Atherosclerosis 2

Question 1

Lipoproteins - what are they and what is their general structure?

Answer 1

Lipoproteins are the main method of transportation around the body.
Central hydrophobic core (cholesterol and triglycerides) and hydrophilic coat consisting of free cholesterol and phospholipids

Question 2

Main classifications for different lipoproteins and why they are classified like this?

Answer 2

Classified according to density and the apolipoprotein that they carry 
LDLs - contain apo-B100
HDLs - contain apo-A1 and apo-A2
VLDLs - contain apo-B100
Chylomicrons - contain apo-B-48
ALL attach Apo-B and Apo-C

Question 3

What are the 3 main pathways for transport of lipoproteins?

Answer 3

Exogenous - dietary –> how we extract lipids from diet to use in tissues
Endogenous - how we get lipids and synthesise in liver to be used in tissues
Reverse cholesterol - how lipids taken from tissues to liver to be excreted or to various other locations

Question 4

Outline the exogenous pathway?

Answer 4

1) Lipids from what we eat. Digested cholesterol travels to the lymph system via the NPC1L1 transporter protein
2) packed into chylomicron in the lymph system
3) enters blood and interacts with HDL forming MATURE chlymicron (accepts Apo-C and E)
4) FLows to target tissues and activates LPLs, breaking up the chylomicron to release cholesterol for reaction
5) What is left of chlyo continues to circulate until taken up in the liver where it binds ApoE/ApoB48 receptors so it can be stored, secreted as bile, oxidised to bile acids or converted to VLDLs

Question 5

Endogenous pathway - outline

Answer 5

Liver synth cholesterol and trigylcerides and they are assembled into VLDLs

1) VLDLs travel in bloodstream and interact with HDLs to receive ApoC and E (forms mature VLDL)
2) reaches tissue and reacts with LPL -> VLDL particle hydrolyses and glycerol/fatty acids released which are used by tissues
3) hydrolysed molecules shrink into IDLs and taken up by liver via ApoE on LDLrs (some stay in circulation and undergo hydrolysis and converted to LDLs)
4) LDL binds to tissues via ApoC and released cholesterol into tissues (atherosclerosis)
5) LDL binds LDLrs on liver (via ApoB100) and removed from circulation

Question 6

Reverse cholesterol pathway - outline?

Answer 6

Pathway removes cholesterol from periph tissues ansd takes back to liver

1) HDL has Apo-A1 attached which binds transport proteins ABC-A1 and ABC -G1 in macrophages and foam cells - HDL then uptakes cholesterol
2) transports cholesterol to liver via indirect pathway or direct pathway
3) cholesterol in liver processed and secreted as bile or trans to intestine via ABC-G5/G8 transport protein for excretion

Question 7

Dyslipidaemia - what is it and what are the 2 main types

Answer 7

Too much circulating lipid
Most hyper
Primary - diet and genetics
Secondary - conceq. of other disease (renal, diabetes, alcoholism, renal failure, liver disease, admin of drugs)

Question 8

FREDRICKSON CLASSIF. - what does it classify lipoproteins on ?

Answer 8

Primary dyslipidaemia - classified according to which lipoprotein is abnormal
6 phenotypes
higher LDL/Lower HDL = higher risk of IHD

Question 9

Incidence of heterozygous LDLr and outcome?

Answer 9

1 in 500. Premature CVD at age 30-40

Question 10

Incidence of homozygous LDLr and outcome?

Answer 10

1 in million. severe CVD in childhood. Poor response to medical therapies - liver transport often required

Question 11

Primary dyslipidaemia - treatment?

Answer 11

Statins, cholesterol adsorption inhibitors, PCSK9 inhibitors

Question 12

Statins - otherwise known as? Mechanism of action? How does it impact the liver?

Answer 12

HMG-CoA Reductase inhibitors
HMG-CoA reductase = rate-limiting enzyme involved in cholesterol synthesis (prevents cholest synthesis
Statins regulate cholesterol by targeting the enzyme
Statins target this enzyme for us - all inactive until they have been synthesised by the liver (pro drug)

Question 13

What happens in the liver if high levels of cholesterol are detected?

Answer 13

Liver detects this and switches OFF HMG-CoA reductase to stop cholesterol synthesis. This off switch is commonly faulty in dyslipidaemia!!

Question 14

Statins and cytochrome P450 or glucuronidation pathway

Answer 14

All follow some sort of synthesis in the liver but better pathway for activation of statin better for one person than another –> personalisation!!!

Question 15

Different types of statins?

Answer 15

Specific/reversible/competitive inhibitor statins
Some longer lasting than others
Short acting taken at night time to reduce cholesterol synthesis in the early morning

Question 16

Statins- mechanism of action

Answer 16

Switch off cholesterol synthesis (via –| of HMG-CoA reductase) –> causes increased LDL clearance from plasma to liver
This reduces plasma LDL, trigylcerides and increases HDLs.
A defect in receptors, increasing how many there are will still increase the chance of LDLs binding

Question 17

Pleiotrophic effects?

Answer 17

Off target effects due to their targeting of the mevalonate pathway (involved in lipidation) which localises proteins to organelles.
Several membrane-bound enzymes modified in this way
Therefore: –| lipidation, improve endothelial functioning, reduce inflammation, reduce platelet aggregation, increased vascularisation of ischaemic tissue, increased endothelial progenitor circulation, stabilisation of atherosclerotic plaques, antithrombotic actions, enhanced fibrosis, inhibited germline migration, immune suppression, protection from sepsis

Question 18

Clinical use of statins

Answer 18

• most common drug used to treat atherosclerosis
• given to stroke and MI to reduced the chance of the second
• given at elevated serum cholesterol concentration amongst patients with other risk factors
• NOT DURING PREGNANCY

Question 19

Where is arvostatin commonly used?

Answer 19

• patients with homoxygous familiar hypercholesterolaemia

Question 20

Adverse effects of statins

Answer 20

Muscle pain
Rash
Skeletal muscle damage
Insomnia
GI disturbance

Question 21

Controversy surrounding statins - what was it?

Answer 21

• Low-risk patients not seeing any benefit from using statins contrary to advice given by NICE which suggested it would lower the threshold of risk for heart attack or stroke
• In high risk patients adverse effects may outweigh the benefits of taking the drug?