Lipoproteins Metabolism Flashcards
What are lipids?
Organic compounds: poorly water soluble but misible in organis solvents
What are important lipids in human physiology?
Steroids (cholesterol and hormones)
Fat soluble vitamins
Sphingolipids
Triglycerides
Phospholipids
What lipids are most involved in CVD?
Cholesterol and triglycerides
What does cholesterol and triglycerides travel attached to?
Lipoproteins
What does the Apolipo protien do for lipids?
Lets if move and interact
What are the different types of lipoproteins?
Chylomicrons
Very low density lipoproteins (VLDL)
Intermediate density Lipoproteins (IDL)
Low density lipoproteins (LDL)
High density lipoproteins (HDL)
What do lipoproteins do?
Transports cholesterol and triglycerides around the body via circulation
Where are lipoproteins created?
Small intestine and liver where they go to peripheral tissue
Where does the exogenous lipid pathway take place about?
The gut
Where does the endogenous lipid pathway take place about?
The liver - these are stored
What is reverse cholesterol transport?
Putting cholesterol into the liver
What is the exogenous lipid pathway?
Dietary lipids and triglycerides assemble into a chylomicron and LPL acts on these to liberate triglycerides in the circulation. This breaks the triglycerides down into glycerol and NEFA which is either stored or put into adipose tissue. They get more and more broken down before becoming a chylomicron remnants which is taken in by the liver
The endogenous lipid pathway
VLDL is secreted into the bloodstream and is progressively degraded by LPL to become IDL. The degraded molecules are NEFA and glycerol which go into muscles or adipose tissue.
The IDL can go back to the liver where it can be further degraded into LDL - this is cholesterol dense as it has lost triglycerides.
what does LDL do?
Takes cholesterol to muscles
What is reverse cholesterol transport?
HDL is synthesised in either gut or liver and returns cholesterol to the liver. This happens through the ABC-A1 transporter freeing cholesterol from tissue and the LCAT making it more hydrophobic so it can enter HDL and goes to the liver via SRB-1.
It can however lose some cholesterol to VLDL via CETP
LDL
Cholesterol rich, small and long lived
HDL
Small, cholesterol rich and long-lived.
VLDL?
Big, triglycerides, short lived
Chylomicrons?
Large, short lived, triglycerides
What is key to the different lipoproteins?
APOA1
What are the roles of apolipoprotein roles 1 in the reverse cholesterol transport?
APOA1 activates LCAT and interacts with SRB-1
Apolipoprotein- what do these do to VLDL?
ApoB100 lets VLDL get secreted into circulation
ApoC2 activates lipoprotein lipase (LPL) which degrades HDL
ApoB3 counteracts the above
ApoBE and apoB100 binds to LDL-receptor (IDL)
How do apolipoproteins influence the exogenous pathway?
ApoB48 allows secretion into circulation
HDL supplies Chylomicrons with ApoC, ApoE
This allows chylomicron to activate LPL and be degraded
HDL ges ApoA1 from the chylomicron
ApoE allows chylomicron uptake by the liver
Plasma lipoproteins and lipid levels - what determines this?
- The supply of lipids from the liver or the diet.
- activity of key enzymes - things which help packaging of cholesterol or trigger re-uptake
- Cellular uptake
What cells does Cholesterol synthesis?
All nucleated cells,
What cells produces lipoproteins in order to transport cholesterol to other tissues?
Hepatocytes
What do cells use to get cholesterol from the plasma?
LDL receptors
What does intracellular cholesterol levels being high do to LDL? This means they have to be tightly regulated
Reduced LDL receptor expression and therefore less cholesterol uptake
What does cholesterol do?
Strength
Helps uptake in to bile
precursor to make hormones
Why do we need triglycerides?
Energy
Lipid vs Lipoprotein measurement - what do we measure are cholesterol and lipids are packaged together?
Plasmid concentration of each lipoprotein class
What is used to measure the levels of lipoproteins within a circulation?
Ultracentrifugation and electrophoreses
How do you measure apoliproteins?
Immunoassays
How do measure lipoproteins routinely?
The would measure the components to cholesterol and triglycerides through blood
What results would you get if you do a lipid profile?
Total cholesterol
HDL cholesterol
Triglycerides
LDL cholesterol - this is a calculation not a measurement
How do you calculate LDL? AKA the friedwald equation
Total cholesterol - (HDL cholesterol + triglycerides/2.2)
This must be a fasting sample
What was the Lipid driven CV disease hypothesis?
Elevated non-HDL cholesterol causes atherosclerosis in particular coronary artery diseases
What is atherosclerosis?
Damage to arterial wall caused by the development of an atheroma (build up of fat in the cell wall - foam cells (immune cells (macrophages) which are laden by fat cells)).
What issues does an atherosclerosis cause?
Hardening/ loss of elasticity
Partially occluded lumen
Prone to rupture leading to occlusion or formation of thromboemboli which can travel to occlude smaller arterial vessels.
What does atherosclerosis do specifically to the body after an obstruction?
Can cause ischemia and tissue death which could cause stroke, heart attack aortic aneurism, renovascular disease, peripheral vascular disease, heart disease
Does CV risk increase with cholesterol level increase?
Yes
Does raised HDL cholesterol levels increase the risk of CV disease?
No it decrease it.
What is the good cholesterol?
HDL
What is the bad cholesterol?
LDL
What drug decreases LDL cholesterol and CVD risk?
Statins
Atherosclerosis and lipoprotein mechanism - what is taken up by the cell wall and why is HDL not?
ApoB carrying lipoproteins (Chylomicrons, LDL, HDL) and if aren’t cleared by the liver risk being taken up into the cell walls.
This is why HDL is good as it does not have ApoB and therefore isn’t taken up by cell walls
Why is LDL so associated with atherosclerosis?
It is long lived and therefore the concentration is high,
What causes the damage to the cell wall seen in atherosclerosis?
Mechanical - hypertension
Chemical - oxidation, glycation
What is the steps of atherosclerosis? Step 1 - forming fatty streaks?
Hypertension, glycation and oxygen-free radicals damage endothelium.
Then Macrophages consume LDL which has been oxidised by oxgen-free radicals. The macrophages then become foam cells which are trapped in the cell wall and form fatty streaks.
How are oxygen free radicals formed?
Glycation reactions (diabetes)
Toxins from cigarette smoke
Macrophages
What is the steps of atherosclerosis? Step 2 - atheromatous plaque formation?
macrophages release cytokines which causes smooth muscles cells to form a fibrous cap through migration, proliferation and differentiation which traps the macrophages within. The macrophages then die as they cannot get out which leaves extra cellular cholesterol. This is a atheroma
What is the steps of atherosclerosis? Step 3 - plaque rupture?
The plaque gets larger and larger which makes it harder to blood and oxygen to pass through - this can cause angina which is pain due to lack of oxygen.
Or
The plaque can rupture causing thrombosis and total lumen obstruction and tissue eschaemia (cell death) can cause MI or stroke
what is the genetic condition which causes high cholesterol and how is it inherited?
Familial hypercholesterolaemia (FH)
Is is autosomal dominant
What causes FH?
mutation in the LDL receptor (or ApoB, PCSK9).
What does FH lead to?
Leads to high LDL cholesterol which left untreated increases risk of coronary heart disease from a young age.
What treatment can help those with FH?
Statin treatment can reduce the risk of CHD.
Does high cholesterol have many symptoms?
High cholesterol has few symptoms until you get a cardiovascular disease.
What are sign that someone has FH? What would you look for/ask?
Family history
Unusually high LDL cholesterol despite very healthy lifestyle
History of hyperlipidaemia from a young age
Can you see high cholesterol?
Yes in eyes, knuckles - skin,
What evidence satisfied the lipid hypothesis?
- strong correlation: CV risk and non HDL-cholesterol
- Consistent relative risk across countries.
- Biological gradient, increased cvd risk = increase HDL cholesterol
- Plausible mechanism
- coherence
- treatment to lover non-HDL cholesterol reduces CV risk