Atherosclerosis, Lipoproteins and Lipid-Lowering Agents Flashcards
What is the main difference in the composition of LDLs and HDLs?
They have different apoproteins
What are dietary triglycerides and cholesterol packaged into once they are absorbed?
Chylomicrons (a type of lipoprotein)
What are chylomicrons broken down into?
Chylomicron remnants
Are most circulating lipids endogenous or exogenous?
Endogenous
What is the significance of chylomicron remnants with regards to atherosclerosis?
They are very good at getting into the tunica intima
Define atherosclerosis.
Atherosclerosis is an inflammatory fibro-proliferative disorder
What cells are recruited in the process of atherosclerosis?
Macrophages (which turn into foam cells)
Fibroblasts
Smooth muscle cells
What must initially happen for the process of atherosclerosis to begin?
- Increase in permeability of the endothelium
- Upregulation of endothelial cell adhesion molecules
- Migration of leukocytes into arterial wall
What can happen as the atheroma grows larger?
Some of the foam cells die and rupture, releasing their toxic contents to form a lipid necrotic core
Which cells are responsible for producing a protective fibrous cap over the fat core?
Smooth muscle cells lay down collagen fibres
Macrophages release complementary protein growth factors that recruit VSMC and stimulate them to proliferate and deposit extracellular matrix (collagen). NB this is a good effect because it makes the fibrous cap stronger and more rupture resistant.
https://www.youtube.com/watch?v=OHE1ig4k64M
What is an unstable atherosclerotic plaque?
The fibrous cap thins and eventually ruptures, exposing the thrombogenic lipid core to the platelets and coagulation factors
This causes THROMBOSIS
Build up of which element is a sign of atherosclerosis and increased risk of cardiovascular events?
Calcium
What are some characteristics of vulnerable plaques?
Thin fibrous cap
A core rich in lipid and macrophages
Less evidence of smooth muscle proliferation
LDL is associated with atherosclerosis. What other factors can act as ‘boosters’ which further increase the risk of atherosclerosis
Low HDL
Diabetes
Smoking
Hypertension
What triglyceride levels do low HDL cholesterol levels tend to be associated with?
High triglyceride levels
What factors can lower HDL cholesterol levels?
Smoking
Obesity
Physical inactivity
State some different drug therapies that have been used to treat high cholesterol.
Bile acid sequestrants Nicotinic acid Fibrates Statins Ezetimibe
Describe the mechanism of action of statins.
They are HMG-CoA reductase inhibitors
Which two important intermediates of the cholesterol synthesis pathway are involved in post translational modification of proteins? Which 2 proteins are affected by this modification? (hint cancer lectures)
Geranyl pyrophosphate
Farnesyl pyrophosphate
They are involved in the modification and activation of proteins rho and ras
How do statins decrease plasma LDL levels?
Statins work by inhibiting HMG CoA reductase and hence cholesterol synthesis within hepatocyte. This starves the liver of cholesterol and so it increases the number of LDL receptor on hepatocytes to suck in LDL from blood stream in order to break it down and get cholesterol from there
What is the selectivity ratio of a statin?
The higher the selectivity ratio, the greater the likelihood of the molecule being concentrated in the liver cell
What is the Rule of 6?
Doubling the dose of any statin will give a 6% reduction in the level of LDL cholesterol
How do fibrates act?
They activate PPAR-alpha
PPAR activation leads to:
- lowered plasma fatty acids and lower triglycerides
- Increased plaque stability (hence) lowers risk of thrombosis from plaque and in general
- decreased inflammation, foam cell formation etc
Name an important drug that can be given with statins to further decrease LDL levels?
Ezetimibe – it inhibits cholesterol absorption
What is this drug activated as?
Glucuronide
Which protein is involved in the transport of cholesteryl esters and triglycerides from HDLs to LDLs?
Cholesteryl Ester Transfer Protein (CETP)
What was the result of attempted inhibition of CETP?
It increased HDL and decreased LDL but it had off target effects that led to increased mortality
NOTE: the drug was called torcetrapib and they stopped its production
What is PCSK9?
It is an inhibitor of LDL receptors
It stops the LDL in the plasma from binding to the LDL receptor and being taken up
If you inhibit PCSK9, it will stop the inhibition of LDL receptors and so more LDL is taken up.
how do bile acid sequestrants work
They bind to bile acids and stop them from being reabsorbed as part of the enterohepatic recycling. Since bile acids are made from cholesterol, this forces the body to use cholesterol to make new bile acids and hence lowers cholesterol
