoprene unit which serves as a key building block (cytoplasm)
2) Condensation of 6 molecules of isopentenyl pyrophosphate to form squalene (cytoplasm)
3) Cyclisation and demethylation of squalene by monooxygenases to give cholesterol. (ER)

Question 4

1st reaction of cholesterol biosynthesis

Answer 4

condensation of two acetyl coA molecules to form acetoacetyl coA. Catalysed by beta-ketothiolase

Question 5

2nd reaction of cholesterol biosynthesis

Answer 5

Condensation of another Acetyl CoA to form HMG-CoA. Catalysed by HMG-CoA synthase

Question 6

3rd reaction of cholesterol biosynthesis

Answer 6

HMG-CoA reduced by 2 NADPH to give Mevalonate. Catalysed by HMG-CoA reductase

Question 7

What’s special about HMG-CoA reductase?

Answer 7

It is under negative back control by cholesterol, bile salts and mevalonate.

Question 8

4th reaction of cholesterol biosynthesis

Answer 8

Mevalonate
(catalysed by mevalonate kinase)
5-phosphomevalonate
(catalysed by phosphomevalonate kinase)
5-pyrophosphate mevalonate
(catalysed by kinase)
intermediate with phosphate group attached to position 3
(catalysed by phosphomevalonate decarboxylase)
3-isopentenyl pyrophosphate

In summary, mevalonate undergoes phosphorylation at positions 3 and 5 and then decarboxylation to give 3-isopentenyl pyrophosphate.

Question 9

5th reaction of cholesterol biosynthesis

Answer 9

3-isopentenyl pyrophosphate
(isopentenyl pyrophosphate isomerase)
dimethylallyl pyrophosphate
(geranyl transferase - condenses a unit of 3-isopentenyl pyrophosphate on)
Geranyl pyrophosphate
(same as above)
Farnesyl pyrophosphate

Question 10

6th reaction of cholesterol biosynthesis

Answer 10

2 farsenyl pyrophosphates condense to form squalene and two pyrophosphates

catalysed by squalene synthetase

Question 11

Describe the steps to make squalene into cholesterol

Answer 11

There are 3 steps

1) Squalene is first reduced in the presence of oxygen to form squalene epoxide. This has a different C=C distribution priming the molecule for carbon ring fusion.
2) The enzyme squalene epoxide lanosterol cyclase catalyses the formation of lanosterol. A series of 1,2 methyl and hydride shifts along the chain of the squalene molecule allow the formation of 4 rings.
3) Lanosterol is then subsequently reduced and demethylated 3 times to form cholesterol.

Question 12

What is the precursor of all 5 classes of steroid hormones? and How is it made from cholesterol?

Answer 12

Pregnenolone is the steroid hormone precursor.

It is made from cholesterol by the action of the enzyme desmolase.

Question 13

Synthesis of Vitamin D from cholesterol

Answer 13

7-dehydrocholesterol
(this conversion requires ultraviolet light)
Previtamin D3

Vitamin D3 (AKA cholecalciferol)
(hydroxylation)
Calcitriol (this is important for calcium metabolism)

Question 14

What is the major breakdown product of cholesterol? What are the two main products?

Answer 14

Bile salts

The primary bile salts are glycocholate and taurocholate

Question 15

In which two ways is cholesterol involved with cell signalling?

Answer 15

1) Lipid rafts - fluctuating assemblies of cholesterol and sphingolipids within the plasma membrane, which organise processes like cell signalling by localising key proteins like cell surface receptors
2) Covalently Attaches to the N terminal of the hedgehog signalling protein (N-Hh) which limits its diffusion into tissues during embryogenesis for successful limb formation

Question 16

What are lipoproteins composed of?

Answer 16

Lipoproteins are composed of a phospholipid bilayer that contains cholesterol and apoproteins. Packed in the core are cholesterol esters and triacylglycerols.

Question 17

Types of apoproteins

Answer 17

Apo E
Apo B-100
Apo A-I

Question 18

How are cholesterol esters synthesised?

Answer 18

Synthesised in the plasma by transferring the acyl group of phosphatidylcholine (lecithin) to cholesterol. Catalysed by lecithin cholesterol acyltransferase.

Question 19

Why are cholesterol esters synthesised?

Answer 19

They are more hydrophobic than cholesterol so pack more tightly within the core of the lipoprotein

Question 20

What is the alternative way of synthesising cholesterol esters? and when is this method used?

Answer 20

From long chain fatty acyl CoA species. The enzyme used is Acyl CoA acyl transferases. ACAT is an intracellular enzyme so acts on cholesterol taken in by endocytosis.

Question 21

How are lipoproteins categorised? Give the names of the 5 lipoproteins. What enables these lipoproteins to be recognised by different cell types.

Answer 21

Categorised by density.

1) Chylomicrons
2) very low density lipoproteins (VLDL)
3) Intermediate density lipoproteins (IDL)
4) low density lipoproteins (LDL)
5) high density lipoproteins (HDL)

The different categories of lipoproteins have different apoprotein content which enables them to be recognised by different cell types

Question 22

What is the route of chylomicrons carrying TAGs following their resynthesis in the enterocytes?

Answer 22

The chylomicrons travel from the lacteals of the intestine to the thoracic duct and left subclavian vein where they reach the bloodstream

Question 23

Where is the enzyme lipoprotein lipase located?

Answer 23

On the capillary endothelial cells lining tissues like skeletal muscle, adipose and the heart.

Question 24

How is lipoprotein lipase activated? what does this enzyme do? What happens to the products?

Answer 24

Lipoprotein lipase is activated by Apo C-II of the chylomicron. The enzyme hydrolyses the TAGs into fatty acids and glycerol. The fatty acids undergo beta oxidation. The glycerol is returned to the liver for gluconeogenesis.

Question 25

Why is HDL good and LDL bad?

Answer 25

HDL functions to take cholesterol from peripheral tissues to the liver for use or disposal (reverse cholesterol transport). This lowers total serum cholesterol.

Prolonged high levels of LDL leads to atherosclerosis. LDLs transport cholesterol to peripheral tissues.

Question 26

Class I FH

Answer 26

Mutation in the LDLR promoter/frameshift/deletion

No synthesis of LDLR

Question 27

Class II FH

Answer 27

Mutation throughout coding region

LDLR not properly transported from ER to Golgi resulting in low surface expression

Question 28

Class III FH

Answer 28

Mutation in region encoding N terminus

LDLR does not bind LDL effectively

Question 29

Class IV FH

Answer 29

Mutation in cytoplasmic region

LDLR: LDL complex does not cluster in clathrin coated pits for receptor mediated endocytosis

Question 30

Class V FH

Answer 30

Mutation in the EGFP domain

LDL is not released from the receptor in the endosome and LDLR is not recycled back to the cell surface

Question 31

What are statins?

Answer 31

HMG - CoA reductase inhibitors