Atherosclerosis, Lipoproteins and Lipid-Lowering Agents

Question 1

What is the main difference in the composition of LDLs and HDLs?

Answer 1

They have different apoproteins

Question 2

What are dietary triglycerides and cholesterol packaged into once they are absorbed?

Answer 2

Chylomicrons (a type of lipoprotein)

Question 3

What are chylomicrons broken down into?

Answer 3

Chylomicron remnants

Question 4

Are most circulating lipids endogenous or exogenous?

Answer 4

Endogenous

Question 5

What is the significance of chylomicron remnants with regards to atherosclerosis?

Answer 5

They are very good at getting into the tunica intima

Question 6

Define atherosclerosis.

Answer 6

Atherosclerosis is an inflammatory fibro-proliferative disorder

Question 7

What cells are recruited in the process of atherosclerosis?

Answer 7

Macrophages (which turn into foam cells)
Fibroblasts
Smooth muscle cells

Question 8

What must initially happen for the process of atherosclerosis to begin?

Answer 8

• Increase in permeability of the endothelium
• Upregulation of endothelial cell adhesion molecules
• Migration of leukocytes into arterial wall

Question 9

What can happen as the atheroma grows larger?

Answer 9

Some of the foam cells die and rupture, releasing their toxic contents to form a lipid necrotic core

Question 10

Which cells are responsible for producing a protective fibrous cap over the fat core?

Answer 10

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

Question 11

What is an unstable atherosclerotic plaque?

Answer 11

The fibrous cap thins and eventually ruptures, exposing the thrombogenic lipid core to the platelets and coagulation factors
This causes THROMBOSIS

Question 12

Build up of which element is a sign of atherosclerosis and increased risk of cardiovascular events?

Answer 12

Calcium

Question 13

What are some characteristics of vulnerable plaques?

Answer 13

Thin fibrous cap
A core rich in lipid and macrophages
Less evidence of smooth muscle proliferation

Question 14

LDL is associated with atherosclerosis. What other factors can act as ‘boosters’ which further increase the risk of atherosclerosis

Answer 14

Low HDL
Diabetes
Smoking
Hypertension

Question 15

What triglyceride levels do low HDL cholesterol levels tend to be associated with?

Answer 15

High triglyceride levels

Question 16

What factors can lower HDL cholesterol levels?

Answer 16

Smoking
Obesity
Physical inactivity

Question 17

State some different drug therapies that have been used to treat high cholesterol.

Answer 17

Bile acid sequestrants  
Nicotinic acid 
Fibrates  
Statins 
Ezetimibe

Question 18

Describe the mechanism of action of statins.

Answer 18

They are HMG-CoA reductase inhibitors

Question 19

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)

Answer 19

Geranyl pyrophosphate
Farnesyl pyrophosphate
They are involved in the modification and activation of proteins rho and ras

Question 20

How do statins decrease plasma LDL levels?

Answer 20

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

Question 21

What is the selectivity ratio of a statin?

Answer 21

The higher the selectivity ratio, the greater the likelihood of the molecule being concentrated in the liver cell

Question 22

What is the Rule of 6?

Answer 22

Doubling the dose of any statin will give a 6% reduction in the level of LDL cholesterol

Question 23

How do fibrates act?

Answer 23

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

Question 24

Name an important drug that can be given with statins to further decrease LDL levels?

Answer 24

Ezetimibe – it inhibits cholesterol absorption

Question 25

What is this drug activated as?

Answer 25

Glucuronide

Question 26

Which protein is involved in the transport of cholesteryl esters and triglycerides from HDLs to LDLs?

Answer 26

Cholesteryl Ester Transfer Protein (CETP)

Question 27

What was the result of attempted inhibition of CETP?

Answer 27

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

Question 28

What is PCSK9?

Answer 28

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.

Question 29

how do bile acid sequestrants work

Answer 29

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