HDL, LDL & Atherosclerosis Flashcards
1
Q
Major steps in pathogenesis of atherosclerotic plaques
A
- Accumulation of LDL because of excessive dietary intake or monogenic causes –> LDL can enter the intima of abnormal vascular epithelium 2. LDL trapped gets oxidized→ modified LDL (mLDL) and promotes leukocyte recruitment and foam cell formation. 3. Oxidative stress induce local cytokine proliferation –> increased expression of adhesion molecules 4. Blood monocytes enter the artery –> contact with macrophage colony-stimulating factor (M-CSF) that increase their expression of scavenger receptors. 5. Scavenger receptors mediate the uptake of modified lipoprotein particles and promote foam cell development. 6. Smooth muscle cells migrate into the intima from the media (intimal thickness increases) 7. Intimal smooth muscle cells divide and elaborate extracellular matrix, promoting matrix accumulation in the growing atherosclerotic plaque. Fatty streak turns into fibrofatty lesion. 8. In later stages, calcification can occur and fibrosis continues→fibrous capsule surrounding a lipid-rich core.
2
Q
Lipoprotein definition
A
- Lipoproteins take water-insoluble fats through the bloodstream
- lipid hydrophobic core (cholesterol, esters and triglycerides) surrounded by hydrophilic phospholipid, free cholesterol and apolipoproteins (aka: apoproteins).
- apoproteins = direct lipoproteins to specific tissue receptors and mediating enzymatic reactions.
- Five major classes of lipoproteins exist (based on density, lipid consituents and associated apoproteins).
3
Q
Main classes of lipids
A
- chylomicrons
- very low density lipoproteins (VLDL)
- intermediate-density lipoproteins
- low-density lipoproteins (LDL)
- high-density lipoprotein (HDL)
4
Q
Chylomicrons characteristics
A
- dietary fats absorbed by the small intestine and repackaged as chylomicrons from the intestine
- large particle, rich in TGs, enter circulation via lymphatic system.
- May be found in plasma if fasting TGs are 500 mg/dl - 1000 mg/dl or more
5
Q
Very low density lipoproteins (VLDLs) characteristics
A
- liver packages cholesterol and TGs into VLDL –> main method of cholesterol release into circulation (from liver)
- increase after carbohydrate intake
- high TG content compared to cholesterol content
6
Q
High-Density Lipoproteins general characteristics
A
- smallest, most dense
- lower HDL level=increased risk of CHD
- acts as anti-atherogenic, anti-inflammatory, anti-oxidative, anti-infectious, anti-thrombotic, anti-apoptotic, vasodilator
- 2 main subpopulations:
- HDL with ApoAI but no ApoAII
- HDL with ApoA1 and ApoAII
7
Q
Total cholesterol (fasting) =
A
- = VLDL-C + HDL-C + LDL-C
- VLDL = TG/5
8
Q
Chylomicron pathway characteristics
A
- formed in intestine after the small intestine absorbs dietary fat
- Enter circulation via lymphatic system.
- lipoprotein lipase (LPL) hydrolyzes the TG’s within chylomicrons into free fatty acids which are stored by adipose tissue or used for energy in cardiac and skeletal muscle
- Chylomicron remnants are removed from the circulation by the liver –> secretion in bile OR VLDLs (?)
9
Q
Summary of liver regulation of LDL-C concentrations
A
- Cholesterol delivered to the liver is derived from
- Uptake of cholesterol synthesized in extrahepatic tissues
- Uptake of cholesterol in LDL particles via the LDL receptor
- Cholesterol leaves the liver via 2 routes
- Secretion in the form of VLDL, most of which is returned to the liver in the form of LDL
- Excretion into the bile
10
Q
VLDL pathway
A
- Liver packages cholesterol and TGs into VLDL particles accompanied by ApoB100 and phospholipid
- VLDL is catabolized by LPL releasing fatty acids to muscle and adipose tissue.
- VLDL also interacts with HDL, exchanging some of its TG for ApoC subtypes, ApoE and cholesteryl ester from HDL. The latter of these is important in reverse cholesterol transport.
- VLDL remnants(“IDL”) –> cleared in the liver or catabolized by LPL to form LDL particles
11
Q
HDL pathway
A
- under conditions of intracellular cholesterol excess –> upregulation of trans-membrane protein transporter –> efflux of cholesterol
- cholesterol picked up by Apoprotein A1 –> forms immature HDL particles
- Free cholesterol is acquired by circulating HDL
- cholesterol esters in HDL can then be exchanged in the circulation with any of the apoB-containing lipoproteins (VLDL, IDL, LDL) which deliver cholesterol back to the liver.
- HDL can also transport cholesterol to the liver.
12
Q
Apolipoprotein definition
A
Apolipoproteins (“apoproteins”) are proteins that bind lipids to carry them through the lymphatics and the blood stream
13
Q
Major types of apolipoproteins
A
- Apoplipoprotein B is highly correlated with the non-HDL cholesterol.
- Apolipoprotein B is used to assess the particle number and it is used to help distinguish the risk of CHD in patients with hypertriglyceridemia.
- ApolipoproteinA1 is the major component of HDL.
- Apo E and apo C are transferred to chylomicrons from HDL particles in the bloodstream
14
Q
Fxns of ApoA, ApoB, ApoC
A
- ApoA may inhibit fibrinolysis and be pro-thrombotic –> associated w/increased risk of CVD
- ApoB is used to asses CVD risk in pts w/elevated TGs but w/out elevated LDLs
- Apo C enhances the interactions of chylomicrons with lipoprotein lipases which hydrolyzes the triglycerides within chylomicrons into free fatty acids.
15
Q
Lipid levels and associations w/CVD
A
- High LDL
- Low HDL
- High Triglycerides
- High lipoprotein A
- **high non-HDL cholesterol = LDL, IDL, VLDL and chylomicron remnants (LDL is major component)
18
Q
HDL subpopulations of shape
A
- HDL particles may be either discoidal or spherical in shape
- majority of particles in normal plasma are spherical
19
Q
HDL subpopulations by size
A
- Ultracentrifugation –> subfractions on the basis of density:
- HDL2 (1.063 < d < 1.125 g/mL)
- HDL3 (1.125 < d < 1.21 g/mL).
- five distinct subpopulations on the basis of particle size, ranging from HDL2b (mean diameter 10.6 nm) to HDL3C (7.6 nm).
