7- Cholestrol

Question 1

What are the 4 main steps in cholesterol synthesis

Answer 1

Synthesisofmevalonatefromthreeacetyl coAunits
o Activationofmevalonatetoisopentenyl pyrophosphate(IPP),afivecarbonprecursor
o ElongationofIPPtosqualene,athirtycarbonspecies
oCyclisationanddemethylationofsqualenebymonooxygenasestogivecholesterol

Question 2

What enzyme do statins effect

Answer 2

HMG coA reductase

Question 3

What 3 compounds give negative feedback to HMG coA reductase

Answer 3

HMG coA reductase is under negative feedback by cholesterol, mevalonate and bile salts It is also the rate limiting step for this pathway

Question 4

In the Activation of mevalonate to isopentenyl pyrophosphate what ion is used as a catalyst

Answer 4

Magnesium

Question 5

What are the 5 classes of steroid hormone that come from pregnenolone

Answer 5

o Progestins
o Glucocorticoids
o Mineralocorticoids 
o Androgens
o Oestrogens

Question 6

What enzyme generates pregnenolone from cholesterol

Answer 6

Cholesterol desmolase

Question 7

How are bile salts produced from cholesterol

Answer 7

Cholesterol is converted into trihydroxycoprostanoate and then into the active intermediate, cholyl coA
The carboxyl carbon of cholyl coA reacts with the amino group of glycine or taurine to form glycocholate of taurocholate respectively

Question 8

What is the composition of a lipoprotein

Answer 8

phospholipid monolayer containing cholesterol and proteins called apoproteins (e.g. Apo A-I, Apo B-100, Apo E)
Packed within the core of the lipoprotein are a mixture of cholesterol esters and triacylglycerols:

Question 9

What do chylomicrons do

Answer 9

“are transported via the lymphatics into the bloodstream and broken down by the enzyme Lipoprotein lipase located on the capillary endothelial cells lining a variety of tissues including adipose, heart and skeletal muscle. The triacylglycerols within the chylomicrons are hydrolysed to glycerol and fatty acids, the latter undergoing β-oxidation

Question 10

What is the function of HDLs

Answer 10

HDLs function to take cholesterol from peripheral tissue to the liver for use or disposal. They
lower total serum cholesterol

Question 11

What is the function of LDLs

Answer 11

LDLs function to take newly synthesised cholesterol from the liver to peripheral tissue, with more
than 40% of their weight made up of cholesterol esters

Question 12

Describe how LDL receptors work

Answer 12

LDLs bind to the receptor and are all endocytosed – LDL and the receptor – into the cell, coated with a protein called clathrin
Clathrin is removed, in a process of uncoating, where the receptor endosome fuses with a big endosome in the cell
The receptor separates and is put back into the membrane
The LDL is transferred to the lysosome where the contents are hydrolysed for use in the cell, and
free cholesterol is let out into the cell

Question 13

What is Familial hypercholesterolaemia

Answer 13

Mutations in the LDL receptor lead to increased cholesterol serum levels because cholesterol uptake is reduced

Question 14

What are some examples of mutations in Familial hypercholesterolaemia

Answer 14

LDLR not properly synthesised
o LDLRisnotproperlytransportedfromtheERtotheGolgiupontranslation,leadingtolow
expression (mutations throughout coding region)
o LDLRdoesn’tbindLDLeffectively(mutationinregionencodingN terminus)
o LDLR:LDL complex does not cluster in clathrin coated pits for receptor mediated
endocytosis (mutations in cytoplasmic domain)
o LDL is not released from the receptor in the endosome and thus LDLR is not recycled to
the cell surface (mutation in the EGFP domain)

Question 15

What agents can be used to control cholesterol metabolism

Answer 15

Resinstocontrolintakeofdietaryfatandcholesterol
These bind or sequester bile acid cholesterol complexes, preventing their reabsorption by
the intestine. They lower LDL by 15 30% and HDLs by 3 5%
o HMG coAreductaseinhibitors.
E.g.statins
Statins are competitive inhibitors of HMG coA reductase

Question 16

How does cholesterol produce vitamin d3

Answer 16

“Exposure of 7-Dehydrocholesterol in the epidermal layers of skin to UV radiation results in its metabolism to calcitriol, the active form of Vitamin D3 which plays a key role in Ca2+ metabolism.”

Question 17

How does cholesterol have a role in cell signalling

Answer 17

“It is a key component of lipid rafts, fluctuating assemblies of cholesterol and sphingolipids within a plasma membrane where they organize signaling molecules into discreet domains. Cholesterol also modifies the hedgehog signaling protein (N-Hh) limiting its diffusion within tissues during embryogenesis.
”

Question 18

Describe an

LDL

Answer 18

With a size of over 20nm and with more than 40% of the lipoprotein’s weight made up of cholesterol esters, the liporotein is a low density lipoprotein (LDL). LDLs transport cholesterol synthesized in the liver to peripheral tissues.