Familial Hypercholesterolemia

Question 1

What is Familial hypercholesterolemia (FH)

Answer 1

An autosomal co-dominant disorder characterized by elevated plasma LDL concentrations and premature atherosclerosis

NOTE: Atherosclerosis also moves within the walls, makes it hard to get rid of

Question 2

High blood pressure cause

Answer 2

High blood pressure is caused by foam cell accumulation because reducing surface inside blood vessel (foam cells are started by high concentrations of LDL becoming oxidized and binding to macrophages)

Question 3

What does FH cause on eye lids

Answer 3

Xanthelasma palpebrarum (eye lids) and cuteneous xanthoma
Deposit of cholesterol-rich materials

Question 4

What does FH cause on eye lids

Answer 4

Xanthelasma palpebrarum (eye lids) and cuteneous xanthoma
Deposit of cholesterol-rich materials

Question 5

Causes of familial hypercholesterolemia

Answer 5

Loss-of-function mutations within the LDLR gene is the most prevalent cause of hypercholesterolemia
-The allele frequency for LDLR mutation is high:
1/500 in general population
More frequent among certain groups (e.g. French-Canadians)

NOTE: Cant bind to LDL so it causes a high build up of LDL = increases blood pressure

Question 6

Mutations within LDLR that cause familial hypercholesterolemia

Answer 6

1. LDLR-null - mutations within exon 1 of the LDLR gene resulting the lack of protein synthesis (French Canadians)
2. ER/Golgi trafficking – mutations causing retention of LDLR within the ER and not transported to the plasma membrane
3. Ligand-binding – mutations within the ligand-binding domain resulting in impaired binding to LDL (apoB100)
4. Internalization – mutations in the intracellular domain of LDLR resulting in inability to internalize LDLR/LDL complex
5. LDLR recycling – mutations preventing dissociation of LDLR/LDL complex within the “sorting” endosome and not allowing LDLR recycle back to the plasma membrane

Question 7

3 ways cholesterol homesostasis is controlled

Answer 7

1. Dietary intake of cholesterol
2. Rate of endogenous synthesis in the liver
3. Rate of cholesterol use by the cells

Question 8

What does deregulation of cholesterol homeostasis due

Answer 8

Deregulation of the control mechanism involved in the synthesis or distribution of cholesterol or an excessive dietary cholesterol can lead to increase in cholesterol, hypercholesterolemia (and atherosclerosis).

Question 9

3 Treatments of hypercholesterolemia to lower cholesterol levels

Answer 9

1) Dietary intake of cholesterol
-Lower cholesterol intake
2) Rate of endogenous synthesis in the liver
-Inhibition of HMG-CoA reductase by the competitive inhibitors
-Statins
3. Rate of cholesterol use by the cells
-Increase cholesterol uptake by the liver
-Statins
-Inhibitors of PCSK9

Question 10

How do statins work

Answer 10

Inhibition of HMG-CoA reductase by the competitive inhibitors (statins)

NOTE: Statin molecules have very minimal side effects, mainly beneficial

Question 11

5 characteristics of statin treatment for hyperchoelsterolemia

Answer 11

1. Reduction of de novo cholesterol biosynthesis
2. Low cellular cholesterol leads to an increase in SREBP2
3. Increase in LDL receptors production
4. Clearance of extracellular cholesterol from the blood
5. Lowering of cholesterol levels in the blood

Question 11

5 characteristics of statin treatment for hyperchoelsterolemia

Answer 11

1. Reduction of de novo cholesterol biosynthesis
2. Low cellular cholesterol leads to an increase in SREBP2
3. Increase in LDL receptors production
4. Clearance of extracellular cholesterol from the blood
5. Lowering of cholesterol levels in the blood

Question 12

Why are statins unable to completely remove LDL from the blood?

Answer 12

1. Variation in population because we all react differently to statins
2. Low cholesterol levels increase expression of PCSK9 which will degrade LDL receptors so we can never get rid of of LDL completely

NOTe; First dose is the most efficient, but as you increase the dose of statins the effects are marginal compared to the first.

Question 13

Statin efficiency in population varies because of

Answer 13

1. LDL-receptors genetic variations
2. PCSK9 genetic variations

Question 14

Compare gain and loss of function for PCSK9 in regards to treatment with statins

Answer 14

Question 15

For individuals with gain of function of PCSK9, we need

Answer 15

Inhibitors of PCSK9

FUN FACT: Researcher found that statin prevents lung infection of covid-19 because PCSK9 was degrading entry way of COVID