Lipid Transport Flashcards
What is the problem for lipid transport in blood?
They are hydrophobic molecules that are insoluble in water
How are lipids transported in blood?
Bound to carriers
What percentage of lipids are carried in blood bound to albumin?
~2%
What type of lipids predominate in those carried by albumin?
Fatty acids
What is the problem with carrying lipids bound to albumin?
It has a limited capacity
What is the capacity of carrying lipids bound to albumin?
~3mmol/L
How are ~98% of lipids carried?
As lipoprotein particles
What do lipoprotein particles consist of?
- Phospholipids
- Cholesterol esters
- Proteins
- TAG
What do the phospholipids in lipoprotein particles act as?
A shell
What do phospholipids consist of?
NAME?
Is a phospholipid molecule hydrophilic or hydrophobic?
NAME?
How are phospholipids classified?
According to head group
What do phospholipids have between their head and tail?
Phosphate and glycerol
What structures do phospholipids form?
- Liposomes
- Micelle
- Bilayer sheet
What is a liposome?
Sphere with bilayer
What is a micelle?
Sphere with single layer
Where does cholesterol in the body come from?
NAME?
What is cholesterol used for?
- Essential component of membranes
- Precursor of steroid hormones
- Precursor of bile acids
Question…
Answer…
Why is cholesterol essential for membranes?
Moderates fluidity
Give 4 steroid hormones that cholesterol is a precursor for
- Cortisol
- Aldesterone
- Testosterone
- Oestrogen
How is cholesterol transported around the body?
As cholesterol esters
What is required to esterify cholesterol?
Enzymes that add a fatty acid
Give 2 enzymes that can produce cholesterol esters?
NAME?
What are lipoproteins?
Lipid carriers
Describe the structure of lipoproteins
- Spheres with phospholipid monolayer
- Have intergral apolipoproteins
- Have peripheral apolipoproteins
What does the phospholipid monolayer of lipoproteins contain?
A small amount of cholesterol
What is meant by integral?
Pass through the membrane
Give 2 examples of integral apolipoproteins
NAME?
Give 2 examples of peripheral apolipoproteins
NAME?
What does the cargo of lipoproteins consist of?
- Triacylglycerols
- Cholesterol esters
- Fat soluble vitamins
How many distinct classes of lipoproteins are there?
5
What are the classes of lipoproteins named according to?
Density
What are the 5 classes of lipoproteins?
- Chylomicrons
- VLDL (very low density lipoproteins)
- IDL (intermediate density lipoproteins)
- LDL (low density lipoproteins)
- HDL (high density lipoproteins)
Which of the lipoprotein classes is very short lived?
IDL
What does each class of lipoprotein contain?
A variable content of apolipoprotein, triglyceride, cholesterol and cholesterol ester
What are the main carriers of fat?
Chylomicrons and VLDL
Why are levels of lipoproteins in blood important?
They are of significant clinical importance
How are levels of lipoproteins in the blood determined?
Density obtained by flotation ultracentrifugation
How is particle diameter related to density?
Inversely proportional
What does a higher % of protein in a lipoprotein mean?
More dense
When are chylomicrons normally present in the blood?
4-6 hours after a meal
What does each class of lipoprotein have?
A particular component of associated proteins- apolipoproteins
What are the 6 major classes of apolipoproteins?
- A
- B
- C
- D
- E
- H
What are the two most important apolipoproteins?
NAME?
Where is apoB found?
NAME?
Where is apoAI found?
HDL
Are apolipoproteins integral or peripheral?
Can be either
What are the roles of apolipoproteins?
- Structural
- Functional
What is the structural role of apolipoproteins?
Help keep integrity of lipoproteins in tact
What are the functional roles of apolipoproteins?
- Cofactors for enzymes
- Ligands for cell surface receptors
Where are chylomicrons loaded at the beginning of their metabolism?
Small intestine
What happens to chylomicrons in the small intestine?
ApoB-48 added
What happens to chylomicrons once apoB-48 has been added?
They enter the lymphatic system
Where do chylomicrons go once in the lymphatic system?
They travel to the thoracic duct, into the left subclavian vein
Why do chylomicrons empty into the left subclavian vein?
It means by avoid the liver the first time round
What happens to the chylomicrons once they’ve been emptied into the left subclavian vein?
ApoC and apoE are added once they’re in the blood
What does apoC on chylomicrons do?
Binds lipoprotein lipase (LPL) on adipocytes and muscle
What is the result of the binding of apoC and LPL?
Released fatty acids enter the cells, depleting the chylomicron of its fat content
To what level is the chylomicrons triglyceride level depleted before the next stage?
~20%
What happens once the chylomicron triglyceride content has depleted to ~20%?
The apoC dissociates and the chylomicron becomes a chylomicron remnant
What happens to chylomicron remnants?
They return to the liver, where the LDL receptor on hepatocytes binds apoE and the chylomicron remnant is taken up by receptor mediated endocytosis. The lysosomes release remaining contents for use in metabolism
What is released from the chylomicron remnants by lysosomes?
NAME?
What is lipoprotein lipase?
An enzyme that hydrolyses triacylglycerols in lipoproteins
What does LDL require to function?
ApoC-11 as a cofactor
Where is LDL found?
Attached to surface of endothelial cells in capillaries
What do chylomicrons carry?
- Fat
- Cholesterol
- Vitamins
Where are VLDLs made?
In the liver
What is the purpose of VLDLs?
Transporting triacylglycerols (TAGs) to other tissues
When are apolipoproteins added to VLDLs?
NAME?
Where do VLDLs bind to LDL?
On endothelial cells in muscle and adipose tissue
What happens when VLDL binds to LDL?
It starts to become depleted of triacylglycerol
What happens to the fatty acids released from VLDLs in muscle?
They are taken up and used for energy production
What happens to the fatty acids released from VLDLs in adipose tissue?
The fatty acids are used for re-synthesis of triacylglycerol and stored as fat
What happens as triacylglycerol content of VLDL particles drops some?
VLDL particles dissociate from the LDL enzyme complex and return to the liver
What happens when VLDL content depletes to ~30%?
Particle becomes short-lived IDL particle
What happens to IDL particles?
They can be taken up by the liver or rebind to LPL enzyme for further depletion of TAG content
What happens to IDL on depletion to ~10%?
IDL loses apoC and apoE, and so becomes a LDL particle
Is the cholesterol content of a LDL particle high or low?
High
What is the primary function of LDLs?
To provide cholesterol from liver to peripheral tissues
What do peripheral tissues express?
LDL receptor
How do peripheral cells take up LDL?
Receptor mediated endocytosis
Do LDL particles have apoC or apoE?
No
What does the lack of apoC and apoE on LDLs mean?
They cannot be effectively cleaved by the liver
Why can LDLs not be effectively cleaved by the liver?
Liver LDL-receptor has a high affinity for apoE
How does the half life of LDL in the blood differ from that of VLDL or LDL?
It is much longer
What is the result of LDLs having a longer half life in the blood?
They are more susceptible to oxidative damage
What happens to oxidised LDL?
It is taken up my macrophages, which can transform to foam cells
What do foam cells contribute too?
The formation of atherosclerotic plaques
What do cells requiring cholesterol express?
LDL receptors on the plasma membrane
What acts as a ligand for the LDL receptors?
ApoB-100 on LDL
How is the receptor/LDL complex taken into cells?
By endocytes, into endosomes
What happens to the endosomes containing receptor/LDL complexes?
They fuse with the lysosome
What is the purpose of the fusing of the endosomes containing the receptor/LDL complex with lysosomes?
Digestion to release cholesterol and fatty acids
How can LDL-R expression be controlled?
Cholesterol concentration in the cell
How can HDL be synthesised?
- Nascent HDL can be synthesised by liver and intestine
- HDL particles can ‘bud off’ from chylomicrons and VLDL as they are digested by LPL
- Free apoA-1 can also acquire cholesterol and phospholipid from other lipoproteins and cell membranes to form nascent-like HDL
How do HDL particles mature?
- Nascent HDL accumulate phospholipid and cholesterol from cells lining blood vessels
- Hollow core of HDL progressively fills, and particle takes on more globular shape
Does transfer of lipids to HDL require enzymes?
No
What do HDL particles have the ability to do?
Remove cholesterol from cholesterol-laden cells, and return it to the liver
What is the ability of HDL’s to remove cholesterol important for?
Blood vessels
Why is the ability of HDL’s to remove cholesterol important for blood vessels?
Reduces the likelihood of foam cell and atherosclerotic plaque formation
What facilitates the transfer of cholesterol to HDL?
ABCA1 protein within the cell
What happens once HDL has taken up cholesterol?
The cholesterol is then converted to cholesterol ester by LCAT
What happens to mature HDL?
It is taken up by the liver by specific receptors
What happens when cells require additional cholesterol?
They can utilise the scavenger receptor to obtain cholesterol from HDL
What is the scavenger receptor?
SR-B1
Why might cells require additional cholesterol?
Steroid hormone synthesis
What can HDL exchange cholesterol ester for?
TAG with VLDL
How can HDL exchange cholesterol ester for TAG with VLDL?
By action of cholesterol exchange transfer protein (CETP)
What is hyperlipoproteinemia?
Raised plasma levels of one of more lipoprotein classes
What causeshyperlipoproteinemia?
Either over-production or under-removal
What are the 6 main classes ofhyperlipoproteinemia?
- I - Chylomicrons in fasting plasma
- IIa
- IIb
- III - Raised IDL and chylomicron remnants
- IV
- V - Raised chylomicrons and VLDL in fasting plasma
Which classes ofhyperlipoproteinemia are associated with coronary artery disease?
IIa (may be severe), IIb, III, IV, V
What causes class I of hyperlipoproteinemia?
Defective lipoprotein lipase
What causes class IIa ofhyperlipoproteinemia?
Defective LDL receptor
What causes class III ofhyperlipoproteinemia?
Defective apoprotein (apoE)
What are the clinical signs ofhyperlipoproteinemia?
- High level of cholesterol in blood
- Cholesterol deposition in various areas of the body
What conditions are caused by cholesterol deposition?
- Xanthelasma
- Tendon Xanthoma
- Corneal arcus
What is xanthelasma?
Yellow patches on eyelids
What is tendon xanthoma?
Nodules on tendons
What is corneal arcus?
An obvious white circle around the eye
What is a raised serum LDL associated with?
Atherosclerosis
Why is raised serum LDL associated with atherosclerosis?
Oxidised LDL is recognised and engulfed by macrophages. Lipid laden macrophages called foam cells accumulate in intima of blood vessel walls to form fatty streak. Fatty streaks can evolve into atherosclerotic plaque, which grows and encroaches on the lumen of artery.
What can atherosclerotic plaques cause?
Angina
What happens if an atherosclerotic plaque ruptures?
It triggers an acute thrombosis (clot)
How does an atherosclerotic plaque rupture trigger a clot?
By activating platelets and clotting cascade
What can a thrombosis cause?
NAME?
What is the first approach to treatment of hyperlipoproteinemia?
Changing diet and lifestyle
How is diet altered to treathyperlipoproteinemia?
NAME?
How is lifestyle altered to treathyperlipoproteinemia?
NAME?
What happens if someoneshyperlipoproteinemia doesn’t respond to diet and lifestyle changes?
Drug therapies
What drug therapies are used to treathyperlipoproteinemia?
- Statins
- Bile salt sequestrants
What do statins do?
Reduce cholesterol synthesis by inhibiting HMG-CoA reductase
How does the inhibition of HMG-CoA reductase reduce cholesterol levels?
By inhibiting HMG-CoA reductase, HMG-CoA not converted to mevalonate, so melavonate not converted to squalene (in several reactions), so squalene not converted to cholesterol (in many reactions)
What do bile salts sequestrants do?
Bind bile salts in GI tract
What is the result of bile salts being binded in the GI tract?
It forces the liver to produce more bile acids using more cholesterol
