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
What are chylomicrons broken down into? What breaks them down?
Chylomicron remnants
By Lipoprotein lipase
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.
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
Up-regulation of endothelial adhesion molecules (key in inflammation)
Leukocyte adhesion
Migration of leukocytes into arterial wall
What can happen as the atheroma grows larger?
Some of the foam cells die + 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? What is the significance of this?
Smooth muscle cells lay down collagen fibres.
It separates the thrombogenic lipid rich core from circulating platelets + other coagulation factors
What happens to unstable atherosclerotic plaques?
Fibrous cap thins + eventually ruptures, exposing thrombogenic lipid core to platelets + coagulation factors
This causes THROMBOSIS
What are some characteristics of vulnerable plaques?
Thin fibrous cap
A core rich in lipid + macrophages
Less evidence of smooth muscle proliferation
What can modify LDL cholesterol?
Low HDL
Diabetes
Smoking
Hypertension
What do low HDL cholesterol levels tend to be associated with?
Higher risk of atherosclerosis + CHD
High triglyceride levels
What 3 factors can lower HDL cholesterol levels?
Smoking
Obesity
Physical inactivity
Other than heart disease, what else is a very high triglyceride level associated with?
Pancreatitis
State 4 different drug therapies that have been used to treat high cholesterol.
Bile acid sequestrants
Nicotinic acid
Fibrates
Statins
Describe the mechanism of action of statins.
HMG-CoA reductase inhibitors (enzyme involved in the RDS in formation of cholesterol)
What are 2 important products of the cholesterol synthesis pathway?
Geranyl pyrophosphate
Farnesyl pyrophosphate
Involved in modification + activation of proteins
How do statins decrease plasma LDL levels?
Statins block the cholesterol synthesis pathway, which leads to the liver responding by producing more LDL receptors
This increases binding + removal of LDL from the blood
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
How do fibrates act? Which patient group are they often used in?
Activate PPAR-alpha
Lead to decreased plasma fatty acids + triglycerides
Often used in diabetics with high triglycerides
Name an important drug that can be given with statins to further decrease LDL levels?
Ezetimibe – it inhibits cholesterol absorption
What is Ezetimibe 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?
Increased HDL + decreased LDL but it had off target effects that led to increased mortality
What is PCSK9?
An inhibitor of LDL receptors
Stops LDL in plasma from binding to the LDL receptor + being taken up
PCSK9 inhibition can lead to a decrease in cholesterol levels
What characterises a stable atherosclerotic plaque?
A necrotic core covered by a thick vascular smooth muscle rich fibrous cap
What can promote rupture of an atherosclerotic plaque?
High BP
Inflammation
Which diseases are strongly associated with high levels of LDL cholesterol?
Atherosclerosis
CHD Events
Expression of what is induced by statins? How does this have a counterintuitive effect?
LDLR + PCSK9
Increase in LDLR to bind LDL
But increase in PCSK9 inhibits LDLR
