Molecular Biology: Clinical Significance of Lipoproteins

Question 1

What is PCSK9?

Answer 1

A regulatory protein in LDL-receptor metabolism

Question 2

What are the pre-2013 guidelines for HDL cholesterol levels that are considered “high risk”?

Answer 2

Question 3

What are the main drugs/drug types that are used to increase HDL levels?

Answer 3

Question 4

Where do fibrates, niacin, and CEPT inhibitors fit into this figure, and what do they do?

Answer 4

• All increase HDL
• CETP inhibitors decrease LDL

Question 5

What are the pre-2013 guidelines for HDL cholesterol levels that are considered “low risk”?

Answer 5

Question 6

Describe how LDL receptors are activated and what happens once they are activated

Answer 6

• Decreases in cholesterol induces an increase in LDL-receptors
  
  • This causes endocytosis of LDL and thus a decrease in serum LDL.
• LDL will donate cholesterol to cells

Question 7

What are the pre-2013 guidelines for total cholesterol levels that are considered “Desirable”?

Answer 7

Question 8

Does the use of Ezetimibe and Simvastatin as combo-therapy cause a decrease in LDL? What about a decrease in cardiovascular disease?

Answer 8

• Does the use of Ezetimibe and Simvastatin as combo-therapy cause a decrease in LDL?
  
  • Yes
• What about a decrease in cardiovascular disease?
  
  • No

Question 9

What are the general ADRs for statins?

Answer 9

Question 10

1. What is the regulatory step in cholesterol synthase?
2. What kind of regulation does this enzyme have?
3. How do statins affect this mechanism?

Answer 10

1. HMG-CoA Reductase
2. Feedback inhibition
   
   • Cholesterol, the product, will inhibit the enzyme, HMG-CoA Reductase
3. Bind to HMG-CoA Reductase as competitive inhibitors, inhibiting cholesterol synthase. The cell then uses the mechanism of increasing LDL receptors to get cholesterol instead of synthesizing it on its own.

Question 11

• What are the pre-2013 guidelines for LDL cholesterol levels that are considered:
  
  • The goal for people with very high attack of heart disease
  • The goal for people with heart disease or diabetes
  • The goal for people who are generally healthy

Answer 11

Question 12

What are the main takeaways from the Framingham Heart Study?

Answer 12

• HDL
  
  • High HDL is good, probably independent of other types of cholesterols
• LDL
  
  • Low LDL levels with high HDL levels has the lowest risk of cardiovascular disease

Question 13

What statistic is important in remembering the relation to lipid profiles and MIs?

Answer 13

Only 50% of PTs who suffer from an MI have bad lipid profiles

Question 14

Concerning algorithms for calculating statin use,

• What alarming pattern is seen in older patients?
• What measurement is being considered as an addition to the algorithms?
• Why should the outcome of an algorithm be taken with a grain of salt?

Answer 14

• Healthy old people are recommended to be on statins
• Coronary artery calcium levels
• Many different algorithms. Some may say a PT needs to be on statins and others say they do not need a statin.

Question 15

What are the pros and cons of PCSK9 inhibitors?

Answer 15

Longterm effects are also unknown

Question 16

Describe the general mechanism for Familial hypercholesterolemia

Answer 16

Question 17

What are the main drugs/drug types that are used to lower LDL levels?

Answer 17

Question 18

What are the most used statins and why?

Answer 18

Top two drugs have the highest half-life and decrease LDL the most compared to others.

Question 19

What are the Pleiotropic Effects of Statins?

Answer 19

Question 20

What kind of drugs are the current PCSK9 inhibitors?

What are their names?

Answer 20

Question 21

What is the Primary vs. Secondary Endpoint for cholesterol clinical trials

Answer 21

• Primary
  
  • Better Cardiovascular Outcomes
• Secondary
  
  • Lower LDL levels

Question 22

• Concerning the 4 main healthy lifestyle changes that people can make to change their lipid profile for the better:
  
  • What are they?
  • Which one does not decrease LDL?

Answer 22

Question 23

How do PCSK9 inhibitors work?

Answer 23

In the liver…

• Normally PCSK9 is secreted into the ECF, which then binds to the LDL-receptor on the cell surface.
• The receptor is endocytosed by the cell and the PCSK9/LDL-receptor complex forces the LDL-receptor into the lysosome degradation pathway rather than the recycling pathway.
• Binding to PCSK9 by PCSK9-inhibitors, therefore, increases the likelihood that LDL-receptors will be recycled, thus decreasing LDL serum concetrations.

Question 24

Describe the two general ways that serum levels of LDL is altered

Answer 24

• Cholesterol sources for cells
  
  • Importing LDL into cells
  • Synthesizing of cholesterol by cell
• LDL receptors
  
  • Degrading after use
  • Recycling after use

Question 25

What is Familial Hypercholesterolemia?

Answer 25

• Familial hypercholesterolemia is a genetic disorder.
  
  • Caused by one of 2 mechanisms
    
    • The LDL-receptors become are defected in these PTs.
• *OR**
  * The APO B-100 on LDL is defective
  
  • The defect makes the body unable to remove LDL cholesterol from the blood, and this serum LDL increases.
  • PTs have an increase in risk cardiovascular disease

Question 26

How does ezetimibe work?

Answer 26

• It Inhibits Uptake of Dietary Cholesterol
  
  • Blocks NPC1L1, which is a gut transporter for dietary cholesterol