Flashcards in Genes and Atherosclerosis Deck (50):
Is atherosclerosis a multifactorial disease?
What is the estimated risk effect of each single genotype?
1.12 - 1.75 (where 1.0= no change at all, but they can add if multiple genes are involved).
Is someone with familial combined hyperlipidemia monogenetic?
NO. There is more than one gene involved.
For what percentage to genes account in CAD?
What are chylomicrons?
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.
What lone protein does a nascent chylomicron contain?
What is important to remember about the ApoB proteins?
ApoB-48 and ApoB-100 come from the same gene, but a stop codon separates the two.
What is lipoprotein lipase (LPL)?
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.
What does HDL donate to chylomicrons?
ApoCII and ApoE
What happens when a large portion of the chylomicron TG core has been hydrolyzed?
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.
Is triglyceride (TG) a risk factor?
YES. Normal fasting levels= 75 mg/dL
What genes are directly involved with TG levels?
ApoA-5, ApoCI, II, III, and lipoprotein lipase (LPL)
Is ApoA-5 good or bad, and why?
GOOD because it lowers TG levels :)
Is ApoC-I good or bad, and why?
GOOD because it may activate PCAT, which helps HDL to do its job :)
Is ApoC-II good or bad, and why?
GOOD (only at intermediate levels) because it activates LPL :)
Is ApoC-III good or bad, and why?
BAD because it inhibits TG hydrolysis by LPL and inhibits VLDL clearance :(
It may contribute to atherosclerotic plaques.
Is lipoprotein lipase good or bad?
GOOD because it releases apoprotein and phospholipids for HDL to reuse.
*S447X variant enhances LPL :)
Where is VLDL made?
by the liver cells
What makes up VLDL?
mainly FAs in the form of TGs from nascent chylomicrons
What Apoproteins does VLDL contain?
Apo-B100, (ApoCII, and ApoE it will aquire from HDL)
What will LPL do to VLDL?
take it to IDL then LDL (1:1, TG:Chol)
What is important about the remnants of chylomicrons, VLDL and IDL?
increased risk for coronary/ischemic heart disease :(
What is LDL?
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).
What happens if LDL remains in the extracellular space too long?
it can become oxidized by peroxidase and be taken up by macrophages forming foam cells that lead to atherosclerosis :(
How do we measure lipoproteins?
as cholesterol (C)
Total cholesterol= LDL + HDL + (TG/5)
* A more reliable alternative is to measure non-HDL cholesterol or to measure ApoB.
What is non-HDL cholesterol?
everything except HDL, which includes (chylo, VLDL, IDL, and LDL)
Why is it better to measure ApoB instead of LDL?
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.
Do ApoB polymorphisms (differences in arrangements) predict risk of ischemic heart disease, MI, or stroke?
NO (except for E4154K, which showed a reduced risk).
What is a new ApoB synthesis inhibitor?
mipomersen = antisense oligonucleotide that binds to ApoB mRNA inhibiting synthesis.
What is ApoE?
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 :)
What are the 3 important polymorphisms of ApoE?
E4, E3, E2; and any combination of these (ex. E4/E4, E4/2, E3/E2...)
If someone does not have enough of the LDL receptors, to what could this lead?
What type of mutation occurs most often with a loss of LDL receptors or loss of ApoB100?
loss of function
What is a very recently discovered circulating enzyme that is inhibiting LDL receptor expression?
Would a loss of function of PCSK9 be good or bad?
GOOD, because more LDL receptors would be expressed :)
Would a gain of function of PCSK9 be good or bad?
BAD, because less LDL receptors would be expressed :(
Are PCSK9 inhibitors under research?
YES. New big thing is antibodies to PCSK9
Would inhibiting ACAT be beneficial?
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.
What is LP(a)?
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)!
Is LP(a) it's own independent risk factor?
YES (1.1 - 2.4), which is very little.
What are the good roles of HDL?
mediates reverse cholesterol transport, has antioxidant activity, anti-inflammatory activity. inhibits platelet activation and vasodilates.
How does the HDL process work?
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.
How does a decrease in HDL relate to an increase in CHD?
for every decrease of 1 mg/dL of HDL, you increase your risk by 2-3% for CHD.
What does ApoCIII do?
inhibits TG hydrolysis by LPL and inhibits VLDL clearance
Is ApoB/ApoA ration low or high better?
low, because that means low ApoB proteins which are the bad ones.
Is HDL particle size more reflective of risk than the levels of HDL?
Which PCAT is found where?
alpha-PCAT= ApoA (HDL)
beta-PCAT= ApoB (chylomicrons, VLDL, LDL)
What PCAT does fish-eye disease affect?
So is PCAT good or bad?
GOOD we need it especially for HDL.