MEH 4. Lipid transport Flashcards
Why do lipids have to be transported in the blood by specific carriers?
They are hydrophobic molecules, so are insoluble in water.
What 2 ways can lipids be carried in the blood?
- Bound to albumin (2%)
2. Lipoprotein particles (98%)
What is the normal range for total cholesterol levels?
< 5 mmol/L
What is the polar head of phospholipids made from?
Choline (+)
How are phospholipids classified?
According to their polar head group.
What is the difference between a liposome and a micelle?
Liposomes are made from a phospholipid bilayer, whereas micelles are comprised of a single phospholipid layer.
Outline some important roles of cholesterol in the body.
- Essential component of membranes
- Precursor of steroid hormones - cortisol, aldosterone,testosterone,oestrogen.
- Precursor of bile acids
Where is most of the body’s cholesterol synthesised?
In the liver
What form is most of the cholesterol transported around the body as?
Cholesterol esters
Which enzyme is responsible for catalysing the formation of cholesterol esters?
Lecithin cholesterol acyltransferase (LCAT)
Or acyl-coenzyme A: cholesterol acyltransferase
What is the broad function of lipoproteins?
Transportation of lipids around the body.
Outline the structure of a lipoprotein.
- Phospholipid monolayer surrounding cargo
- Peripheral apolipoproteins lying over the monolayer
- Integral apolipoproteins within the monolayer
What is carried in the cargo of lipoproteins?
- Triacylglycerol
- Cholesterol ester (cholesterol linked to FA)
- Fat soluble vitamins (A,D,E,K)
What are the 5 classes of lipoproteins?
Chylomicrons VLDL IDL LDL HDL
How do the classes of lipoproteins differ?
They each contain variable content of apolipoprotein, cholesterol ester, triglyceride and cholesterol.
Which 2 lipoproteins are the main triglyceride carriers?
Chylomicrons and VLDL
Which lipoproteins are the main carriers of cholesterol esters?
IDL, LDL, HDL
Name the classes of lipoprotein, from smallest to largest.
HDL, LDL, IDL, VLDL, chylomicron.
Which lipoproteins possess the apolipoprotein apoB?
VLDL, IDL and LDL
Which lipoproteins possess apoA1?
HDL
What are the 2 main roles of apolipoproteins?
- Structural - packaging water insoluble lipid
- Functional - co-factor for enzymes
- ligands for cell surface receptors
What is the transport function of chylomicrons?
Transport dietary triglycerol from the intestine to tissues such as adipose tissue.
Which apolipoprotein is added to chylomicrons in the small intestine?
apoB-48
Which lipoprotein travels through the lymphatic system, explain its route.
Chylomicrons are taken into the lymphatic system after entering the small intestine. They then enter the thoracic duct which empties into the left subclavian vein.
Which 2 apolipoproteins do chylomicrons acquire once entering the blood?
ApoC and apoE
How do the tissues obtain the lipid from the lipoproteins?
Adipocytes and skeletal muscle express lipoprotein lipase (LPL) on their surface.
The released fatty acids enter the cells, depleting the fat within the lipoprotein.
How do chylomicrons become chylomicron remnants?
When the triglyceride content is reduced to 20%, apoC dissociates from LPL and the chylomicron becomes a chylomicron remnant.
What is the fate of chylomicron remnants in the blood?
They are returned to the liver where the LDL receptor binds to apoE and the remnant is taken up by receptor mediated endocytosis. Lysosomes release remaining contents for use in metabolism.
What is lipoprotein lipase?
Enzyme that hydrolyses triacylglycerol in lipoproteins.
Where is lipoprotein lipase found?
Attached to the surface of endothelial cells in capillaries of muscle and adipose.
What co-factor does lipoprotein lipase require?
ApoC-II
What is the transport function of VLDL’s?
They transport triacylglycerol synthesised in the liver to adipose tissue for storage.
Which apolipoprotein is added to VLDL during formation and which are added in the blood?
apoB100 during formation.
apoC and apoE added from HDL particles in the blood.
How does the fate of the released fatty acids differ in muscle and adipose tissue?
Muscle: fatty acids oxidised to produce energy
Adipose: fatty acids re-synthesised to TAG and stored as fat.
How are IDL (intermediate density lipoproteins) formed?
As the triglycerol content of VLDL’s depletes to 30%, it can either return to the liver or it becomes a short lived IDL particle.
What is the function of IDL particles?
They can either be taken up by the liver, or they can re-bind LPL enzyme and further deplete their TAG content.
At what point to IDL’s become LDL’s?
Upon depletion to 10%, when the IDL will lose apoC and apoE, it will become an LDL particle.
What is the main contents of LDL particles?
Cholesterol, as the triglycerol has all been removed at this point.
What is the primary function of LDL?
Provide cholesterol from the liver to peripheral tissues.
How do peripheral cells take up LDL from the blood?
Cells that require cholesterol will express LDL receptors on their plasma membrane. ApoB-100 on LDL is a ligand for these receptors.
They take up LDL through receptor mediated endocytosis.
Fuse with lysosomes for digestion and release of cholesterol and fatty acids.
How does the surface of LDL’s differ to other lipoproteins, what is the consequence of this?
It does not have apoC or apoE.
This means that it is not efficiently cleared by the liver, as the liver LDL-receptor has a high affinity for apoE.
The half life of LDL is much longer than VLDL’s or IDL’s. What is the clinical significance of this?
It is much more susceptible to oxidative damage.
Oxidised LDL is taken up by macrophages which can transform into foam cells and begin to form fatty streaks, contributing to the development of atherosclerosis.
What are the 3 ways that HDL can be synthesised?
- Nascent HDL synthesised by liver and intestine
- HDL particles can “bud off” chylomicrons and VLDL as they are digested by LPL
- Free apoA-1 can acquire cholesterol and phospholipids from other lipoproteins and cell membranes to form nascent-like HDL.
What occurs during HDL maturation?
Nascent HDL accumulate phospholipids and CHOLESTEROL from cells lining blood vessels.
Hollow core progressively fills and particle becomes globular.
Does the transfer of lipids to HDL require enzyme activity?
No
What is the role of HDL’s and why is this so important for blood vessels?
Remove cholesterol from cholesterol-laden cells and return it to the liver.
In blood vessels, this reduces the likelihood of foam cell and atherosclerotic plaque formation.
Which protein within cells facilitates the transfer of cholesterol to HDL?
ABCA1 (atp-binding cassette protein)
What is the fate of mature HDL?
- Taken up by the liver via receptors.
- Cells needing more cholesterol can use scavenger receptor to obtain cholesterol from HDL.
- HDL can exchange cholesterol ester for TAG with VLDL via action of cholesterol exchange transfer protein (CETP)
Which cells are likely to require extra cholesterol from HDL particles?
Steroidogenic cells
How is the nascent HDL different to the mature HDL?
It is empty in its nascent state and fills with cholesterol as it matures.
How does the liver dispose of cholesterol?
As bile salts
What are the 2 mechanisms which can result in hyperlipoproteinaemias?
- Over-production
2. Under-removal
What is the cause of type I hyperlipoproteinaemia?
Defective lipoprotein lipase. No link with coronary artery disease.
What is the cause of type IIa hyperlipoproteinaemia?
Defective LDL receptor. Associated with coronary artery disease.
What is the cause of type III hyperlipoproteinaemia?
Defective apoE.
Associated with CAD
Raised IDL and chylomicron remnants.
What are the clinical signs of hypercholesterolaemia?
- high cholesterol in the blood
- cholesterol depositions in various areas of the body- eyelids, tendons and around eye.
Xanthelasma is cholesterol deposition in which location?
eyelids - yellow patches
Tendon Xanthoma a sign of _________.
Hypercholesterolaemia. Cholesterol nodules on tendons
What is corneal arcus and it’s clinical significance?
White circle around the eye.
Common in older people but if present in the young then could indicate hypercholesterolaemia.
Outline how oxidised LDL particles can lead to the formation of an atherosclerotic plaque.
The oxidised LDL is engulfed by macrophages, forming foam cells in the intima of blood vessels walls.
Foam cells accumulate to form a fatty streak which can evolve into an atherosclerotic plaque.
How can an atherosclerotic plaque result in stroke or MI?
Rupture of the plaque triggers thrombosis by activating platelets and clotting cascade.
Thrombosis in coronary artery will result in MI.
Thrombosis in brain will result in stroke.
What should be the first approach when treating hyperlipoproteinaemias?
- Diet - reduce cholesterol and saturated lipid.
Increase fibre intake. - Lifestyle - Increase exercise
Stop smoking to reduce CV risk.
Why might reducing dietary cholesterol intake only have a small effect on total cholesterol levels?
The vast majority of cholesterol is synthesised by the liver, rather than taken up from the intestine.
What drugs can be used to treat hyperlipoproteinaemias?
- Statins
2. Bile salt sequestrants
What is the mechanism of action of statins?
Inhibit cholesterol synthesis by inhibiting the first enzyme in the synthesis pathway (HMG-CoA reductase).
Give an example of a statin.
Atorvastatin
What is the mechanism of action of bile salt sequestrants?
They bind to bile salts in the GI tract. This forces the liver to produce more, rather than recycling, which will use up more cholesterol.
E.g Colestipol
What enzyme do statins inhibit?
HMG-CoA reductase
What is a possible explanation for the side effect profile associated with statins.
They inhibit the first step of cholesterol synthesis, which will have an effect on many intermediates downstream.
How are lipids transported around the body?
2% bound to albumin
98% in lipoproteins
What is the normal level of plasma total cholesterol?
<5 mmol/L
What is cholesterol needed for in the body?
- Component of cell membranes
- Precursor of steroid hormones
- Precursor of bile acids
Outline the structure of a lipoprotein.
Cargo core - TAG, cholesterol, proteins, fat soluble vitamins
Phospholipid monolayer
Peripheral apolipoproteins
Integral apolipoproteins
Which apolipoproteins are integral?
A+B
Which apolipoproteins are peripheral?
C+E
What are the 5 classes of lipoproteins?
Chylomicron, VLDL, LDL, IDL, HDL
Which apolipoproteins are the main carriers of TAG?
VLDL, Chylomicrons
Which apolipoproteins are the main carriers of cholesterol?
IDL, LDL, HDL
Which apolipoproteins are normally only present in the blood 4-6 hours after a meal?
Chylomicrons - creamy appearance
Which apolipoproteins express apo B?
VLDL, IDL, LDL
Which apolipoproteins express ApoA-1?
HDL
What are the roles of apolipoproteins?
- Structural -packaging insoluble lipid
2. Functional - co-factor for enzymes, ligand for cell surface receptors
What apolipoprotein is added to chylomicrons in the small intestine?
Apo B-48
What other apolipoproteins do chylomicrons acquire and where?
Once in the blood they acquire apo C and E
At what stage do chylomicrons become remnants, how does this happen?
Once 20% depleted, they lose apo C and the ability to bind to LPL.
Which apolipoprotein does the LDL receptor in the liver have affinity for?
Apo E
By what process are chylomicron remnants taken up into the liver?
Receptor-mediated endocytosis
What does lipoprotein lipase do and where is it found?
Hydrolyse TAG, allowing uptake of fatty acids into cells.
Attached to surface of endothelial cells in capillaries
What co-factor does LPL require?
ApoC-II
Which apolipoprotein is added to VLDL’s during synthesis in the liver?
ApoB100
At what stage does a VLDL become an IDL?
depletion of TAG content to 30%
What is the fate of IDL?
Short-lived, either return to the liver or re-bind to LPL and deplete contents further
At what stage does an IDL become a LDL? What changes take place?
Depletion to 10%. Dissociation of ApoE and ApoC.
What is the significance of the absence ApoE and C on LDL particles?
They can no longer bind to LPL and deplete content without Aop C and they cannot be taken up by the liver LDL receptor without ApoE. Must enter tissues.
What is the fate of LDL?
Taken up into peripheral cells that require cholesterol. They express the LDL receptor which binds to ApoB100
What is the clinical relevance of LDL?
They have a long half life, so are susceptible to oxidative damage. Once oxidised, LDL can be taken up by macrophages and form foam cells which contribute to atherosclerotic plaques.
What are the 3 ways that nascent HDL can be formed?
- Synthesis in the liver and intestine when TAG levels are low
- Bud off chylomicrons or VLDL’s as they are digested by LPL
- ApoA1 accumulates phospholipid and cholesterol from other lipoproteins and cell membranes
What happens during HDL maturation?
The nascent HDL accumulates cholesterol and phospholipids from cells lining blood vessels.
What is reverse cholesterol transport, does it require enzyme activity?
The transfer of cholesterol from cholesterol-laden cells to HDL which returns it to the liver.
No enzymes required.
Which cell protein facilitates transfer of cholesterol to HDL?
ABCA1
Which enzyme converts cholesterol to cholesterol esters in HDL?
LCAT
What is the fate of mature HDL?
- Taken up by liver
- Taken up by cells via scavenger receptor
- Exchange of cholesterol for TAG with VLDL
What protein facilitates exchange of cholesterol and TAG between HDL and VLDL?
Cholesterol exchange transfer protein
What cells would you expect to express the scavenger receptor?
Steroidogenic cells
What is the cause of Type 1 hyperlipoproteinaemia?
Defective LPL
What abnormality would you expect to see in the fasting plasma sample in patients with type 1 hyperlipoproteinaemia?
Chylomicrons
Which type of hyperlipoproteinamia has been linked to CAD?
Type 2a and type 3
What is the cause of type 2a hyperlipoproteinaemia?
Defective LDL receptor
What is the cause of type 3 hyperlipoproteinaemia?
Defective Apo E
Raised IDL and chylomicron remnants
What are the clinical signs of hypercholesterolaemia?
Cholesterol depositions - Xanthelasma, tendon xanthoma, corneal arcus
What is xanthelasma?
Yellow deposit on skin - usually on eyelids
What is a corneal arcus, in which patients is it likely to be due to raised cholesterol?
White circle around the eye Younger patients (<40) as it is common in old people
How do raised serum LDL levels contribute to atherosclerosis?
Oxidised and engulfed by macrophages to form foam cells which accumulate in the intimate to form a fatty streak which can progress into a plaque.
What is the first treatment approach taken to treat hyperlipoproteinaemias?
Diet and lifestyle change - increase exercise, stop smoking to decrease risk of CVD
Increase fibre intake, reduce cholesterol and saturated lipid intake
How could increasing dietary fibre act to decrease cholesterol levels?
Fibre sequesters the bile salts, preventing them from being recycled. Liver produces more bile salts and uses up cholesterol.
What drugs might be used in patients with hypoerlipoproteinaemias?
Statins
Bile acid sequestrants
Which drug is a bile acid sequestrate?
Colestipol
Which class of lipoprotein particle typically contains the greatest amount of cholesterol and cholesterol ester?
LDL
What is hyperlipoproteinaemia?
Any condition in which, after a 12 hour fast, the plasma cholesterol and/or plasma triglyceride is raised
Which is sequence of lipoproteins in the order of most to least dense?
HDL >LDL >VLDL >chylomicrons
