Atherosclerosis and lipo metabolism

Question 1

what do apoproteins show about a lipoprotein?

Answer 1

They define the type of lipoprotein - A1 is HDL and B is LDL

Question 2

what is a summary of what happens in the exogenous pathway?

Answer 2

When we eat food, it is broken down into chylomicrons (large) which are further broken down into FFAs and chylomicron remnants which can deposit in vessels and cause atheroma

Question 3

What happens in the endogenous pathway?

Answer 3

Lipoprotein lipase and hepatic lipase metabolise th emost and IDL and LDLs are deposited in vessels forming atheromas

Question 4

What is the reverse cholestrol transport?

Answer 4

Removal of cholesterol from the vessel walls back to the liver by HDL

Question 5

What happens in atherosclerosis? There are 8 steps

Answer 5

1. LDL enters endothelium into tunica intima
2. LDLs oxidised by macrophages and VSMCs
3. release of growth factors and cytokines
4. additional monocytes and macrophages are recruited
5. foam cell accumulation
6. VSMC migration
7. VSMC proliferation
8. plaque growth

Question 6

What is atherosclerosis?

Answer 6

An inflammatory fibro proliferative disorder

Question 7

What happens due to the endothelial dysfunction in atherosclerosis?

Answer 7

Increased endothelial permeability and an upregulation of adhesion molecules leads to leukocyte adhesion and migration of leukocytes into the artery wall

Question 8

How are fatty streaks formed in atherosclerosis?

Answer 8

Migration of VSMCs and activation of t cells lead to an adherence and activation of platelets and formation of of foam cells

Question 9

How is a complicated plaque formed in atherosclerosis?

Answer 9

Formation of a fibrous cap and an accumulation of macrophages causes the formation of a necrotic core

Question 10

What are the different types of atherosclerotic lesions?

Answer 10

1. lesion prone location - adaptive thickening
2. type 2 lesion - foam cells
3. type 3 lesion (preatheroma) - extracellular lipid
4. type 4 lesion (atheroma) - bigger core of extracellular lipid
5. type 5 lesion (fibroatheroma) - fibrous thickening
6. type 6 lesion (complicated lesion) - fissure and haematoma

Question 11

what are remnant lipids?

Answer 11

Chylomicron remnants that are very good at infiltrating the endothelial wall

Question 12

What are found in remnant lipids?

Answer 12

VLDLs, chylomicron remnants, IDL - the remnants are more important than the LDLs here

Question 13

What is the inflammatory part of atherosclerosis caused by?

Answer 13

Lipid remnants - not LDL!

Question 14

What is the difference between a stable and unstable plaque?

Answer 14

Stable - thick and fibrous and sometimes has a thinner lumen but are less likely to rupture.
Unstable plaques - thin fibrous cap with rich core of lipids and macrophages, less evidence of VSMC proliferation

Question 15

What are the differences between LDLs and HDLs?

Answer 15

LDLs are strongly associated with atherosclerosis and CHD events - 10% increase in LDL leads to a 20% increase in CHD events
HDL is protective for atherosclerosis and CHD events and tends to be low when TG high

Question 16

How do you modify LDL levels

Answer 16

Smoking
Low HDL
Hypertension
Diabetes

Question 17

How do you lower HDL

Answer 17

Smoking
Diabetes
Physical inactivity

Question 18

How do statins work? - mechanism of action

Answer 18

HMG-CoA reductase inhibitors - halt the cholesterol synthesis pathway by halting the rate limiting step so reducing the modification of proteins involved in modifying gene translation to create LDL
- this has the effect of up regulating the LDL receptors expressed in hepatocytes in the liver which results in more LDL being removed from the blood and more HDL in the blood

Question 19

What does the selectivity ratio of different statins show?

Answer 19

The higher the selectivity ratio, the greater the chance of it being concentrated in the hepatocyte

Question 20

What does the potency of different statins show?

Answer 20

lower the number, the more powerful the drug is as an inhibitor of the enzyme

Question 21

Which statin has the greatest effect in reducing LDL and raising HDL?

Answer 21

Rosuvastatin

Question 22

What is the ‘rule of 6’ in statins?

Answer 22

Doubling the dose ONLY makes a 6% extra reduction

Question 23

What happens if LDLs are lowered too much?

Answer 23

Problems with CNS and memory

Question 24

What is a pleiotropic effect? what drug can be described to have this effect?

Answer 24

Both good and bad effects - statins can be described like this. They have multiple effects that are not directly related to lowering cholesterol

Question 25

What do fibrates do?

Answer 25

PPAR alpha receptor agonist that acts on the liver. It decreases FFAs and TGs and increases HDL very effectively but LDL doesn’t change

Question 26

What does PPAR stand for?

Answer 26

Peroxisome proliferator activated receptors

Question 27

What is different between thiazolidinediones and fibrates? What’s similar about them?

Answer 27

Fibrates: PPAR alpha receptor agonists and thiazolidinediones are PPAR gamma receptor agonists. Fibrates act on liver. Thia.. act on adipose tissue

Question 28

What does ezetimibe do? What are they?

Answer 28

Inhibits cholesterol absorption. It turns into glucuronide in the intestines which activates it, and can be co-administered with statins to avoid the rule of 6 and to have more of a dramatic effect at lowering LDL

Question 29

What are CETP inhibitors? what is an example of one?

Answer 29

Cholesterol Ester Transfer Protein converts HDL into LDL and inhibiting it leads to increased HDL levels but CePT inhibitors lead to a lot of unsuspected deaths so discontinued. - torcetrapib

Question 30

What is PCSK9

Answer 30

An inhibitor of the LDL receptor. Monoclonal anti-PCSK9 antibodies have been made to inactivate PCSK9 and so more LDL can be absorbed by the liver.

Question 31

What group of patients really benefit from PCSK9 inhibition?

Answer 31

People with familial hypercholesterolemia