Lipid Transport Flashcards
Why can’t lipids be transported in the blood as they are?
Insoluble in water - have to be bound to carriers
How are most lipids carried in the blood?
As lipoprotein particles consisting of phospholipid, cholesterol, proteins and TAG
What is the range of concentration of total lipids in the blood?
4000-8500 mg/L
How are phospholipids classified?
According to their polar head group
Eg
Choline - phosphatidylcholine
Inositol - phosphatidylinositol
Where does the cholesterol in our body come from?
Some obtained from diet but most synthesised in liver
What is cholesterol an essential component of?
Membranes (modulates fluidity)
What is cholesterol a precursor of?
Steroid hormones (eg cortisol, aldosterone, testosterone, oestrogen)
Bile acids
How is cholesterol transported around the body?
As cholesterol ester
Which enzymes catalyse the esterification of cholesterol?
Lecithin cholesterol acyltransferase (LCAT)
Or
Accl-coenzyme A: cholesterol acyltransferase
What does the cargo of lipoproteins consist of?
Triacylglycerol
Cholesterol ester
Fat soluble vitamins
What are the fat soluble vitamins?
A D E and K
What are the five classes of lipoproteins?
1) Chylomicrons
2) VLDL
3) IDL
4) LDL
5) HDL
What do each of the classes of lipoproteins contain variable contents of?
Apoliportein, triglyceride, cholesterol and cholesterol ester
What are the six major classes of apolipoproteins?
A B C D E and H
What are the important apolipoproteins?
apoB (CLDL, IDL and LDL)
ApoAI (HDL)
Which two positions can apolipoproteins take?
Can be integral passing through phospholipid bilayer or peripheral ‘resting’ on top
What are the two roles of apolipoproteins?
1) Structural - packaging water insoluble lipid
2) Functional - co-factor for enzymes, ligands for cell surface receptors
Where are chylomicrons loaded and what is added to them before they enter the lymphatic system?
Loaded in small intestine and apoB-48 is added
Where do chylomicrons travel to and empty into?
Travel to thoracic duct which empties into left subclavian vein
Once in the blood, chylomicrons acquire 2 new apoproteins. What are these?
ApoC and apoE
What does apoC do?
Binds lipoprotein lipase on adipocytes and muscle. Released fatty acids enter cells depleting chylomicrons of their fat concentration.
When does apoC dissociate?
When triglyceride reduced to about 20% - leaving the chylomicron as a chylomicron remnant
Where do chylomicron remnants return?
Liver
How is the chylomicron remnant taken up by hepatocytes?
LDL receptor on hepatocytes binds apoE and chylomicron 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
What does lipoprotein lipase require?
ApoC-II as a cofactor
Where is lipoprotein lipase found?
Attached to surface of endothelial cells in capillaries
VLDL are made in the liver for what purpose?
Transporting TAG to other tissues
What is added to VLDL during its formation?
ApoB100 and apoC and apoE added from HDL particles in blood
What does VLDL bind to?
LPL on endothelial cells in muscle and adipose tissue and starts to become depleted of TAG
When does VLDL. Dissociate from the LPL complex and return to liver?
As triacylglycerol content of VLDL particles drops
When does VLDL become a short-lived IDL particle?
If content depletes to around 30%
When does IDL lose apoC and apoE and become an LDL particle?
Upon depletion to around 10%
What is the primary function of LDL?
To provide cholesterol from liver to peripheral tissues
How do peripheral cells taken up LDL?
Express LDL receptor and take up LDL via process of receptor mediated endocytosis
Why aren’t LDL particles not efficiently cleared by the liver?
They do not have apoC and apoE - liver LDL-receptor has a high affinity for apoE
Why is LDL more susceptible to oxidative damage?
Half life of LDL in blood is much longer than VLDL or IDL
How do LDL particles contribute to formation of atherosclerotic plaques?
Oxidised LDL taken up by macrophages that can transform to foam cells and contribute to formation of atherosclerotic plaques
What cells can lead to atherosclerosis?
Foam cells
What do cells requiring cholesterol express on plasma membrane?
LDL receptors
What acts as a ligand for LDL receptors?
ApoB-100 on LDL
What happens after LDL enters cells by receptor mediated endocytosis?
Fuse with lysosomes for digestion to release cholesterol and fatty acids
What is LDL receptor expression controlled by?
Cholesterol concentration in the cell
How can HDL be synthesised?
1) Nascent HDL synthesised by liver and intestine (low TAG levels)
2) Can also bud off from chylomicrons and VLDL as they are digested by LPL
3) Free apoA-I can also acquire cholesterol and phospholipid from other lipoproteins and cell membranes to form nascent-like HDL
Where do nascent HDL accumulate phospholipids and cholesterol?
From cells lining blood vessels
True or False:
Transfer of lipids to HDL requires enzyme activity
False
How can HDL particles reduce the likelihood of foam cell and atherosclerotic plaque formation?
HDL have ability to remove cholesterol from cholesterol-laden cells and return it to liver
What facilitates the transfer of cholesterol to HDL?
ABCA1 protein - cholesterol then converted to cholesterol ester by LCAT
How do cells requiring additional cholesterol obtain cholesterol from HDL?
Utilise scavenger receptor
How can HDL exchange cholesterol ester for TAG with VLDL?
Via action of cholesterol exchange transfer protein (CETP)
What are hyperlipoproteinaemias caused by?
Either over-production or under removal
Defects in:
Enzymes
Receptors
Apoproteins
What causes type I hyperlipoproteinaemia?
Defective lipoprotein lipase
Chylomicrons in fasting plasma (no link with coronary artery disease)
What causes type IIa hyperlipoproteinaemia?
Defective LDL receptor
Associated with coronary artery disease
What causes type IIb hyperlipoproteinaemia?
Defect unknown
Associated with coronary artery disease
What causes type III hyperlipoproteinaemia?
Defective apoE
Raised IDL and chylomicron remnants
Associated with coronary artery disease
What causes type IV hyperlipoproteinaemia?
Defect unknown
Associated with coronary artery disease
What causes type V hyperlipoproteinaemia?
Cause unknown
Raised chylomicrons and VLDL in fasting plasma
Associated with coronary artery disease
What are some clinical signs of hypercholesterolaemia?
1) High level of cholesterol in blood
2) Xanthelasma
3) Tendon xanthoma
4) Corneal arcus
Raised serum levels of what is associated with atherosclerosis?
LDL
Which layer of blood vessel walls do foam cells accumulate in to form fatty streaks?
Intima
What is initially used to treat hyperlipoproteinaemias?
Dietary changes - reduce cholesterol and saturated lipids in diet and increase fibre intake
Lifestyle changes - increase exercise, stop smoking
If diet and lifestyle changes have no effect, what is used to treat hyperlipoproteinaemias?
Statins - reduce cholesterol synthesis
Bile salt sequestration - bind bile salts in GI tract and forces liver to produce more bile acids using more cholesterol
How do statins reduce cholesterol synthesis?
Inhibit HMG-CoA reductase
What is an example of a statin?
Atorvastatin
What is the ideal total cholesterol level?
5mmol/L or less
What is the ideal non HDL cholesterol level?
4 mmol/L or less
What is the ideal LDL cholesterol level?
3 mmol/L or less
What is the ideal HDL cholesterol level?
Over 1mmol/L in men
Over 1.2mmol/L in women
What ratio of total cholesterol:HDL-C is considered high risk?
Ratio above 6 - the lower the ratio the better
What is the ideal level of triglyceride?
< 2mmol/L in a fasted sample
