Genes and Atherosclerosis

Question 1

Is atherosclerosis a multifactorial disease?

Answer 1

YES

Question 2

What is the estimated risk effect of each single genotype?

Answer 2

1.12 - 1.75 (where 1.0= no change at all, but they can add if multiple genes are involved).

Question 3

Is someone with familial combined hyperlipidemia monogenetic?

Answer 3

NO. There is more than one gene involved.

Question 4

For what percentage to genes account in CAD?

Answer 4

10-20%

Question 5

What are chylomicrons?

Answer 5

lipoprotein particles that are made in the endoplasmic reticulum of enterocytes/epithelial cells of the small intestine. They are derived from dietary lipids and contain up to 90% of triglycerides (TG»Chol). Their function is to transport lipids absorbed from the intestine to adipose, cardiac, and skeletal muscle tissue, where their TG components are hydrolyzed by the activity of lipoprotein lipase to FAs and glycerol to be absorbed by the tissue.

Question 6

What lone protein does a nascent chylomicron contain?

Answer 6

ApoB-48.

Question 7

What is important to remember about the ApoB proteins?

Answer 7

ApoB-48 and ApoB-100 come from the same gene, but a stop codon separates the two.

Question 8

What is lipoprotein lipase (LPL)?

Answer 8

extracellular enzyme that lines lumen of blood vessels and hydrolyzes TG down to FAs and glycerol. The glycerol gets used as energy and the FAs go into the epithelial cell to be packaged.

Question 9

What does HDL donate to chylomicrons?

Answer 9

ApoCII and ApoE

Question 10

What happens when a large portion of the chylomicron TG core has been hydrolyzed?

Answer 10

Chylomicron remnants (TG:Chol= 1:1) remain and are taken up by the liver and dock via ApoE, thereby transferring dietary fat also to the liver.

Question 11

Is triglyceride (TG) a risk factor?

Answer 11

YES. Normal fasting levels= 75 mg/dL

Question 12

What genes are directly involved with TG levels?

Answer 12

ApoA-5, ApoCI, II, III, and lipoprotein lipase (LPL)

Question 13

Is ApoA-5 good or bad, and why?

Answer 13

GOOD because it lowers TG levels :)

Question 14

Is ApoC-I good or bad, and why?

Answer 14

GOOD because it may activate PCAT, which helps HDL to do its job :)

Question 15

Is ApoC-II good or bad, and why?

Answer 15

GOOD (only at intermediate levels) because it activates LPL :)

Question 16

Is ApoC-III good or bad, and why?

Answer 16

BAD because it inhibits TG hydrolysis by LPL and inhibits VLDL clearance :(
It may contribute to atherosclerotic plaques.

Question 17

Is lipoprotein lipase good or bad?

Answer 17

GOOD because it releases apoprotein and phospholipids for HDL to reuse.
*S447X variant enhances LPL :)

Question 18

Where is VLDL made?

Answer 18

by the liver cells

Question 19

What makes up VLDL?

Answer 19

mainly FAs in the form of TGs from nascent chylomicrons

Question 20

What Apoproteins does VLDL contain?

Answer 20

Apo-B100, (ApoCII, and ApoE it will aquire from HDL)

Question 21

What will LPL do to VLDL?

Answer 21

take it to IDL then LDL (1:1, TG:Chol)

Question 22

What is important about the remnants of chylomicrons, VLDL and IDL?

Answer 22

increased risk for coronary/ischemic heart disease :(

Question 23

What is LDL?

Answer 23

remnant of VLDL composed mainly of cholesterol and cholesterol ester. It’s role is to pass between the vessel walls, bind to it’s cellular LDL receptor (via ApoB100 recognition) and be taken up via endocytosis to release its cholesterol, which is acted on by intracellular ACAT to convert it to cholesterol ester (storage form).

Question 24

What happens if LDL remains in the extracellular space too long?

Answer 24

it can become oxidized by peroxidase and be taken up by macrophages forming foam cells that lead to atherosclerosis :(

Question 25

How do we measure lipoproteins?

Answer 25

``` as cholesterol (C) Total cholesterol= LDL + HDL + (TG/5) * A more reliable alternative is to measure non-HDL cholesterol or to measure ApoB. ```

Question 26

What is non-HDL cholesterol?

Answer 26

everything except HDL, which includes (chylo, VLDL, IDL, and LDL)

Question 27

Why is it better to measure ApoB instead of LDL?

Answer 27

because if the number of the LDL particles differ between two groups, but the overall LDL cholesterol content is the same between the two groups, the group with the greater number of particles (and hence more ApoB) has a higher cardiovascular risk.

Question 28

Do ApoB polymorphisms (differences in arrangements) predict risk of ischemic heart disease, MI, or stroke?

Answer 28

NO (except for E4154K, which showed a reduced risk).

Question 29

What is a new ApoB synthesis inhibitor?

Answer 29

mipomersen = antisense oligonucleotide that binds to ApoB mRNA inhibiting synthesis.

Question 30

What is ApoE?

Answer 30

resides on VLDL and chylomicrons (supplied by HDL for both) and is used as a dock for binding to liver cells. It lowers risk for atherosclerosis by preventing oxidation of LDL, peroxidation of lipids, and platelet aggregation :)

Question 31

What are the 3 important polymorphisms of ApoE?

Answer 31

E4, E3, E2; and any combination of these (ex. E4/E4, E4/2, E3/E2...)

Question 32

If someone does not have enough of the LDL receptors, to what could this lead?

Answer 32

familial hypercholesterolemia

Question 33

What type of mutation occurs most often with a loss of LDL receptors or loss of ApoB100?

Answer 33

loss of function

Question 34

What is a very recently discovered circulating enzyme that is inhibiting LDL receptor expression?

Answer 34

PCSK9 :(

Question 35

Would a loss of function of PCSK9 be good or bad?

Answer 35

GOOD, because more LDL receptors would be expressed :)

Question 36

Would a gain of function of PCSK9 be good or bad?

Answer 36

BAD, because less LDL receptors would be expressed :(

Question 37

Are PCSK9 inhibitors under research?

Answer 37

YES. New big thing is antibodies to PCSK9

Question 38

Would inhibiting ACAT be beneficial?

Answer 38

even though it is used to take turn cholesterol into CE within the tissues (a good thing), ACAT is also found in macrophages and contributes to foam cells. So inhibiting ACAT in the macrophages could be beneficial. More neutral than anything. So not a reasonable target.

Question 39

What is LP(a)?

Answer 39

a type of LDL with attached apoprotein (a) and kringles surrounding it. It is a BAD player because it can be oxidized like LDL in the extracellular matrix and cuz rupturing of plaques, making it both atherogenic and thrombogenic (because it competes with plasminogen (has kringles also) which normally breaks up clots)!

Question 40

Is LP(a) it's own independent risk factor?

Answer 40

YES (1.1 - 2.4), which is very little.

Question 41

What are the good roles of HDL?

Answer 41

mediates reverse cholesterol transport, has antioxidant activity, anti-inflammatory activity. inhibits platelet activation and vasodilates.

Question 42

How does the HDL process work?

Answer 42

the liver produces ApoA which is transferred to the macrophages in the periphery where they change it to a pancake-like shaped HDL as cholesterol is added via ABCA1. As cholesterol is changed to CE via LCAT/PCAT to make a spherical shape more cholesterol is added (via ABCG1 this time). Meanwhile CETP and PLTP are transferring TG from VLDL and chylomicrons in exchange for CE.

Question 43

How does a decrease in HDL relate to an increase in CHD?

Answer 43

for every decrease of 1 mg/dL of HDL, you increase your risk by 2-3% for CHD.

Question 44

What does ApoCIII do?

Answer 44

inhibits TG hydrolysis by LPL and inhibits VLDL clearance

Question 45

Is ApoB/ApoA ration low or high better?

Answer 45

low, because that means low ApoB proteins which are the bad ones.

Question 46

Is HDL particle size more reflective of risk than the levels of HDL?

Answer 46

YES

Question 47

Which PCAT is found where?

Answer 47

``` alpha-PCAT= ApoA (HDL) beta-PCAT= ApoB (chylomicrons, VLDL, LDL) ```

Question 48

What PCAT does fish-eye disease affect?

Answer 48

alpha-PCAT (HDL)

Question 49

So is PCAT good or bad?

Answer 49

GOOD we need it especially for HDL.

Question 50

What will happen if you have low ABCA1 (ATP-Binding Cassette Transporter)? *Tangier's Disease

Answer 50

you will have low HDL :(