Atherosclerosis and lipo metabolism Flashcards
what do apoproteins show about a lipoprotein?
They define the type of lipoprotein - A1 is HDL and B is LDL
what is a summary of what happens in the exogenous pathway?
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
What happens in the endogenous pathway?
Lipoprotein lipase and hepatic lipase metabolise th emost and IDL and LDLs are deposited in vessels forming atheromas
What is the reverse cholestrol transport?
Removal of cholesterol from the vessel walls back to the liver by HDL
What happens in atherosclerosis? There are 8 steps
- LDL enters endothelium into tunica intima
- LDLs oxidised by macrophages and VSMCs
- release of growth factors and cytokines
- additional monocytes and macrophages are recruited
- foam cell accumulation
- VSMC migration
- VSMC proliferation
- plaque growth
What is atherosclerosis?
An inflammatory fibro proliferative disorder
What happens due to the endothelial dysfunction in atherosclerosis?
Increased endothelial permeability and an upregulation of adhesion molecules leads to leukocyte adhesion and migration of leukocytes into the artery wall
How are fatty streaks formed in atherosclerosis?
Migration of VSMCs and activation of t cells lead to an adherence and activation of platelets and formation of of foam cells
How is a complicated plaque formed in atherosclerosis?
Formation of a fibrous cap and an accumulation of macrophages causes the formation of a necrotic core
What are the different types of atherosclerotic lesions?
- lesion prone location - adaptive thickening
- type 2 lesion - foam cells
- type 3 lesion (preatheroma) - extracellular lipid
- type 4 lesion (atheroma) - bigger core of extracellular lipid
- type 5 lesion (fibroatheroma) - fibrous thickening
- type 6 lesion (complicated lesion) - fissure and haematoma
what are remnant lipids?
Chylomicron remnants that are very good at infiltrating the endothelial wall
What are found in remnant lipids?
VLDLs, chylomicron remnants, IDL - the remnants are more important than the LDLs here
What is the inflammatory part of atherosclerosis caused by?
Lipid remnants - not LDL!
What is the difference between a stable and unstable plaque?
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
What are the differences between LDLs and HDLs?
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
How do you modify LDL levels
Smoking
Low HDL
Hypertension
Diabetes
How do you lower HDL
Smoking
Diabetes
Physical inactivity
How do statins work? - mechanism of action
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
What does the selectivity ratio of different statins show?
The higher the selectivity ratio, the greater the chance of it being concentrated in the hepatocyte
What does the potency of different statins show?
lower the number, the more powerful the drug is as an inhibitor of the enzyme
Which statin has the greatest effect in reducing LDL and raising HDL?
Rosuvastatin
What is the ‘rule of 6’ in statins?
Doubling the dose ONLY makes a 6% extra reduction
What happens if LDLs are lowered too much?
Problems with CNS and memory
What is a pleiotropic effect? what drug can be described to have this effect?
Both good and bad effects - statins can be described like this. They have multiple effects that are not directly related to lowering cholesterol
What do fibrates do?
PPAR alpha receptor agonist that acts on the liver. It decreases FFAs and TGs and increases HDL very effectively but LDL doesn’t change
What does PPAR stand for?
Peroxisome proliferator activated receptors
What is different between thiazolidinediones and fibrates? What’s similar about them?
Fibrates: PPAR alpha receptor agonists and thiazolidinediones are PPAR gamma receptor agonists. Fibrates act on liver. Thia.. act on adipose tissue
What does ezetimibe do? What are they?
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
What are CETP inhibitors? what is an example of one?
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
What is PCSK9
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.
What group of patients really benefit from PCSK9 inhibition?
People with familial hypercholesterolemia
