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

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

- causes inflammation

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

monocytes–>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 leukocytes and cell adhesion molecules

adhesion of leukocytes

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

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

NOTE: plaque erosion is also associated with hardening of the arteries, leading to weakening and thickening of the vessel wall leading to aneurysm and possible haemorrhage

Question 12

What do complicated lesions often contain?

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

What can modify LDL cholesterol?

Answer 14

• Low HDL
• Diabetes
• Smoking
• Hypertension

All of these raise LDL

Question 15

What 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

What is considered a normal triglyceride level?

Answer 17

< 200 mg/dL or 2.3 mmol/L

Question 18

Other than heart disease, what else is a very high triglyceride level associated with?

Answer 18

Pancreatitis

Question 19

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

Answer 19

Bile acid sequestrants

Nicotinic acid

Fibrates

Statins

Question 20

Describe the mechanism of action of statins.

Answer 20

They are HMG-CoA reductase inhibitors

Question 21

What are two important products of the cholesterol synthesispathway?

Answer 21

Geranyl pyrophosphate —> Farnesyl pyrophosphate

They are involved in the modification and activation of proteins (Rho, Ras)

Question 22

How do statins decrease plasma LDL levels?

Answer 22

Statins block the cholesterol synthesis pathway (block HMG-CoA reductase), which leads to the liver responding by producing more LDL receptors

Having more LDL receptors means that more LDL can be removed from the blood

Question 23

What is the selectivity ratio of a statin?

Answer 23

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

Question 24

What is the Rule of 6?

Answer 24

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

Question 25

How do fibrates act?

Answer 25

They activate PPAR-alpha (this is a TF that makes a gene involved in FA uptake and metabolism.
They lower plasma fatty acids and lower triglycerides
They are often used in diabetics with high triglycerides

Question 26

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

Answer 26

Ezetimibe – it inhibits cholesterol absorption in small intestine

Question 27

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

Answer 27

Cholesteryl Ester Transfer Protein (CETP)

Question 28

What was the result of attempted inhibition of CETP?

Answer 28

It increased HDL and decreased LDL but it had off target effects that led to increased mortality and raised BP

NOTE: the drug was called torcetrapib

Question 29

What is PCSK9?

Answer 29

It is an inhibitor of LDL receptors

It stops the LDL in the plasma from binding to the LDL receptor and being taken up (in liver)

PCSK9 inhibition can lead to a decrease in cholesterol levels