Metabolomics 7 - Lipoproteins Flashcards
1
Q
What are Lipoproteins?
A
- Supramolecular assemblies of lipids, triglycerides, cholesterol and apolipoproteins
- part of a transport system for cholesterol and particles for steroid hormone and membrane synthesis
- relevant for processing of fatty acids
2
Q
Overview of lipoproteins
A
- Supramolecular assembly of lipids, triglycerides, and cholesterol and apolipoproteins.
- Significant diagnostic importance of LDL cholesterol
- increased concentrations of LDL cholesterol are associated with an increased risk of myocardial infarction and
vascular death - early exposure to excessive LDL cholesterol, which is often the result of mutations of the LDL receptor, results in
markedly early atherothrombosis - those who inherit two copies of a defective LDL receptor- related gene or who inherit combined genetic defects (homozygous familial hypercholesterolaemia) face myocardial infarction and stroke in their teens and early 20s
- more than a third of all middle-aged or older adults in the USA and the UK will be recommended for statin therapy
3
Q
Endogenous pathway to the liver
A
VLDL -> IDL -> LDL
4
Q
Reverse Transport Pathway (HDL)
A
HDL is transported away from the liver
5
Q
Clinical role of lipoproteins
A
- Total cholesterol is made up of LDL cholesterol, HDL cholesterol, and VLDL cholesterol. A desirable level of total cholesterol is less than 200.
- LDL cholesterol is the so-called bad cholesterol because it deposits on the inside of your vessels to make plaques. Elevated levels of LDL in- crease your risk of heart disease and stroke. Your doctor will determine your LDL goal based on your number of risk factors and medical his- tory. An optimal level of LDL is less than 100.
- HDL cholesterol is the good cholesterol because a high HDL level de- creases your risk of cardiovascular disease. For men, an HDL less than 40 is considered a risk factor for cardiovascular disease. For women, an HDL less than 50 is considered a risk factor for cardiovascular disease.2
- Triglycerides are the most common type of fat in your body. When cholesterol should not be more than 30 above your LDL goal.
6
Q
Role of individual lipoprotein particles
A
- Chylomicrons carry triglycerides (fat) from the intestines to the liver, to skeletal muscle, and to adipose tissue.
- Very-low-density lipoproteins (VLDL) carry (newly synthesised) triglycerides from the liver to adipose tissue.
- Intermediate-density lipoproteins (IDL) are intermediate between VLDL and LDL. They are not usually detectable in the blood when fasting.
- Low-density lipoproteins (LDL) carry 3,000 to 6,000 fat molecules (phospholipids, cholesterol, triglycerides, etc.) around the body.
- LDL contains apolipoprotein B (apoB), which allows LDL to bind to different tissues.
- LDL particles are sometimes referred to as “bad” lipoprotein because concentrations, dose related,
correlate with atherosclerosis progression. - If oxidised, the LDL can become trapped in the proteoglycans, preventing its removal by HDL
cholesterol efflux - HDL can prevent pathogeic LDL oxidisation
- Sub-classes: large buoyant LDL (lb LDL) particles, small dense LDL (sd LDL) particles
- High-density lipoproteins (HDL) collect fat molecules from the body’s cells/tissues and take them back to the liver.
- HDLs are sometimes referred to as “good” lipoprotein because higher concentrations correlate with low rates of atherosclerosis progression and/or regression.
- HDL binds LPS (lipopolysaccharide) and LTA (lipoteichoic acid) which is a major pathogeic factor
7
Q
Lipoprotein Tests
A
- Electrophoresis
- HPLC
- Ultrazentrifugation (also preparative)
- Enzymatic (?) tests
-> VAP (verticle auto profile) test
-> sets a fixed factor to estimate VLDL from triglyceride concentrations
-> LDL-cholesterol (LDL-C) is not directly measured, rather estimated by the Friedewald
formula: LDL-Cholesterol = Total-Cholesterol − (HDL + [Triglycerides / 5])
-> will underestimate true concentrations when triglycerides are high
*->generally inaccurate when patients are not fasting because of its dependence on triglycerides levels in the calculation
-> LDL-C is falsely low when directly measured
-> Underestimated LDL-chol when LDL is aggressively lowered by potent statins and other lipid-lowering interventions - NMR Liposcience
-> Vantera Analyzer (clinical choice)
8
Q
VAP test
A
- The VAP test directly measures and routinely reports all five lipoprotein classes and sub-classes, including LDL, HDL, intermediate-density lipoprotein (IDL), very low density lipoprotein (VLDL), and lipoprotein (a) [Lp(a)].
- In routine cholesterol testing, LDL-cholesterol (LDL-C) is not directly measured, rather it is estimated using the Friedewald equation, is generally inaccurate when patients are not fasting because of its dependence on triglycerides levels in the calculation.
- Also, estimated LDL-C is falsely low when directly measured LDL-C is < 100 mg/dL or when triglycerides are elevated. The VAP technology also measures and reports LDL particle concentration (LDL-P).
9
Q
Friedewald-Formel (VAP test)
A
LDL-Cholesterin = Gesamt-Cholesterin - (HDL + (Triglyceride/5))
->LDL-C is falsely low when directly measured
10
Q
Principle of NMR Lipoprotein Test
A
18 sub-components used for plasma line shape analysis
11
Q
Subclasses by NMR
A
VLDL (biggest particles) -> subclasses = V6, V4, V2
LDL
HDL
12
Q
Moieties observed by NMR
A
- cholesterol ester
- cholines
- free fatty acid Monoglycerides, Diglycerides, Phospholipids and Triglycerides
- monounsaturated fatty acid (MUFA)
- polyunsaturated fatty acid (PUFA)
13
Q
Lipoproteins and Corona
A
- Several publications now show massive characteristic changes in lipoprotein profiles
- Consistent between different sites
- Suggesting that COVID-19 is associated with massive increases in TG subclasses and shifts in Chol subclassess
14
Q
COVID-19 vs Controls
A
Small molecules
- Lowered Gln/Glu - Lowered his
- Increased Phe
Cholesterol
- Increased VLDL4/5 Chol
- Lowered LDL Chol
- Lowered HDL-3/4 Chol
Triglycerides
- VLDL4/5 increased
- LDL1-4 increased
Phospholipids
- VDL-4/4 increased
- LDL3-6 decreased
Apolipoprotein B
- VLDL increased
- IDL increased
- LDL1 increased
- Apolipoprotein A1 decreased
- Apolipoprotein A2 decreased
15
Q
COVID-19 vs Cardiogenic shock
A
VLDL ↑
VLDL-PL ↑
TG almost all ↑
LDL-1 particles ↑
LDL-1 PL ↑
Apolipoprotein fractions similar
